Research Article

Occupational, Environmental exposure, and Lifestyle factors: Declining Male Reproductive Health

Sunil Kumar1*, Riddhi Thaker1, Vinita Verma1, Mansi Gor1, Rohina Agarwal2 and Vineet Mishra2

1Division of Reproductive & Cyto-toxicology, National Institute of Occupational Health, (ICMR), Ahmedabad, India
2Dept of Gynecology and Obstetrics, IKDRC, Civil hospital campus, Ahmedabad, India

Received date: June 14, 2018; Accepted date: July 30, 2018; Published date: August 07, 2018

*Corresponding author: Dr. Sunil Kumar, MSc. PhD, FAEB, Former, Director-in- Charge & Scientist ‘G’ National Institute of Occupational Health (ICMR), Meghani Nagar, Ahmedabad-380016, Gujarat, India, Ph: (O) 079-22688841; (R) 079- 22864939; (M) 09426395738; Fax: 091-079-22 686110; Email: sunilnioh@yahoo. com; sunilnioh@gmail.com

*Citation: Sunil Kumar, Riddhi Thaker, Vinita Verma ,et al. (2018) Occupational, Environmental exposure, and Lifestyle factors: Declining Male Reproductive Health J Gynecol Infertility. 1(1)

Abstract

Human and all the living beings are exposed to certain chemical, physical, biological, environmental as well as occupational factors during their day to day activities. Some of them may have adverse impact upon health including reproduction. There are reports which suggest that deterioration of reproductive health occurs in industrialized countries in recent decades. Thus, exposure to certain synthetic chemicals and changing life styles might be one of the cause behind the deterioration of reproductive health in recent decades.

The available data indicated that occupational/environmental exposure especially to some of the organic solvents, pesticides, metals, plasticizers such as phthalates; ionizing and nonionizing radiations, extreme heat, stress might have adverse effects on male reproduction and associated function which depends upon the dose, duration of exposure, age, time of exposure, and health status of exposed person, nutrition etc. Some of the life styles factors such as tobacco smoking and chewing, excessive use of alcohol, certain illicit drugs and sedentary life style, working in hot environment etc. may also have some impact upon male reproduction in addition to host factors. Human are exposed to some of them simultaneously so that there may be of synergistic effects of these factors behind the cause of deterioration of reproductive health. Hence it is difficult to pinpoint a single compound or factor responsible for the cause of declining semen quality.

There is a need for awareness among the society about the adverse effects of these factors behind the cause for the deterioration in semen quality and associated reproductive health impairments observed in recent decades so that preventive measure can be adopted to safeguard reproductive health.

Keywords: Occupational; Environmental, Life style; Semen quality; Reproductive impairment; Spermatogenesis;

Introduction

Reproduction is a key biologic event in human as well as for all the living beings and any threat to reproductive health evokes significant response not only from the scientific community but also from all walks of life including from public media as our future is depend upon the sound reproductive health of the parents. There are ample reports which indicated that the reproductive health is deteriorating from the last 5-6 decades from different parts of the world especially from industrialized /developed countries indicating the role of industrial chemicals as well as modern sedentary life styles behind the cause of these disorders. Human are exposed to several chemicals and life style facors simultaneously during their day to day activities as well as during occupations and some of them are endocrine disrupting chemicals and they act at a very low concentration. These chemical compounds may directly have the reproductive toxc potential or indirectly affect through their metabolic compounds or may also have synergistic effect.

A meta-analysis published in 1992 stating a significant decline in sperm concentration and semen volume over the period from 1938-1990 (Carlsen et al., 1992). Thereafter several reports were published regarding deteriorating male reproductive health from different parts of the world even though some contagious data also existed. Jacques et al. (1995) suggested a population-wide decline in the semen quality over the past 50 years. They measured the sperm quality parameters in healthy fertile men during 1973- 1992 and reported that there has been a decline in the sperm concentration, motility and percentage of morphologically normal sperm in fertile men. Later Toppari et al. (1996) reported that male reproductive health has worsened in many countries i.e. Denmark, Belgium, France, and Great Britain. The incidence of testicular cancer has increased; cryptorchidism and hypospadias also shown to be increasing. Similar reproductive troubles occur in numerous wildlife species also. However, there are obvious geographic differences in the prevalence of male reproductive disorders. The growing number of reports demonstrating that environmental contaminants and natural factors possess estrogenic activity suggests the hypothesis that the trends in adverse male reproductive health may be, at least in part, linked with exposure to estrogenic or hormonally active environmental chemicals during fetal and childhood development. Later Ten et al. (2008) reviewed the data on occupational, life style exposures and male infertility and reported that human semen quality may be decreasing due to exposure to environmental toxicants, occupational exposures and lifestyle factors. In another review Queiroz and Waissmann (2006) reported that a significant increase in the incidence of male infertility may be the result from exposure to substances like pesticide such as DDT, linuron, and others, heavy metals like mercury, lead, cadmium, copper, and substances from industrial uses and residues such as dioxins, polychlorinated biphenyls (PCBs), ethylene dibromide (EDB), phthalates, polyvinyl chloride (PVC) and ethanol can cause male infertility. The elucidation of relationship between an occupational exposure and a reproductive health effect is almost hampered by the fact that many adverse outcomes may be caused by multiple (work-related) factors, making it difficult to pinpoint a specific outcome to a precise occupational exposure. Another significant issue is that occupational exposure may only be pertinent during specific time windows, such as shortly before conception or during initial pregnancy (Burdorf et al., 2006). Recently, Mansour (2014) evaluated the impact of occupational and environmental exposures on reproductive health and suggested that there are strong and rather consistent signs that the reproductive system is vulnerable to insult from exposure to widespread occupational and environmental agents. Earlier Chia (2000) reported that semen quality has deteriorated in many countries over the last few decades and the incidence of testicular cancer has increased world-wide. A biological possible hypothesis has suggested that man-made chemicals act as endocrine disruptors ensuing in alteration of the development of the reproductive tract causing the observed effects.

Owing to these, author’s laboratory engaged from the last ~ two decades to understand the role of occupational, environmental exposure, lifestyle factors on reproductive health. The present review is written with the view to look in to the role of occupational, environmental and life style factors and male reproductive health as data are accumulated steadily in recent years on these aspects.

Materials and Methods

The literature was collected through searching various websites such as PubMed, Google, Toxnet and through books and journals pertaining to reproductive, environmental and occupational health. The paper is divided in to different sections based upon the occupational, environmental and life style factors associated with reproductive health. The data are summarized with respect to occupational and environmental exposure in Table-1, and life style factors and reproductive health in Table-2.

Table 1: Occupational/environmental exposure associated with male reproduction

Exposure

Effects

Reference

Heavy Metals

Hair Hg

Higher level in the hair of sub fertile

Dickman et al. (1998)

Mercuric chloride & methyl mercuric chloride: in vitro

Decreased sperm motility

Ernst and Lauritsen (1991)

Blood Hg

Sperm concentration, normal & motile sperm, curvilinear, straight-line & average path velocity, & amplitude of lateral head displacement reduced with blood Hg level

Leung et al. (2001)

Pb and Hg

Correlated negatively with sperm count, progressive motility, total motility & morphology

Emokpae et al. (2016)

Pb

Decreased libido & an increase in semen abnormalities

Lancranjan et al. (1975)

Heavy occupational exposure linked diffuse disturbances of reproductive & endocrine functions in men

Cullen et al. (1984)

Decreased sperm count with elevation BPb in lead smelters

Alexander et al. (1998)

Decreased sperm count in Pb exposed workers

Assennato et al. (1986)

Pb conc > 40ug/dL associated with decreased sperm count

Apostoli et al. (1995)

Decreased ejaculation vol, sperm count, alive spermatozoa, sperm activity, density of semen fluid in workers with Pb-B over 40 µg/dl

Xuezhi et al. (1992)

Moderate exposure associated with minor changes in male endocrine function, affecting hypothalamic-pituitary axis

Erfurth et al. (2001)

Lower sperm count, motility with ≥15 yrs exposure
Subjects with PbB ≥20 μg /dl significantly declined sperm motility & increased testosterone.

Hosni et al. (2013)

Sperm counts & % of sperm motility affected while % of abnormal spermatozoa elevated

Chowdhury et al. (1986)

Significant relationship between elevated % of morphologically abnormal sperm & higher blood Pb among lead acid battery workers

Robins et al. (1997)

Fertility of lead-exposed workers was declined significantly

Gennart et al., (1992)

Workers with exposure > 5 yrs reduced likelihood of fathering a child.

Lin et al. (1996)

Environmental Pb exposure

At low Pb (20 μg/dL), a reduction in haploid sperm counts & chromatin condensation

Awadalla et al. (2011)

Cd

Serum & seminal plasma Cd significantly higher in azoospermics

Akinloye et al. (2006)

Moderate exposures Cd (BCd< 10 µg/L) reduce semen quality

Telisman et al. (2000)

BCd associated with a decrease in testis size and an increase in serum estradiol, FSH, & testosterone

Jurasovic et al. (2004)

Pb & Cd

Pb & Cd in seminal plasma associated with alteration of seminal parameters.

Mendiola et al. (2011)

Environmental Cd exposure

Testicular dysfunction is mediated initially via its effects on the occludin/ZO-1/proteins at the Sertoli-Sertoli cell interface & disrupt blood-testis barrier

Cheng et al. (2011)

 

Affects semen quality & oxidative sperm DNA damage

Xu et al. (2003)

Cr & Ni

Sperm quality deteriorated in welders exposed to Ni & Cr
Positive correlation between % of tail defects & blood Ni & a negative correlation with sperm concentrations & blood Cr
Reduction in sperm count, motility, Zn in exposed workers.

Danadevi et al. (2003)

Blood Cr

A positive correlation between % of abnormal sperm morphology and blood Cr level.

Kumar et al. (2005)

Arsenic

Elevated urinary AsiV level associated with male infertility
Exert toxicity via oxidative stress & hormone disruption.

Shen et al. (2013)

Alternated spermatogenesis, declined testosterone, gonado-trophins, & steroidogenesis disruptions

Kim and Kim (2015)

As & Cd

Inverse association between sperm count & content of heavy metals in drinking water & seminal plasma

Sengupta et al. (2013)

Mo

An inverse relationship between Mo & semen quality.

Meeker et al. (2008)

Cd, Cr and Pb

Significantly higher concentration of these metals in hypospadias cases

Sharma et al. (2014)

Aluminum

Decreased sperm motility

Hovatta et al. (1998)

Oligozoospermia had a higher Al level in spermatozoa.

Klein et al. (2014)

Increased oxidative stress, alteration in spermatogenesis. steroidogenesis, membrane function, cell signalling, blood test is barrier impairment, affect on endocrine system behind the cause Al induced male reproductive toxicity

Pandey and Jain (2013)

Zinc

Deficiency impairs angiotensin converting enzyme activity, & leads to reduction in testosterone & spermatogenesis

Bedwal and Bahuguna (1994)

Copper

Copper nanoparticles generate oxidative stress in vitro.
Decrease in sperm concentration, viability & motility.

Roychoudhury et al. (2016)

SOLVENTS

Organic Solvents

Positive association between paternal exposure to organic solvents & congenital malformations in offspring

Roeleveld (2006)

Toluene

Induce male reproductive dysfunctions & induces reproductive toxicity via oxidative damage of spermatozoa

Nakai et al. (2003)

Hydrocarbon

Increased rate of abnormalities in the semen 

De Celis et al. (2000)

Styrene

Elevation in sperm DNA damage in exposed workers

Migliore et al. (2002)

Significant decline in sperm concentration during styrene exposure

Kolstad et al. (1999)

Benzene

Increased frequency of aneuploid sperms

Xing et al. (2010)

Higher concentration of benzene damage to the sperm DNA.

Song et al. (2005)

Increased incidence of chromosomally defective sperm,

Marchetti et al. (2012)

Duration dependent decline in total sperm count, % of motility & elevation of abnormal sperm morphology

Katukam et al. (2012)

Mixture- benzene, toluene & xylene (BTX).

Negative correlation between sperm vitality, activity, acrosin activity, or LDH-C4 relative activity with working history of BTX.

Xiao et al. (2001)

Trichloroacetic acid (TCA)

Hyperzoospermia higher with increasing urine TCA levels

Chia et al. (1996)

Ethylene dibromide (EDB)

Significant decreases in sperm count, % of viable, motile sperm, & elevated morphological abnormalities

Ratcliffe et al. (1987)

Perchloroethylene

Subtle effects on sperm quality

Eskenazi et al. (1991)

Ethylene glycol ether

Painters had an increased prevalence of oligospermia & azoospermia

Welch et al. (1988)

RADIATION

Ionizing radiation

Decrease semen volume, elevation of immovable & degenerated forms of spermatozoa. Maximal changes among men exposed to dose of 10 rem & above

Cheburakov and Cheburakova (1993)

Spermatogenesis in human is ~ 3.1 times more sensitive to ionizing irradiation as compared to the mouse,

Clifton & Bremner, (1983)

Direct irradiation at lower doses to testis, affects germinal epithelium: doses of irradiation > 0.35 Gy cause reversible aspermia.

Ogilvy-Stuart and Sahlet et al. (1993)

Electro Magnetic Field

Both in vivo and in vitro studies suggest that EMF can alter cellular homeostasis, endocrine, reproductive function, & fetal development

Gye & Park (2012)

Mobile Phone Use- EMR

Spermatozoa exposed to RF-EMR, decreased motility, elevate morphometric abnormalities, oxidative stress, Men using mobile phones have decreased sperm concentration, motility, normal morphology, viability.

Vignera et al. (2012)

Duration of possession & daily transmission time correlated negatively with rapid progressive motile sperm.

Fejes et al. (2005)

Use of cell phones decreases semen quality which dependent on the duration of daily exposure.

Agrwal et al. (2008)

EMR emitted by cellular phone influences sperm motility, long-term exposure lead to behavioral or structural changes of the male germ cell

Erogul et al. (2006)

Mobile phone radiation associated DNA–fragmentation level & decreased sperm motility

Gorpinchenko et al. (2014)

RF-EMR enhances mitochondrial reactive oxygen species, decreasing motility and vitality while stimulating DNA base adduct formation, ultimately DNA fragmentation

De Iuliis et al. (2009)

Significant effect on sperm morphometry, decrease in sperm binding to hemizona & affect sperm fertilization potential

Falzone et al. (2011)

Pesticide

 

 

DBCP

Difference in the distribution of sperm counts and median counts between exposed and the not-exposed men to DBCP

Whorton et al. (1977)

Complete atrophy of the seminiferous epithelium

Postashink et al. (1978)

High level of LH and FSH in serum and reduced sperm count among workers involved in the DBCP manufacturing

Mattison et al. (1990)

2-bromopropane (2-BP) and 1–2, Dibromo-3-chloro propane (DBCP)

2-BP & DBCP decrease germ cell viability by apoptosis in vitro. Both 2-BP & DBCP induce ROS formation
2-BP reduces spermatocyte viability whereas DBCP exerts greater effect on spermatogonia

Easley et al. (2015)

Carbaryl

A significantly higher proportion of sperm with abnormal head shapes among exposed workers

Wyrobek et al. (1981)

Higher % of sperm abnormality & fragmented DNA in carbaryl-exposed workers

Xia et al. (2004)

1-naphthol

Associations between altered semen quality & 1-naphthol

Meeker et al. (2004a)

Carbaryl and Chlorpyrifos

Environmental exposure to carbaryl and chlorpyrifos may be associated with elevated DNA damage in human sperm

Meeker et al. (2004b)

DDT

DDT has estrogenic potential
The metabolite p,p′-dichlorodiphenyl-dichloroethylene (p,p′-DDE) : potent antiandrogen
A significant positive association between astheno-zoospermia (32%) and p,p′-DDT  and p,p′-DDE.

Aneck-Hahn et al. (2007)

p,p'-DDE induces [Ca(2+)]i elevation in human sperm through the opening of CatSper consequently compromising male  fertility

Tavares et al. (2013)

Risk of conception delay among the green house workers with high pesticide exposure

Petrelli and Figà-Talamanca (2001)

Certain pesticides enhance risk for sperm abnormalities, decreased fertility, & deficit of male children, birth defects, spontaneous abortion or fetal growth retardation

Frazier et al. (2008)

pesticide & Heavy metal

Spontaneous abortion (20.6/ 1000 live births) and premature births (6.7/ 1000 live births) significantly higher in an area affected by both pesticide & heavy metal pollution

Thakur et al. (2010)

HEAT

 

 

 

Artificial increases in scrotum or testicle temperature in fertile men reduce sperm quality.Heat risk factor for sperm morphology & delayed conception

Thonneau et al. (1998)

42.8% of infertile men were exposed to heat during work

Vaziri et al. (2011)

Welders experienced a reversible decrease in semen quality, likely caused by a moderate exposure to radiant heat

Bonde (1992)

Higher prevalence of pathologic sperms among ceramics oven operators

Figa-Talamanca et al. (1992)

Daytime scrotal temperature negatively correlates with semen quality

Jung and Schuppe (2007)

Prolonged urban automobile driving risk factors for sperm quality, &  morphology

Figà-Talamanca et al. (1996)

 Increase in scrotal temperature associated with impaired sperm parameters & higher FSH plasma levels.

Garolla et al. (2015)

AIR POLLUTANTS

 

Ambient air pollutants are associated with low birth weight, intrauterine growth retardation, prematurity, neonatal death, & decreased fertility in males

Veras et al. (2010)

Association between ambient air pollution and sperm quality

Radwan et al. (2016)

Ambient PM exposure during sperm development adversely affects semen quality.

Wu et al. (2017)

Air PM10 and PM10-2.5 exposures, not PM2.5, are risk factors of semen quality

Zhou et al. (2018)

Ambient air pollution associated with oxidative stress, to which sperm are sensitive. Air pollution exposure not associated with semen quality, except sperm head parameters. Moderate ambient air pollution may not be a contributor to semen quality

Nobles et al. (2018)

PLASTICIZER

 

Urinary monobutyl phthalate associated with sperm concentration & count. A significant relationship of urinary mono-(2-ethylhexyl) phthalate (MEHP) and % of di-(2-ethylhexyl)-phthalate metabolites (DEHP) excreted as MEHP with an increased % of abnormal sperm heads.  

Wang et al.  (2015)

Anti-androgenic action for several phthalates ate consistent

Swan (2008)

Infertile men showed higher phthalate esters in semen. A negative correlation between semen phthalate level & sperm quality, elevation in ROS, LPO, DNA fragmentation

Pant et al. (2008)

Positive correlation between MEP & straight-line sperm velocity

Liu et al. (2012)

Urinary metabolites of DEHP inversely associated with circulating steroid hormone.

Meeker et al. (2009)

DEHP showed positive associations with sperm DNA denaturation induction, DNA fragmentation index & negative associations with motility.

Huang et al. (2011)

Phthalates interfere sperm motility: in vitro study.
Sperm motility more affected by diethyl-hexyl & dibutyl phthalates. Significant effects noted for the different phthalates with regard both % motility & velocity, linearity & amplitude of the track. 

Fredricsson et al. (1993)

An interquartile range change in monobenzyl phthalate exposure associated with 10% decrease in FSH with a 4.8% increase in inhibin B

Duty et al. (2005)

MMP, MEP, MBP, MEHP & MiNP positively correlated with the LH/testosterone ratio
A small anogenital index in infant boys with increasing levels of MEP, MBP, mono-isobutyl & monobenzyl- phthalate in maternal urine.

Lottrup et al. (2006)

Altered DNA integrity in human sperm, elevation in monoethyl phthalate level, comet extent increased.

Duty et al. (2003b)

AGD significantly correlated with penile volume & proportion of boys with incomplete testicular descent with respect to prenatal phthalate exposure.

Swan et al. (2005)

Direct effects of di-(2-ethylhexyl) phthalate and mono-(2-ethylhexyl) phthalate on organo-cultured adult human testis and a human cell line inhibited testosterone production.

Desdoits-Lethimonier et al. (2012)

People exposed to phthalates, especially to DBP & DEHP, observed reduced quality in human.  

Zhang et al. (2006)

Phthalate anti-androgenicity is plausible in adult men.

Oceane &Bernard (2014)

Monoethyl phthalate (MEP) increased DNA damage in sperm

Duty et al. (2003a)

DBP exposure during pregnancy significantly decreased sperm counts in F1 through F3 generation.

Yuan et al. (2017)

Endocrine Disruptors

 

Persistent environmental chemicals- dioxins and PCBs modify the activities of several hormones

Birnbaum (1994)

Synthetic estrogenic chemicals & related endocrine-active compounds responsible for a global decline in sperm counts diminished male reproductive capacity.

Safe (2000)

Humans and wildlife species suffered adverse health effects after exposure to endocrine-disrupting chemical Kavlock et al. (1996)



Table 2: Life style factors associated with male reproduction

Life style factor

Effects

Reference

Tobacco Smoking

 

Reduces sperm production, motility, normal forms & fertilising capacity through elevated seminal oxidative stress & DNA damage.

Mostafa, (2014)

Negatively affect seminal vesicles, volume

Lotti et al. (2015)

Significantly lower sperm concentration and motility and higher serum testosterone and LH levels

Al-Matubsi et al. (2011)

Abnormalities in histone-to-protamine transition & alteration of protamine mRNA expression in human sperm.

Yu et al. (2014)

The % of sperm DNA fragmentation index, sperm with abnormally high DNA stainability (HDS%) and round-head sperms increased in idiopathic infertile men; these associated with smoking.

Elshal et al. (2009)

Deleterious effects on the semen volume & sperm morphology and decreases sperm DNA integrity & nuclear maturation.

Niu et al. (2010)

Significantly lower sperm Creatine kinase activity & sperm movement in smokers

Ghaffari and Rostami (2013)

Detrimental effects on sperm motility, viability, DNA fragmentation, seminal zinc levels, & semen reactive oxygen species levels

Taha et al. (2012)

Significant decline in semen quality & higher levels of leukocytes

Zhang et al. (2013)

Tobacco chewing

 

Adverse impact on semen quality.
With intensive chewing habits, defects in the head & cytoplasmic residue

Sunanda et al. (2014)

An inverse dose–response relationship between tobacco chewing & semen volume, sperm count, motile, viability.
Heavy or long-term tobacco chewers had a lower sperm concentration

Patel et al. (2015)

Cigarettes smoke extract (CSE)

CSE suppressed sperm motility, increased the number of spermatozoa with low MMP, the source of energy for sperm motility

Calogero et al. (2009)

Smoking & Tobacco chewing

Deteriorating sperm quality

Choksi et al. (2015)

Alcohol and tobacco

Reduction in sperm concentration, motility, viability, & normal morphology

Stutz et al. (2004)

Alcohol

 

Deterioration of sperm parameters that partially reversible

La Vignera et al. (2013)

Linear association between alcohol consumption and total or free testosterone

Jensen et al. (2014)

Targets sperm morphology and sperm production

Gaur et al. (2010)

Caffeine

Non-significant reduction in sperm concentration and  count

Jensen et al. (2010)

Alter human Sertoli cells (hSCs) metabolism and oxidative profile, that are essential for spermatogenesis

Dias et al. (2015)

Current male caffeine intake associated with increasing testosterone levels

Ramlau-Hansen et al. (2008)

Prenatal Caffeine consumption

Sons of mothers consuming 4-7 cups/day had lower testosterone levels

Ramlau-Hansen et al. (2008)

In vitro Caffeine treatment

Caffeine added to frozen-thawed human semen, induced a significant elevation in the % of motile spermatozoa

Aitken et al. (1983)

7.2 mM caffeine proved to be optimum and resulted in increased sperm motility by 40% to 80%

Barkay et al. (1977)

In vitro caffeine treatment of donor semen does not damage the spermatozoa; it seems to improve the fertilizing capacity

Barkay et al. (1984)

Increased the % of motile spermatozoa by 30% to 50%

Makler et al. (1980)

Drugs

Decrease in sperm motility with moderate amounts of aspirin

Stutz et al. (2004)

 

Permanent azoospermia is related to the specific agents & doses. Most damaging are alkylating agents (chlorambucil, cyclophosphamide, procarbazine, busulfan, melphalan), cisplatin & radiation

Meistrich (2009)

Metandienone

The sperm density reduced 46% after 1 month and 73% after 2 months of use.

Holma (1977)

Steroid

5-year history of steroid use subject was azoospermic & underwent replacement of gonadotropin, conception was achieved after 3 months.

Turek et al. (1995)

Anabolic-androgenic steroids associated to transient or persistent impairment on male reproductive function

El Osta et al. (2016)

Azoospermia may be associated to the use of androgenic anabolic steroids

Moretti et al. (2007)

Sugar-sweetened beverages (SSB)

High sugar-sweetened beverages associated with lower sperm motility among healthy men

Chiu et al. (2014)

Obesity

 

Data confirmed relationship between BMI & sperm quality, suggesting obesity may be a detrimental factor of male infertility.

Guo et al. (2017)

Obesity negatively affects male reproductive potential, alters the physical & molecular structure of germ cells in  testes & ultimately affects maturity & function of sperm cells

Shukla et al. (2014)

Sperm concentration was significantly lower in the obese group than in normal & lower BMI group

Koloszar et al. (2005)

Men with BMI greater than 25 kg/m2 have fewer chromatin-intact normal-motile sperms/ ejaculate & total motile sperm

Kort et al. (2006)

BMI positively related to estradiol levels & inversely related to total testosterone, sex hormone-binding glogulin levels.
Extreme level of obesity negatively influences male reproductive potential.

Chavarro et al. (2009)

Body size is negatively associated with semen parameters

Eisenberg et al. (2014)

Increase abnormal semen parameters among overweight men, & an elevated risk for sub-fertility among couples with male partner obese

Du Plessis et al. (2010)

Psychosocial stress

 

Mild-to-severe emotional stress depresses testosterone & interferes with spermatogenesis

McGrady (1984)

Psychologic job strain does not affect male reproductive function

Hjollund et al. (2004a)

Decreased sperm concentration

Zorn et al. (2008)

Stress correlated negatively with semen volume & % normal morphologic forms

Giblin et al. (1988)

Psychosocial distress contributes infertility

Wasser et al. (1993)

Stressful life events associated with decreased semen quality

Gollenberg et al. (2010)

An inverse association between perceived stress score & sperm concentration, motility, morphology

Janevic et al. (2014)

Psychological stress associated with reduced paternity & abnormal semen parameters

Nargund (2015)

The emotional stress in an IVF program negatively affects the quality of semen

Ragni and  Caccamo, (1992)

Occupational Exposure and Reproductive Health
It is rational to believe that workers are exposed to higher doses of certain chemical and physical factors during their occupation as compared to environmental exposure. Workers are exposed to higher doses of toxic metals, organic solvents, phthalates, pesticides, ionizing and non-ionizing radiations and extreme heat, noise, etc. as compared to environmental exposure. Exposures to some of these factors might affect the male reproduction. However, it is sometime very difficult to pin point a single chemical and/or any exogenous factors behind the cause of reproductive impairments as workers or even general population are exposed to a minute’s concentration of number of toxic chemicals during day to day activities through various sources even without the knowledge of the exposed person. The impact of this low level of exposure can only be predicted/suspected /assessed when couple is interested to go for pregnancy or its outcome and faces difficulty in conceiving.

Metals
Human are exposed to some of the toxic as well as essential metals from their environments, occupations as well as through their dietary habits and life style. Some of the metals are essentials for the certain physiological function of the body at trace level, are known as trace element or essential element. Reproductive dysfunction has been reported among workers exposed to certain metals like lead, cadmium, mercury, chromium, copper etc. at the workplace which depends upon the toxic potential of the metal in question, exposure concentration and duration of exposure and host factor such as age and sex. These heavy metals may affect male reproductive function at the cellular and sub cellular levels and their effect can be seen on semen quality, libido and male mediated reproductive outcome. The vast experimental data are available on the toxic potential of various heavy metals such as lead, mercury, cadmium, chromium to male reproduction. However, the data on reproductive toxic potential of metals on human are scanty except some judicious data on lead with regards to male reproduction.

Mercury
Mercury compounds are present in three forms i.e. elemental, inorganic, and organic. Exposure to mercury has the potential to affect most of the organs of the body including reproductive system. The foremost course of human exposure to methyl mercury (MeHg) is mostly through eating contaminated fish, seafood, through dental amalgam etc. Recently Rice et al. (2014) reported that mercury has profound cellular, cardiovascular, renal, haematological, pulmonary, neurological, immunological, endocrine, reproductive, and embryo toxic effects. Several animal studies indicated that mercury is a male reproductive toxicant, but human studies are scanty and inconsistence. Mercury has been implicated in male subfertility in Hong Kong and found higher level of mercury in the hair of sub fertile compared to the fertile male (Dickman et al., 1998). Earlier, Ernst and Lauritsen (1991) investigated the effects of mercuric chloride and methyl mercuric chloride on the human spermatozoa motility in vitro and found that organic as well as inorganic mercury decreased the sperm motility. Later, Leung et al. (2001) investigated the association between whole blood mercury concentrations and semen quality in sub-fertile men. The semen quality parameters and hormone profile were linked between subjects with normal and elevated mercury level concentrations. The semen quality parameters such as concentration of sperm, percentage of motile sperm and morphologically normal sperm, curvilinear velocity, average path velocity, straight-line velocity, and amplitude of lateral head displacement were reduced in subjects with elevated blood mercury concentrations, although the difference was statistically nonsignificant. However, findings of Mocevic et al. (2013) do not support that environmental mercury exposure in European and Greenlandic men with median blood mercury concentration up to 10 ng ml−1 has negative effects on male reproductive health. Recently, Emokpae et al. (2016) reported mean seminal plasma lead and mercury levels were significantly higher in infertile males. Mercury and lead correlated negatively with sperm count, total motility, progressive motility, and morphology but not with semen volume. However, Hanf et al. (1996) could not established positive correlation between subject with mercury concentrations in urine and the semen quality. Equally, no such relationship could be established between the fertility index and the number of dental amalgam fillings. They mentioned that no evidence can be derived between the mercury burden from dental amalgam fillings and male fertility disorders from their study. Very recently Mínguez-Alarcón et al. (2018) found the median hair Hg levels of the men was 0.72ppm (0.03 to 8.01ppm) and hair Hg levels were positively related with sperm concentration, sperm count, progressive motility, after adjusting potential confounders.

Lead
Lead poisoning has been recognised as a major public health problem which is widely used in acid battery plant refinery, smelter, fuel combustion industry, printing press, etc. The main source of lead contamination arises mainly from occupation since as of now de-leaded gasoline is not sold in most part of the world which was a major source of lead contamination. Earlier Lancranjan et al. (1975) reported that increased levels of lead were associated with decreased libido and an increase in semen abnormalities in men who were exposed to lead in the workplace. It is also reported that heavy occupational exposure to lead is sufficient to cause clinical poisoning, may be associated with disturbances of endocrine and reproductive functions in men (Cullen et al., 1984). Later Alexander et al. (1998) examined the blood and semen lead concentrations in lead smelter workers and found decline in total sperm count with increasing blood lead concentration. Semen lead concentration was inversely significantly related to total sperm count, ejaculate volume and serum testosterone, but not to sperm concentration. They also suggested that blood lead concentration was more reliably associated with indicators of sperm production than semen lead level. Later Pant et al. (2003) from Lucknow, India measured the concentration of lead and cadmium in the seminal plasma and found an elevation in lead and cadmium concentrations in infertile men and there was a significant negative association of cadmium and lead concentration with sperm concentration and sperm motility in oligoasthenospermic men. A study from Zagreb, Croatia of reproductive endocrine function of male industrial workers indicated that moderate exposures to Pb (BPb<400 μg/L) can significantly reduce human semen quality without conclusive evidence of impairment of male reproductive endocrine function (Telisman et al., 2000). Earlier Assennato et al. (1986) also observed sperm count suppression without endocrine dysfunction in lead-exposed battery workers. Later Apostoli et al. (1998) also mentioned that concentration of lead > 40 μg/dl seemed to be associated with decline in sperm count, volume, motility, and sperm morphological alterations and modest effect on endocrine profile. Impairment of male reproductive function such as decreased volume of ejaculation, prolonged latency of semen melting, reduced total sperm count and live spermatozoa, retarded sperm activity and lowered density of seminal fluid was observed in lead exposed male workers with Pb-B over 40 μg/dl by Xuezhi et al. (1992). Later Erfurth et al. (2001) mentioned that a moderate exposure to lead was associated with only minor alterations in the male endocrine function, especially affecting the hypothalamic-pituitary axis. Recently Hosni et al. (2013) found a significantly lower sperm motility, count in subjects with duration of exposure was ≥15 years, but no significant difference was found for PbB and serum levels of LH, FSH, PRL and Testosterone. Patients with PbB ≥20 μg /dl showed a significant decline in sperm motility and elevation in testosterone alone among all measured hormones. Earlier Chowdhury et al. (1986) studied semen qualities in workers occupationally exposed to lead in a printing press and reported the average lead content in blood and seminal plasma were 42.5 μg/100 ml and 14.80 μg/100 ml, respectively and sperm counts and percentage of motile sperm were significantly declined while abnormal spermatozoa were elevated. The levels of seminal succinic dehydrogenase, acid phosphatase, and fructose were also found to be significantly low. Later Robins et al. (1997) studied semen quality and fertility potential of men employed in a lead acid battery plant and significant associations were found between an increased percentage of sperm with abnormal morphology and higher concentration of current blood lead, cumulative blood lead, and duration of exposure.

Several reports have also appeared in recent decades which indicated that lead affect the semen quality even at lower doses. Hernández-Ochoa et al. (2005) evaluated environmental lead affects semen quality, sperm chromatin, in view of Pb in spermatozoa (PbSpz), seminal fluid (PbSF), and blood (PbB) as exposure biomarkers in men. About 44% subjects showed decrease in sperm quality; sperm concentration, motility, morphology and viability associated adversely with PbSpz, whereas semen volume associated negatively with PbSF. However, PbB was not associated with semen quality or nuclear chromatin condensation. These data suggest that Pb in semen compartments is better biomarkers of low Pbexposure. Later Awadalla et al. (2011) reported that semen quality of men with primary infertility does not have any correlation with BLL at the cutoff value of 20μg/dL. However, a significant reduction in haploid sperm counts and chromatin condensation was observed. Mendiola et al. (2011) also reported that lead and cadmium in the seminal plasma is associated with moderate alteration of seminal parameters. In recent years more, data appeared which indicated that lead can affect human reproduction at lower doses than reproductive toxic doses of lead reported earlier. In addition, the effect of cadmium, lead, or manganese on male reproductive function was examined in workers exposed to cadmium in smelters, to lead in battery workers, or to manganese in a dry alkaline battery plant. The likelihood of a live birth was not different between the cadmiumor manganese-exposed workers and unexposed workers. However, the fertility of the lead-exposed workers was deteriorated (Gennart et al., 1992). Later Lin et al. (1996) also reported that workers with more than five years of exposure to lead had reduced likelihood of fathering a child as compared with a shorter duration of exposure. These studies indicated that lead exposure might have reduced the fertility potential of male.

There are reports which indicated that lead also induces oxidative stress and promotes the generation of hydrogen peroxide (Ni et al., 2004; Vaziri and Khan, 2007) and reactive oxygen species. Very recently Kasperczyk et al. (2015) investigated the relationship between environmental exposure to lead and cytokines in seminal plasma among subjects with normal semen profile. The total oxidant status value and the level of protein sulfhydryl groups, activities of catalase and manganese superoxide dismutase were significantly higher in the higher lead exposure group, whereas the total antioxidant capacity and the activities of glutathione reductase and glutathione-S-transferase were reduced. TNF-α and IL-7, IL-10, IL-12 levels were also significantly higher in the high Pb exposure group. This suggests that lead induce oxidative stress in seminal plasma and alter antioxidant defence system. Based upon the available data it can be concluded that Pb has reproductive toxic potential, induces oxidative stress and impaired fertility and no safe dose can be prescribed for lead exposure.

Cadmium
Cadmium is also a toxic heavy metal and found in ores together with zinc, copper and lead. Cadmium is used generally in, Nickel-Cadmium rechargeable batteries, cadmium coating, production of pigments, cadmium alloys etc. and humans are normally exposed to either by ingestion or inhalation. Smokers are also exposed through tobacco smoking. Akinloye et al. (2006) estimated serum and seminal plasma cadmium concentrations in infertile Nigerian males. The serum and seminal plasma Cd levels were increased significantly in azoospermics in comparison to oligozoospermic and control subjects. Earlier Chia et al. (1992) noted the mean blood concentrations of lead, mercury, copper, and zinc were within the normal values whereas cadmium concentration (1.35μg/L) was much higher among subjects with no medical cause of impaired semen quality. Asthenozoospermics subjects had significantly higher blood cadmium levels than normozoospermic subjects. Later Telisman et al. (2000) reported that even moderate exposures to Cd (BCd< 10 μg/L) can significantly reduce human semen quality without evidence of impairment of male reproductive endocrine function. Zeng et al. (2004) concluded that oral Cd exposure is not a critical determinant of hormone homeostasis in males, but lifestyle and biological factors, such as age and BMI, are important. The relationship found between urinary Cd and high T levels may be of importance for male reproductive morbidity. Jurasovic et al. (2004) studied semen quality and reproductive endocrine function with respect to blood cadmium in Croatian male and found the median and range BCd values were significantly higher in smokers. After adjusting for potential confounding variables by multiple regressions, BCd was significantly associated with a decrease in testis size and an increase in serum estradiol, FSH, and testosterone. Later Cheng et al. (2011) reported that environmental toxicants, such as cadmium-induced disruption of testicular function which is mediated primarily through its effects on the occludin/ZO-1/focal adhesion kinase complex at the bloodtestis barrier (BTB), producing reallocation of protein at the Sertoli-Sertoli cell interface, and leading to the BTB interruption. The destructive effects of cadmium to testicular function are facilitated by mitogen-activated protein kinases (MAPK) downstream, which in turn disturbs the actin bundling and accelerates the actin-branching activity, instigating disruption of the Sertoli cell tight junction (TJ)-barrier function at the BTB and disturbing spermatid adhesion at the apical ectoplasmic specialization that leads to untimely release of germ cells. Cadmium concentration was elevated, and zinc was reduced in the seminal plasma of men with varicocele (Benoff et al., 1997). A significant opposite relationship exists between Cd and sperm number per ejaculum, and sperm density. Further, 8-OHdG was significantly interrelated with Cd in seminal plasma and seminal plasma Cd could affect semen quality and induce oxidative DNA damage in human spermatozoa (Xu et al., 2003). Based upon the data, it can be inferred that cadmium has the reproductive toxic potential affecting semen quality.

Chromium and other
Chromium is naturally occurring compound present in rocks, soil, plants, animals, volcanic dust etc. Trivalent chromium is an essential element for living being. Chromium is generally used in metallurgy, chrome plating, welding, chemical industry, wood preservation, photography and as pigment etc. Occupational exposure to chromium generally occurs through inhalation and dermal contact, although the general population is exposed frequently by ingestion. Some reports appeared on semen quality with respect to Cr exposure in humans in recent years. Danadevi et al. (2003) reported deterioration in sperm quality among welders exposed to nickel and chromium. They reported a significant positive correlation between the percentages of tail defects and blood nickel concentration in exposed workers and a negative correlation with sperm concentrations and blood Cr levels. Further, a significant reduction in the sperm count, motility and Zn levels whereas serum FSH level was significantly higher among Cr exposed workers than the control (Li et al., 2001). Later Kumar et al. (2005) reported that exposure to Cr has some effect on human sperm as a significant positive association was observed between percentages of abnormal sperm morphology and blood Cr levels. Further, CrVI disrupts spermatogenesis by inducing free radical toxicity in non-human primate- Macacaradiata Geoffroy, and supplementation of antioxidant vitamins may be favourable to the affected subjects (Aruldhas et al., 2005).

Earlier Kumar (2004) reported that lead, cadmium and mercury may have reproductive toxic potential to male reproductive health. In addition, Meeker et al. (2008) reported the evidence for an inverse association between molybdenum (Mo) and semen quality in human and found the relationships are consistent with available animal data, but additional clinical studies are needed. The data available suggests toxic potential of some of the metals on male reproduction and metals may directly affect the testicular tissues and affect hormonal production and release or both or accumulate in reproductive organs causing long term deleterious effects to the cellular and subcellular levels. Earlier, Danielsson et al. (1984) reported based upon auto-radiographic studies in rodents that Cd and Cr gathered in the interstitial tissues, demonstrating an effect on hormone production, blood supply or both. Chowdhury (2009) mentioned that metals could obstruct the gametogenic cells or Leydig cell or spermatozoa directly. These effects may result in reduced fertility or associated pregnancy waste, congenital malformation related with genetic diseases. Moreover, the features of heat stress protein, Androgen-Binding Protein, Cadherin and various stressor proteins alongwith reactive oxygen species and neuro-endocrine mechanism are greatly affected by some of heavy metals. Recently Sharma et al. (2014) found significantly higher concentration of chromium, cadmium and lead in hypospadias subjects, which indicated association between high levels of cadmium, chromium, and lead and risk of hypospadias.

Some other metals are also having reproductive toxic potential, but epidemiological studies are inadequate and inconsistent. Bolt et al. (2012) reported that reproductive toxicity of boric acid and borates is an issue of concern. Based on experimental studies in rats, no-observed-adverseeffect levels (NOAEL) dose were found to be 17.5 for male fertility and 9.6 mg Boron/kg b.wt. for developmental toxicity. Recently, occupational studies in exposed cohorts were reported from Turkey and China which showed negative results on male reproduction. Exogenous environmental or workplace boron exposures were related with declines in Y- versus X-bearing sperm. This can be undestood with the changes in offspring sex ratios among men exposed to boron (Robbins et al., 2008). Later, Scialli et al. (2010) reported non-significant differences in semen characteristics, except sperm Y: X ratio in boron exposed workers. They concluded that while boron has been shown to adversely affect male reproductive system in laboratory animals, there is no obvious evidence of male reproductive effects of boron to exposed workers.

Aluminium is one of the ubiquitous metals and used in industries, pharmaceuticals, food additives and consumer products. Higher concentration of aluminium in spermatozoa was associated with decreased sperm motility (Hovatta et al. 1998). Recently Klein et al. (2014) reported that the patients with oligozoospermia had a statistically higher aluminum semen concentration and further analysis showed the presence of aluminum in spermatozoa. Recently Berihu (2015) reported increase oxidative stress, alteration in spermatogenesis as well as membrane function, disruption in cell signaling and the impairment of blood testis barrier, disturb the endocrine system which might be another possible mechanism of Al induced male reproductive toxicity. Earlier, Pandey and Jain (2013) provided a comprehensive account of the aluminium induced male reproductive toxicity data on animal models. They reported that increased oxidative stress, alteration in spermatogenesis as well as in steroidogenesis, disruption in cell signalling, alterations in membrane function and the diminishing of blood testis barrier, disturbance in the endocrine system might be the several likely mechanisms of Al induced male reproductive toxicity. Earlier Bedwal and Bahuguna (1994) reported that Zinc content is high in the testis, and the prostate has a highest concentration than other organs. Zinc deficit affects angiotensin converting enzyme activity, and this leads to depletion of testosterone and inhibition of spermatogenesis. Very recently, Roychoudhury et al. (2016) summarized the existing knowledge on the effects of copper (Cu) on the reproductive system. Short term administration of Cu was found to exert harmful effect on intracellular organelles of rat ovarian cells. Adverse effect of Cu on male reproductive functions has been indicated by the decline in sperm concentration, viability and motility. Copper nanoparticles can cause oxidative stress in vitro so leading to reproductive toxicity. Recently Tvrda et al. (2015) mentioned that iron and copper are essential trace nutrients playing significant roles in general health and fertility. However, both are highly toxic when accumulating in huge quantities and their impact on the structure and function of male gonads and gametes is not known fully. Excess or deficiency of either may lead to defective spermatogenesis, reduced libido, and induce oxidative damage to the testicular tissue and spermatozoa.

Arsenic
Arsenic has chemical and physical properties intermediate between a metal and a non-metal and is frequently mentioned to as a metalloid or semi-metal (IARC, 2012). Arsenic is a common environmental pollutant derived from both natural and anthropogenic sources and is extensively circulated all over the environment in the water, air and land. People are exposed to higher levels of inorganic arsenic through drinking contaminated water in various parts of world including eastern part of India. Shen et al. (2013) investigated that environmental arsenic exposure can impair male fertility. They showed that elevated urinary concentrations of inorganic arsenic (AsiV) from general arsenic exposure are significantly associated with male infertility, and arsenic species may put forth toxicity via oxidative stress and sexual hormone disrupting mechanisms, as showed by related biomarkers. Earlier, Xu et al. (2012) also reported that reduced parameters in human semen quality are positively associated with as exposure in a reproductive-age Chinese cohort.

Recently Sengupta et al. (2013) carried out a survey of geogenic groundwater contamination with the heavy metals arsenic and cadmium in Assam, India and found an increase in the incidence of male infertility in this area. They enrolled patients with sperm concentration < 20x106/ml were cases (oligozoospermic and azoospermic) and subjects with > 20x106/ ml (normozoospermic) and having fathered a child as control. They found an inverse relationship between total sperm count and heavy metal in drinking water as well as seminal plasma. The study also found significant differences in the sperm function parameters like acrosome reaction, hypo-osmotic swelling and nuclear chromatin de-condensation in the patient group. Recently, Kim and Kim (2015) also reported that exposure to inorganic arsenic induces alterations of spermatogenesis, reductions of testosterone and gonadotrophins, and interruptions of steroidogenesis. However, the mechanism of the reproductive and developmental problems following arsenic exposure is poorly understood and need more studies.

Solvent
It is known that some of the solvents especially organic solvents are having toxic potential to human health including reproductive system of both sexes. Human can get exposed to solvents from various sources mainly through inhalation, dermal and sometime less likely through ingestion. They have been alleged to exert harmful effects on human reproduction and associated function. Cherry et al. (2001) reported a significant relationship between intensity of exposure to solvents and clinical findings of < 12×106/ml motile sperm. Odds ratios, after controlling for confounding factors, were 2.07 for moderate exposure to solvents and 3.83 for high exposure. In the second series, the effect was confirmed at high exposure to solvents but not at moderate exposure. A statistically significant decline in sperm concentration was observed during styrene exposure from 63.5 to 46.0 million sperm/ml. The total sperm count was almost halved from an initial sperm value/ejaculate (Kolstad et al., 1999). Later Migliore et al. (2002) examined sperm DNA integrity in individuals occupationally exposed to styrene and found a significantly higher DNA damage in sperm between subjects exposed to styrene and the reference group.

Several reports are available with respect to exposure to benzene and associated male reproductive health impairments. Marchetti et al. (2012) reported that occupational exposures to benzene were linked with increased incidence of chromosomally defective sperm, which raise concerns for workers’ infertility, spontaneous abortions, mental retardation and inherited defects in children. They also pointed out benzene as a possible risk factor for de novo 1p36 deletion syndrome. Because chromosomal aberrations in sperm can arise from faulty stem cells/spermatogonia and promote concerns that occupational exposure to benzene may have persistent reproductive effects in earlier exposed workers. Later Xing et al. (2010) reported that the work-related exposures to benzene nearby 1 ppm induce aneuploidy in sperm. Sperm aneuploidy elevated across low- and high-exposed groups for disomy X, and for overall hyperhaploidy for the three chromosomes investigated. They also found raised disomy X and hyperhaploidy in the nine men exposed to ≤ 1 ppm benzene. Song et al. (2005) assessed the effect of benzene on sperm DNA of workers and found that higher concentration of benzene could damage sperm DNA. Earlier Liu et al. (2003) also showed that benzene exposure at higher concentration (42.29 mg/m3) may induce elevation in occurrences not only of numerical aberrations for chromosome 1 and 18, but also induce structural aberrations in sperm chromosome 1 in exposed workers. Further, Katukam et al. (2012) reported a duration dependent decrement in total sperm count and the percentage of motility and increment of abnormal sperm morphology among the benzeneexposed industrial workers. A significant increase in comet tail length was also observed. Earlier, Xiao et al. (2001) also found a negative correlation between sperm vitality, sperm activity, acrosin activity, or LDH-C4 relative activity with working history of benzene, toluene, and xylene. These data suggest that the mixture of these solvents could affect the sperm quality. Later Barreto et al. (2009) reported that bioactivation of benzene can lead to the development of harmful metabolites such as phenol, hydroquinone, and catechol. Catechol forms semiquinones and reactive quinones that might play a significant role in the generation of reactive oxygen species. ROS can induce single and double strand breaks in the DNA, oxidized nucleotides, and hyper-recombination, and consequently induces deleterious genetic changes.

Toluene is a widely used industrial solvent, and humans may also exposed to toluene through inhalation. Roeleveld (2006) assessed the risks of reproductive disorders and birth defects in offspring of male painters exposed to organic solvents. They found a positive relationship between paternal occupational exposure to organic solvents and congenital malformations. Nakai et al. (2003) investigated the effects of toluene on the male reproductive system and injected toluene subcutaneously to male rat for 10 days and found a decrease in the epididymal sperm counts and the serum testosterone. Whereas 8-oxo-7,8-dihydro-2’-deoxyguanosine formation in testes was increased. These suggest that toluene induces reproductive toxicity via direct oxidative damage of spermatozoa.

Earlier Chia et al. (1996) examined the effects of trichloroacetic acid (TCA) on spermatogenesis among workers exposed to TCA in an electronics factory. Prevalence rate ratios of hyperzoospermia were higher with respect to elevation of urine TCA levels compared to the “low exposure” group, suggesting a dose-response relationship. Ratcliffe et al. (1987) examined the semen quality of workers of the papaya fumigation industry exposed to ethylene dibromide (EDB) and found statistically significant decrease in sperm count per ejaculate, the percentage of viable and motile sperm, and elevated morphological abnormalities (tapered heads, absent heads, and abnormal tails). Earlier, Eskenazi et al. (1991) investigated the effects of perchloroethylene (PCE) exposure dry cleaners and laundry workers and reported that occupational exposures to PCE can have subtle effects on sperm quality. Earlier, Welch et al. (1988) examined the semen quality of painters who work in a large shipyard. The industrial hygiene survey revealed that the painters were exposed to 2-ethoxyethanol (2-EE) and to 2-methoxyethanol (2-ME). They found that painters had an increased prevalence of oligospermia and azoospermia and an increased odds ratio for a lower sperm count per ejaculate. Eldesouki et al. (2013) studied painting workers exposed directly or indirectly to a mixture of toluene, styrene and benzene at the work place and reported that the testosterone was found to be significantly lowered, while, FSH and LH, were found to be significantly elevated in the exposed group. Exposure to different concentrations of mixture of organic solvents (VOC’S) had harmful effects on male reproductive hormones through a direct testicular damage, especially in the long-term exposure workers. De Celis et al. (2000) found that hydrocarbon exposure was associated with an increased rate of semen abnormalities of exposed workers. The data suggests that solvents especially organic solvents have adverse effects on human reproduction and may also be associated with adverse pregnancy outcome.

Radiation
The reproductive hazards and associated function due to ionizing radiation have been well established, whereas reproductive hazards associated from non-ionizing radiations are under intensive study. The schedule of the delivered irradiation (total dose, chronic or acute, number of fractions, and duration) is an important determinant of the radiobiological effect of radiation on the tissues involved and differs from tissue to tissue among different organ system (Ogilvy-Stuart and Shalet, 1993). The age of the exposed person is also an important factor for radiation effect. It is known that radiation is toxic to the reproductive system and particularly the foetus and young ones and radiation may affect chromosome, which may lead to congenital abnormalities. Streffer (1995) mentioned that the embryo and fetus are extremely radiosensitive. During the pre-implantation period radiation exposure at doses of 0.2 Gy and higher can cause death of the embryo. Based on experimental data with mammals, it was presumed that a radiation dose of about 0.2 Gray (Gy) doubles the malformation risk. He further reported that studies in humans suggest that the human embryo is more radio resistant than the embryos of mice and rats. The time course of the loss of sperm production is based on the fact that the rapidly dividing differentiating spermatogonia are much more sensitive against ionizing radiation (Meistrich, 2013). He also mentioned that treatment of cancer either with chemo- or radiotherapy causes decline in sperm counts often to azoo-spermic levels. This may persist for several years or be permanent. Recovery from oligoo azoospermia is variable and depends on rate of killing of stem cells and alteration of the somatic environment that normally supports differentiation of stem cells.

A study of semen quality of cleaners of the Chernobyl sites, Ukraine showed the decline of ejaculate volume, and spermatozoa with higher immovable and degenerated forms. Maximal changes have been observed among men who were exposed to 10 rem and above (Cheburakov and Cheburakova, 1993). Later Goncharov et al. (1998) studied hormonal and semen parameters in men who cleaned the territory around the Chernobyl nuclear reactor (called ‘liquidators’). They reported that short-term radiation exposure did not cause long-lasting disorder of endocrine status and spermatogenesis. However, the study was 7-9 years retrospective; therefore, it is not possible to understand the immediate effects of the radiation exposure on endocrine status and spermatogenesis. Further, Fischbein et al. (1997) also studied liquidators at Chernobyl in Ukraine and found a significant difference in certain ultra-morphological parameters of the sperm head between clean-up workers and controls of similar age. Earlier Clifton and Bremner (1983) suggested that, spermatogenesis in man is approximately 3.1 times more sensitive to ionizing irradiation as compared to the mouse. Ogilvy-Stuart and Sahlet (1993) reported that straight irradiation to the testis at lower doses; distress the germinal epithelium and doses larger than 0.35 Gy led to reversible aspermia. The time taken for regaining increases with larger doses; however, aspermia may be permanent after doses above 2 Gy. Further, at higher doses i.e. > 15 Gy, Leydig cell function will also be impaired and in addition to dose of radiation, the testis susceptibility is also dependent upon the age and the pubertal status.

The safety of human exposure to various electromagnetic field sources has become a debatable issue because of public health matter. Some data are also available on low frequency magnetic fields and reproductive health. Recently Gye and Park (2012) reported that various in vivo and in vitro studies showed that electromagnetic field (EMF) exposure can alter cellular homeostasis, reproductive and endocrine function, and fetal development in animal systems. EMF exposure may change the reproductive parameters such as male germ cell death, reproductive endocrine hormones, sperm motility, the estrous cycle, early embryonic development, reproductive organ weights, and pregnancy success. Further, the effect of exposure on reproductive function differs with respect to frequency and wave, strength, and duration of EMF exposure. Vignera et al. (2012) reviewed both clinical and experimental studies on effects of the exposure to mobile phones radiofrequency electromagnetic radiation (RF-EMR) on male reproduction. They reported that human spermatozoa exposed to RF-EMR have decreased motility, increased morphometric abnormalities and oxidative stress; furher men using mobile phones have also decreased sperm concentration, motility (especially rapid progressive motility), viability and normal morphology. These seem to be related to the duration of mobile phone use. There are number of in vitro and in vivo reports which indicated that radiofrequency electromagnetic radiation (mobile phones radiation) affects semen quality especially motility (Erogul et al., 2006; Agarwal et al., 2008; Fejes et al., 2005; Gorpinchenko et al., 2014). Fejes et al. (2005) found that the duration of possession and the daily transmission time linked negatively with the rapid progressive motile sperm. The low and high transmitter time groups also differed with respect to the proportion of rapid progressive motile sperm. Agarwal et al. (2008) reported that use of cell phones declines the semen quality by diminishing the sperm count, motility, viability, and normal morphology. The decline in sperm parameters was dependent on the period of exposure to cell phones. Erogul et al. (2006) suggested that EMR emitted by cellular phone affects human sperm motility and long-duration EMR exposure may lead to structural or behavioral changes of the male germ cell. Further, Gorpinchenko et al. (2014) also found an association between mobile phone radiation exposure, DNA–fragmentation level and decreased sperm motility.

De Iuliis et al. (2009) reported that mobile phone radiation induces DNA damage in human spermatozoa and Reactive Oxygen Species production in vitro. RF-EMR enhances mitochondrial reactive oxygen species generation by human spermatozoa, declining the motility and vitality while motivating DNA base adducts formation and eventually DNA fragmentation. Agarwal et al. (2009) also mentioned that radiofrequency electromagnetic waves may lead to oxidative stress in human semen. They speculated that possessing the cell phone in a trouser pocket in talk mode may adversely affect spermatozoa and impair male fertility. At the cellular level, an elevation in free radicals and [Ca2+] i may facilitate the effect of EMFs and causes cell growth inhibition, protein misfolding, and DNA breaks. The effect of EMF exposure on reproductive function depended upon frequency and wave, strength, and duration of exposure (Gye and Park (2012). Falzone et al. (2011) concluded that although RF-EMF exposure did not negatively affect the acrosome reaction, it had a noteworthy effect on sperm morphometry. A significant decline in sperm binding to the hemizona was observed. This shows a noteworthy effect of RF-EMF on sperm fertilization potential. However, a study from Denmark reported that exposure to extremely low frequency magnetic fields is not deleterious to fertility (Hjollund et al., 1999). Most of the available data suggest that exposure to ionizing and non-ionizing radiation particularly EMF may have significant adverse effect on human sperm which are associated with fertility reduction.

Exposure to plasticizers
Plasticizers are substances which generally added to a material usually the PVC to boost its flexibility and elasticity. They are widely used in many commercial applications. The general population is exposed to these chemicals through consumer products as well as through diet and medical treatments. A concern exists over whether additives in plastics, such as phthalates, bisphenol A or polybrominated biphenyl ethers, may affect human health by changing endocrine function or through other biological mechanisms. Several clinical and experimental studies were published on exposure to phthalates and reproductive health. Duty et al. (2003a) determined the effect of environmental levels of phthalates on DNA integrity in human sperm. They reported that elevation in specific gravityadjusted monoethyl phthalate (MEP) level, the comet extent increased significantly; the tail distributed moment also increased. Monobutyl, monomethyl, monobenzyl, and mono-2-ethylhexyl phthalates were not associated with comet assay parameters. This demonstrated that at environmental levels of urinary MEP, is related with the increased DNA damage in human sperm. Later, Zhang et al. (2006) monitored the phthalates such as di-ethyl phthalate; di-n-butyl phthalate; di-2-ethylhexyl phthalate were detected in semen of most of the samples. A significant positive association was noticed between liquefied time of semen and phthalate concentrations. However, no significant difference was found between phthalate concentrations and sperm density or livability. Although the level of phthalates is relatively mild, but an association of phthalate levels and reduced semen quality was noticed. Further, Wang et al. (2015) found the urinary concentrations of monobutyl phthalate were positively associated with the below-reference sperm concentration and sperm count. They also observed significant dose-dependent relationships of the urinary mono-(2-ethylhexyl) phthalate (MEHP) and the percentage of di-(2-ethylhexyl)-phthalate metabolites (DEHP) excreted as MEHP with an increased percentage of abnormal sperm heads. Duty et al. (2003b) explored the association whether environmental levels of phthalates are related with altered semen quality in humans. They reported that there were dose-response relations for monobenzyl phthalate and monobutyl phthalate with one or more semen parameters, and suggestive confirmation for monomethyl phthalate with sperm morphology. The lack of a relationship for other phthalates may indicate a difference in spermato-toxic potential among phthalates. Later, Pant et al. (2008) found that urban population have significantly higher levels of phthalate esters than the rural. Further, infertile men showed significantly higher levels of pollutants in the semen than fertile men. A negative relationship was found between semen level of DEHP and sperm quality and positive link with depolarized mitochondria, elevation in LPO and ROS production, DNA fragmentation. These findings suggest that phthalates might be one of the causative factors associated with the deterioration in semen quality and adverse effects of phthalate might be through mitochondrial dysfunction, ROS, and LPO mediated. Swan (2008) did a literature survey, on human health endpoints following prenatal, neonatal, childhood, as well as adult exposures to phthalates. At least one significant link has been stated for urinary metabolites of butylbenzyl phthalate, diethyl phthlate, di-n-butyl phthalate, and di-isononyl phthalate and for three of the urinary metabolites of di(2-ethylhexyl) phthalate. Many of the findings reported, have been found in males are consistent with the antiandrogenic action. Earlier, Murature et al. (1987) mentioned the existence of significant negative correlations between mean sperm densities and production of synthetic organic chemicals. Phthalate esters are one class of organic chemicals that are identified to disrupt testicular function in laboratory animals.

Swan et al. (2005) provide information on Ano-genital distance (AGD) and other genital assessments with respect to prenatal phthalate exposure in humans. AGD was significantly interconnected with penile volume and the section of boys with incomplete testicular descent. They calculated the ano-genital index (AGI) as AGD divided by weight and found that urinary concentrations of four phthalate metabolites (monoethyl, monobenzyl, mono-n-butyl, and monoisobutyl phthalate) were inversely associated to AGI. The associations between male genital development and phthalate exposure are steady with the phthalate-associated syndrome of incomplete virilization that has been described in prenatally exposed rodents. The data obtained support the assumption that prenatal exposure to phthalate at environmental levels can unfavourably affect male reproductive development. Later, Desdoits-Lethimonier et al. (2012) investigated the effects of mono-(2-ethylhexyl) phthalate (MEHP) and di-(2-ethylhexyl) phthalate (DEHP) on organo-cultured adult human testis and a human cell line. In both models, DEHP and MEHP significantly repressed testosterone production and provide evidence that DEHP and MEHP can prevent testosterone production in the adult testis. They mentioned that this observation is consistent with recent epidemiological findings of an inverse relationship between exposure to MEHP and testosterone concentrations. However, Jönsson et al. (2005) mentioned no clear pattern of links were observed between mono butyl phthalate (MBP), mono benzyl phthalate (MBzP), and mono ethylhexyl phthaltale (MEHP) with any of the reproductive biomarkers. Subjects within the highest quartile for mono ethyl phthalate had fewer motile sperm, more immotile sperms, and lower LH values, but there was no harmful effect for most other endpoints. They found weak links between one phthalate biomarker and impairment of reproductive function biomarkers. Duty et al. (2005) assessed an association between environmental levels of phthalates and reproductive hormones in men. An interquartile range (IQR) change in MBzP exposure was associated with a 10% decline in FSH level. Further, an IQR change in monobutyl phthalate (MBP) exposure was linked with a 4.8% elevation in inhibin B. An association was found between urinary concentrations of MBP and MBzP and altered levels of inhibin B and FSH, but, the hormone concentrations did not change in the anticipated patterns.

Liu et al. (2012) investigated the exposure of a Chinese reproductive age cohort to ubiquitous phthalates pollutants and semen quality. They observed a borderline-significant dose–response relationship between MBP and sperm concentration. But not significant relationship with MMP and MEP, a significant positive correlation between MEP and straight-line velocity of sperm motion was observed. Ealier, Meeker et al. (2009) reported that the ratio of testosterone to estradiol was positively associated with MEHP, suggesting prospective relationships with aromatase suppression. These results suggest that urinary metabolites of DEHP are inversely related with circulating steroid hormone levels. Huang et al. (2011) investigated possible associations between semen quality and di(2-ethylhexyl) phthalate (DEHP) in personal air of workers of polyvinyl chloride plants. The workers were divided into low- and high- DEHP-exposed groups with respect to the levels of DEHP in personal air. DEHP showed positive associations with sperm DNA denaturation induction and DNA fragmentation index and negative associations with sperm motility.

Fredricsson et al. (1993) studied the effect of various phthalates and extracts from diesel particulate material on human spermatozoa in vitro. All these compounds inhibited sperm motility in a dose-response manner. Sperm motility was more affected by diethylhexyl and dibutyl phthalates. Significant effects were noted for phthalates with regard both to motility and to some form of the qualities of motility, such as velocity, linearity and amplitude of the track. Regarding the effects on sperm motion, di-noctyl phthalate appeared to be the least toxic, trailed by dibutyl phthalate. The initial effects of diesel particulate extracts were moderate with respect to percent motile sperm but higher exposure the effects became more pronounced. Later Lottrup et al. (2006) reported that phthalates adversely affect the male reproductive system in animals, inducing hypospadias, and cryptorchidism, reduced testosterone production and declined sperm counts. Exposre to phthalate effects are much more severe after in utero than adult exposure. They also mentioned that human testicular development might be susceptible to phthalates. Five of six phthalates [monoethyl-(MEP), monobutyl- (MBP), mono-2-ethylhexyl- (MEHP), monomethyl- (MMP), and mono-isononyl phthalate (MiNP)] revealed relationship with hormone levels in healthy boys, which were indicative of poorer androgen activity and reduced Leydig cell function. MEP and MBP were positively related with serum sex hormone-binding globulin levels. MMP, MEP, MEHP MBP, MBP, and MiNP were also positively related with the LH/testosterone ratio. A reduction of the anogenital index (AGI) in infant boys with rising concentrations of MBP, MEP, monobenzyland mono-isobutyl phthalate in maternal urine during late-pregnancy was also reported. Boys with lower AGI showed a high occurrence of cryptorchidism and small genital size. Recently Oceane and Bernard (2014) highlights the fact that i) there is a vast gap between the number of studies executed in animals and humans, ii) there are differences in the mode of rats, mice, primates and humans to respond to phthalates iii) additional work is necessary to clarify the contradictions, in the few prevailing human epidemiological studies, which may be partly explained by different methods of exposure assessment iv) in accordance with latest findings in rodents, it cannot be excluded that transgenerational effects of phthalates and/or epigenetic alterations exist in humans v) methodological restrictions need to be solved for the xenografting and in vitro models using human fetal testis to fulfil ‘missing link’ amongst epidemiological studies and rodent models and vi) epidemiological and in vitro studies generally converge adequately to determine that phthalate anti-androgenicity is plausible in adult men. Recently Yuan et al. (2017) also reported that DBP exposure during pregnancy (8 to 14 days) significantly decreased the sperm counts in F1 through F3 generation. They found distinct metabolic changes in the testis of both F1 and F3 generation offspring.

Pesticides/Insecticides
The World Health Organization (2001) reported that there are about 3 million cases of pesticide poisoning every year and up to 220,000 deaths occurs, mostly in developing countries. The application of pesticides is often not very specific, and sometime unintended exposures occur without the knowledge of exposed persons. Pesticides also have the potential to damage the nervous system, endocrine system and the reproductive system. Pesticides can even be harmful to foetuses because the chemicals can pass from the mother to developing foetus in the womb during pregnancy and affect the pregnancy and outcome. Pesticides can enter the body during mixing, applying, or clean-up operations through dermal, inhalation and ingestion. Apart from pesticide factory workers and/or applicators, the general population is also exposed to these pesticides or their metabolite to some extent, even through the food chain. It is rational to believe that pesticides, which are toxic to pest, might produce some adverse health effect including reproductive effect on living beings including humans. The United Nations Environment Protection (UNEP) agency reported that nine of the twelve most unwanted persistent organic pollutants (POPs) are pesticides used on agriculture crops and for public health vector control programmes. These twelve POPs have been acknowledged by the UNEP organization as a powerful threat to human and wildlife health on a global basis (Fisher, 1999). Exposure to pesticides could be one of the contributing cause to the falling semen quality and growing trends of infertility. Adverse effects of pesticides in the environment received extensive attention about half century ago. It has been hypothesized that long term, low level of exposure of these chemicals are more linked to human health effects such as endocrine disruption, immuno-suppression, reproductive abnormalities and cancer (Srinivasa et al.2005).

Exposure of human to pesticides may occur by their occupation, environment or food chain. A classic example of reproductive toxicant is 1, 2-dibromo-3-chloropropane (DBCP), spermatotoxic effects of DBCP was reported in the 60s in rats but its harmful effects on human spermatogenesis were revealed only in 1977. Paucity of children was noted among the workers in a 1–2, Dibromo-3-chloropropane (DBCP) manufacture plant, USA (Whorton et al., 1977). Further, they reported the clear-cut difference in both the distribution of sperm counts and the median counts between the exposed and the non-exposed men with DBCP. Another study on DBCP exposed workers in a pesticide factory in Israel reported complete atrophy of the seminiferous epithelium (Postashink et al., 1978). This suggests that DBCP is a powerful male reproductive toxicant. Later Mattison et al. (1990) studied the hormonal profile and semen of male workers involved in the DBCP manufacture and reported high level of LH and FSH in serum and a reduced sperm count. Recently, Easley et al. (2015) examined the effects DBCP and 2-bromopropane (2-BP) on in vitro human spermatogenesis. They reported that acute exposure to 2-BP or DBCP induces a decline in germ cell viability by apoptosis. DBCP and 2-BP affect viability of diverse cells as 2-BP mainly reduces spermatocyte viability whereas DBCP exerts higher effect on spermatogonia. Both 2-BP and DBCP induce reactive oxygen species leading to an oxidized cellular environment. Based upon the data one can conclude that DBCP is an effective male reproductive toxicant affecting both reproductive and endocrine function.

In addition to DBCP, there are reports of reproductive toxicity of a few other pesticides also. Carbaryl (1-naphthyl-N-methyl carbamate) is a broad-spectrum insecticide used to protect fruits, vegetables, cereals, cotton, and other crops against a variety of insects and pests. Wyrobek et al. (1981) reported that the carbaryl induced a significantly higher amount of sperm with abnormal head shapes among workers and confounders like age, smoking habits, and medical problems did not appear to affect the result. Later Meeker et al. (2004a) also found associations between altered semen quality and 1-naphthol (1N), a metabolite of carbaryl and naphthalene are consistent with previous studies of carbaryl exposure. They also reported that environmental exposure to carbaryl and chlorpyrifos may be associated with elevated level of DNA damage in human sperm (Meeker et al., 2004b). Xia et al. (2004) also showed a significant higher percentage of sperm abnormality and fragmented DNA in carbaryl-exposed workers. Further, the frequencies of aneuploidy and numerical chromosomal abbrations showed significant difference between exposed and control groups. They suggested that carbaryl might induce spermatozoa morphologic abnormalities as well as genotoxic defects among exposed workers. The available studies indicate the toxic effects of carbaryl on testicular functions that are essential for reproductive success.

DDT is given credit to help ~1 billion people live free from malaria, which in turn saved millions of lives. In 1973, after 30 years of worldwide use of DDT, a WHO report concluded that the benefits derived from use of this pesticide were far bigger than its possible hazards (WHO, 1973). This suggests the benefits of DDT, however its stability, persistence in the environment and ubiquitous presence, accumulation in adipose tissues, and estrogenic properties raise concern about its possible longterm adverse effect (Turusov et al., 2002). DDT might be beneficial in controlling malaria, but the evidence of its harmfull effects on human health necessities appropriate research on whether it attains a favourable balance of risk versus benefit (Rogan and Chen, 2005). Aneck-Hahn et al. (2007) reported that DDT has estrogenic potential, and its main metabolite, p, p′-dichlorodiphenyl-dichloroethylene (p, p′-DDE), is a potent antiandrogen. In a cross-sectional study, male subjects were enrolled from an endemic malaria area where DDT is sprayed annually. The data indicated that mean sperm motility was lower with a higher p, p′-DDE level and a significant positive relationship was found among percent sperm with cytoplasmic droplets and p, p′-DDT level. The ejaculate volume was poorer than the normal range. Twenty-eight percent of the study subjects presented with oligozoospermia, with a significant positive association with p, p′-DDE. Further, a significant positive association was observed with asthenozoospermia (32%) and p, p′-DDT and p, p′-DDE. The results suggest that non-occupational exposure to DDT is associated with impaired seminal quality. Later, Tavares et al. (2013) showed a novel nongenomic mechanism specific to sperm. They reported that p, p’-DDE was able to induce [Ca (2+)]i in human sperm through the opening of CatSper subsequently conceding male fertility. The promiscuous nature of CatSper stimulation may predispose human sperm to certain persistent endocrine disruptors.

A few studies are also available on the effects of multiple pesticides exposure on the reproductive system of male workers, which may also affect the reproductive outcome. A study conducted by Rupa et al. (1991) among male workers who were exposed to several pesticides such as DDT, BHC, endosulfan; and organophosphorus pesticides i.e. malathion, methyl-parathion, dimethiote, monocrotophos, phosphamidon and quinalphos; synthetic pyrethroids such as fenvelrate and cypermethrin during mixing and spraying of pesticides showed male mediated adverse reproductive outcome such as abortion, stillbirths, neonatal deaths, congenital defects, etc. However, it is not possible to identify any specific pesticide based on these results as these are cumulative effects of several pesticides. Later, Petrelli and Figà-Talamanca (2001) examined the interference of pesticide exposure on male fertility by studying time to pregnancy (TTP) among green house workers and found an elevation in the risk of conception delay among the green house workers with high pesticide exposure. Further, Frazier (2008) reported that exposure of men or women to certain pesticides at adequate doses may elevate the risk for sperm abnormalities, decreased fertility, and a deficit of male children, spontaneous abortion, fetal growth retardation or birth defects.

Thakur et al. (2010) conducted a study to ascertain an association between heavy metal, pesticide exposure and reproductive and child health. Spontaneous abortion and premature births were considerably higher in area affected by heavy metal and pesticide pollution. A larger percentage of children were reported to have delayed milestones, language delay, mottling of teeth, blue line in the gums, and gastrointestinal morbidities. They concluded that although no direct association could be established, but heavy metal and pesticide exposure may be potential risk factors for reproductive and child health outcomes. Earlier Petrelli et al. (2000) conducted study among male pesticide applicators occupationally exposed to pesticides and control (food retailers). The ratio of abortions/ pregnancies among wives of applicators was 0.27 and for retailers 0.07. The Odd Ratio for spontaneous abortion adjusted for age of wife and smoking of parents was 3.8 times greater than for the control population. Queiroz and Waissmann (2006) provide a critical review on work-related chemical substances capable of causing male infertility. They reported that pesticides such as DDT, linuron, and some others, heavy metals like mercury, cadmium, lead, copper and industrial substances and residues such as polychlorinated biphenyls, dioxins, ethylene dibromide, polyvinyl chloride, phthalates etc are among the main endocrine disruptors that can affect male infertility. Gonadal dysfunction and congenital malformation are the main alterations produced by these in the male reproductive system. Recently, Mehrpour et al. (2014) reviewed the data on exposure to pesticides and semen quality and fertility and reported that semen quality changes are multifactorial in origion as there are numerous factors affecting sperm quality in occupational exposures. Most of pesticides including organophosphoruses may affect the male reproductive system by reduction of motility and sperm density, inhibition of spermatogenesis, reduction of testis weights, sperm counts, viability, motility, density, and inducing sperm DNA damage, and increasing abnormal morphology. Reduced weight of testes, epididymis, seminal vesicle, and ventral prostate, seminiferous tubule degeneration, change in plasma levels of testosterone, follicle-stimulating hormone, and luteinizing hormone, decreased level of the antioxidant enzymes in testes, and inhibited testicular steroidogenesis are other possible mechanisms of male reproductive health impairment.

Exposure to Heat
It is known that temperature influences the development of germ cells as well as reproductive cycle of living beings. Temperature plays an important role in the spermatogenesis of human beings. Therefore, nature has kept the scrotum outside the human body so that the temperature of the testis lowers than that of the body temperature. The first report of working heat exposure was in 1775 when an English physician Percival Pott recognized a high occurrence of scrotal cancer in chimney sweepers. It is well known that in most of the living being including human spermatogenesis is temperature dependent phenomenon. Mammalian testes are located outside the body to keep temperature below the core body temperature which is necessary for normal spermatogenesis. Elevation in scrotal temperature can disrupt its progression leading to poor sperm quality and infertility. Thonneau et al. (1998) reported that several experimental studies showed that artificial increases in scrotum or testicle temperature in fertile men lessen both sperm productivity and quality. They concluded that occupational heat exposure is an important risk factor for male infertility, affecting sperm morphology and followed delayed conception. Sadighi et al. (2003) from Iran, pointed out that some factors in the human environment, such as certain working conditions, can put the human reproductive system at risk. This study showed that 34.1% affected by heat. Another study which was carried out among men who reported problems with infertility attended at infertility clinic, Iran also showed that out of 1164 subjects. 42.8% were exposed to heat during the work (Vaziri et al., 2011).

It is known that work processes such as iron foundry, baking, ceramic industry, welding etc generate high temperatures, which are unfavourable to the functioning of the reproductive system. Earlier Bonde (1992) investigated the semen quality and sex hormone levels among welders with a moderate exposure to radiant heat, but without substantial exposure to welding fume toxicants and found that the welders experienced a reversible decrease in semen quality, likely caused by a moderate exposure to radiant heat. Later, Kumar et al. (2003) also reported that, welding may have had some adverse effects on sperm motility, morphology and physiologic function even though sperm concentration was in the normal range. Earlier Figa-Talamanca et al. (1992) carried out a study among ceramics oven operators with a longer exposure to high temperatures. The data showed that exposed individuals had a higher incidence of childlessness and struggle in conceiving. The semen analysis showed no significant alterations except in sperm velocity. Although changes in semen parameters, taken singly, were not statistically significant, hoewever, the overall assessment of the sperm parameters indicated a higher occurrence of pathologic sperm profiles among the exposed ceramics workers.

Jung and Schuppe (2007) reported that duration of sitting during work positively associated with daytime scrotal temperatures and daytime scrotal temperature negatively links with semen quality. They mentioned that fertility parameters of professional drivers with long periods of sitting in vehicles were impaired. Further, relationship between wearing tight fitting underwear and higher scrotal temperatures was also observed. The observations suggesting a link between tight-fitting underwear and impaired semen quality are not convincing. They further reported that scrotal and testicular cooling is capable to recover semen quality. Earlier, Figà-Talamanca et al. (1996) explored the possible association between the work exposures of professional drivers and reproductive health; the data suggest that prolonged urban automobile driving might be risk factors for sperm quality, and especially for sperm morphology. Recently Garolla et al. (2015) reported a significant increase in 24-h mean scrotal temperature in both obese and men with a varicocele. The increase in scrotal temperature was associated with higher FSH plasma levels and impaired sperm parameters as compared to controls. Hjollund et al. (2002a) mentioned that measuring scrotal temperature offers a valid assessment of testicular temperature. They mentioned that work position is an important determinant of testicular temperature. They also reported that both scrotal temperature and semen quality are closely related. Sedentary work in ordinary jobs, although a strong determinant of scrotal temperature, does not seem to affect semen quality (Hjollund et al., 2002b). Later Stoy et al. (2004) conducted a study to understand the possible deleterious effects of sedentary work on semen characteristics and found that sedentary work is a risk factor for impairment of semen characteristics.

Nowadays laptop computers (LC) have become part of a modern lifestyle and have gained popularity among the younger reproductive age population all over the world. Sheynkin et al., (2005) evaluated the thermal effect of LC on the scrotum. Working on LC in a laptop position causes significant Scortal Temperature elevation because of heat exposure. Long-term exposure to LC-related scrotal hyperthermia may have a negative impact upon spermatogenesis. Further, studies of such thermal effects on male reproductive health are needed. Based on these data one can suggest that exposure to high temperatures has an adverse effect on male reproductive system and it is one of the important risk factors for male infertility.

Environmental Exposure and Reproductive Health
All the living being including human beings are exposed to several toxicants, physical factor such as natural radiation, ultraviolet radiation, heat etc. during their day-to-day activities without the knowledge of exposed individuals. Some of them may affect their reproductive health and outcome.

Air pollutants
There is a growing epidemiologic literature reporting association between air pollutants and reproductive outcomes in recent decades. The air pollutants are both man made as well as natural. The major air pollutants are toxic gases and metals, particulate matter, etc. in the environment. Jurewicz et al. (2009) evaluated the impact of environ¬mental toxicants exposures such as pesticides, phthalates, air pollutants, PCBs, trihalomethanes (THMs), mobile phones on semen quality and suggested that there are strong signs that some pesticides besides DBCP (DDT/ Dichlorodiphenyldichloroethylene), eth¬ylene dibromide, organophosphates) affects sperm count. PCBs are detrimental to sperm motility while air pollution, data advocate a link between ambient air pollutants and semen characteristics. Several recent studies showed that exposure to environmental air pollutants affect reproductive functions especially, produced adverse effects on pregnancy outcomes, fertility, and fetal health. Epidemiological studies demonstrated that exposure to ambient levels of air pollutants related to intrauterine growth retardation, low birth weight, prematurity, neonatal death, and reduced fertility in males (Veras et al., 2010).

Recently Rzymski et al. (2015) reported that environmental deterioration can lead to the higher risk of exposure to heavy metals, and subsequently, health implications including impairments in reproduction. Thus, it is therefore important to continue the studies on metal-induced mechanisms of fertility impairment on the genetic, epigenetic and biochemical level. Very recently Skakkebaek et al. (2016) mentioned that environmental exposures arising from modern lifestyle, then genetics, are the most important factors in the observed deteriorating trends of male reproductive health. These might act either directly or via epigenetic mechanisms. In the later case, the effects might have an impact upon their offsprings after exposure. The potential effect of POP related air pollution on male reproductive system has attracted scientific community, policymakers and the public in recent decade. Therefore, epidemiological studies should examine the impact of chronic exposure of POPs via inhalation on fertility (Hsu et al., 2014). Later Radwan et al. (2016) provides suggestive evidence of a relationship between ambient air pollution and sperm quality. Recently Wu et al. (2017) quantitatively assessed the association between particulate matter PM exposure and semen quality and reported that ambient PM exposure during sperm development, adversely affects semen quality, especially sperm concentration and count. Later Zhou et al. (2018) investigated the associations between air pollutants PM10, PM10-2.5, and PM2.5 exposures and semen quality, sperm DNA fragmentation and reproductive hormones. They found the evidence that air PM10 and PM10-2.5 exposures, not PM2.5, are the risk factors of semen quality. Very recently Nobles et al. (2018) reported that ambient air pollution is associated with increases in oxidative stress, to which sperm are particularly sensitive. They concluded that air pollution exposure was not associated with semen quality, except for sperm head parameters. Moderate ambient air pollution may not be a major contributor to semen quality. Further research is needed to explore this association. Individual precise exposure assessment would be needed for more detailed risk characterization with respect to air pollutants.

Endocrine Disruptors
There is mounting evidence that exposure to some of the pesticides/ metals/plasticizers disrupts the endocrine system, creating disorder with the complex regulation of hormones, the reproductive system, embryonic development and pregnancy outcome. Endocrine disruption can create infertility, a diverse birth and developmental defects in offspring, including hormonal imbalance and incomplete sexual development, impaired brain development, behavioural disorders, etc. A wide range of substances in addition to some of the pesticides, both natural and man-made substances, reported to cause endocrine disruption, which includes some pharmaceuticals, polychlorinated biphenyls, dioxin and dioxin-like compounds, DDT and some other pesticides, and plasticizers such as bisphenol A and few phthalates and phytoestrogens etc. Birnbaum (1994) reported that some of the environmental chemicals may be associated with endocrine modifications in people, wildlife, and experimental animals. Persistent environmental chemicals such as dioxins and PCBs have been shown to modify the activities of several different hormones. He also mentioned that the unborn child or the neonate may be at danger from these chemicals because of their rapid growth and development. Safe (2000) hypothesized that environmental exposure to synthetic estrogenic chemicals and related endocrine-active compounds may be responsible for a global decline in sperm counts, diminished male reproductive capacity, and breast cancer in women. The data on organochlorine contaminants (DDE/PCB) levels indicated no significant difference between breast cancer patients and control. Thus, many of the male and female reproductive tract problems associated with endocrine-disruptive hypothesis have not elevated and are not associated with these contaminants. However, they mentioned that this does not exclude an endocrine-etiology for adverse environmental effects or human problems associated with exposures to such chemicals. Murray et al. (2001) mentioned that there is now considerable evidence that male reproductive function is declining. Some chemicals have shown to disturb the developing fetal endocrine system in laboratory animals treated in utero. Studies on animal in vivo and human in vitro have identified EDC sensitive genes. Therefore, hypotheses are being postulated with respect to the mechanism of action e.g. disturbed testicular apoptosis and altered hepatic biotransformation of steroids. They reported that several confounding factors include: a) the huge number of chemicals termed EDCs, b) the capability of chemicals to bioaccumulate in body lipid, c) the metabolism of body lipid during pregnancy releasing the EDC legacy into circulation and (d) the poorly understood kinetics of EDC transfer across the placenta. Despite substantial effort to understand the mechanisms by which these endocrine disrupting chemicals exert their effects are still mostly unknown.

Earlier Kavlock et al. (1996) put forward a hypothesis that humans and wildlife species suffered adverse health effects after exposure to endocrinedisrupting chemicals. These adverse effects include declines in wildlife populations, upsurges in cancers, and reduced reproductive function. Sikka and Wang (2008) reported that endocrine disruptors are estrogenlike and anti-androgenic chemicals in the environment. They mimic natural hormones, inhibit the action of natural hormones, or modify the normal function of the endocrine system and have potential harmful effects on male reproductive axis causing infertility. Although testicular and prostate cancers, undescended testis, chronic inflammation, Sertolicell- only pattern, abnormal sexual development, hypospadias, altered pituitary and thyroid gland functions are also observed, the available data are insufficient to assume worldwide conclusions. They also reported that newer tools for the recognition of Y-chromosome deletions further strengthened the assumption that the decline in male reproductive health and fertility might be related to the presence of certain toxic chemicals in the environment. Maffini et al. (2006) also reported that the quantity and quality of human sperm has declined and the incidence of male genital tract defects, prostate, testicular, and breast cancer has elevated during the last 60 years. During the same time, developmental, reproductive and endocrine effects have also been recognized in wildlife species. They mentioned that perinatal exposure to environmentally relevant BPA doses results in functional and morphological changes of the female and male genital tract and mammary glands that may predispose the tissue to prior commencement of disease, reduced fertility and prostate and mammary cancer.

Mendiola et al. (2010) observed no significant associations between semen parameters and urinary BPA concentration. However, a significant reverse association was found between urinary BPA concentration and free androgen index (FAI) levels and the FAI/LH ratio, and a significant positive association were also found between BPA and SHBG. They suggested that, in fertile men, exposure to low environmental levels of BPA may be associated with a modest decrease in markers of free testosterone, but effects on reproductive function are expected to be small. Further, Bustamante et al. (2010) concluded that the levels of the metabolites pp’DDT and β-HCH are higher among mothers of newborns with cryptorchidism. They mentioned that exposure to substances during fetal development with anti-androgenic effects could produce endocrine disruption, such as cryptorchidism. Earlier Waliszewski et al. (2005) also noted that the levels of the metabolites pp’DDT and β-HCH are higher among mothers of newborns with cryptorchidism. It is possible that substances with anti-androgenic effects could produce such effect. Rignell-Hydbom et al. (2005) conducted a study among Swedish fishermen who were consuming low and high fatty fish, an exposure source of persistent organochlorine pollutants (POPs) and found that exposure to POP may have a minor negative impact on sperm chromatin integrity. Knez (2013) mentioned that Bisphenol A, phthalates and alkylphenols are essential components of multiple products, thus they are ubiquitously present in the environment. They can exert detrimental effects on the male reproductive system under laboratory conditions. However, human exposure data are scanty and do not support toxicity data of these substances at environmental concentrations level. Recently Jeng (2014) reported that the male reproductive system may be vulnerable to the effects of endocrine disrupting chemicals. He emphasized the need for 1) well-defined longitudinal epidemiology studies, with properly designed exposure assessment to understand exposure and effect causal relationships; 2) chemical and biochemical approaches intended to understand the mechanism of action of xenoestrogens with respect to low-dose effects, and to identify genetic susceptibility factors associated with the risk of harmful effects of EDCs.

The data available suggests that the chemical having endocrine distrupting potential may have adverse effect on male reproduction and associated reproductive function by affecting the endocrine system and these chemicals act at an environmentally relevant very low doses.

Life style and reproduction
It is establishing that lifestyles associated diseases are increasing worldwide including India during the last few decades because of changes in lifestyle pattern. There have been progressive changes in many aspects of our diet, lifestyle as well as environment during the last half century. Poor lifestyle adopted by the human such as tobacco smoking and chewing, excess use of alcohol, use of illicit drugs, unhealthy diet, lack of physical activity, excess use of electric gadgets etc may lead to several diseases which are yet preventable by switching over to healthy life style. It is also getting to establish the fact that some of these life styles factor might also be behind the cause of deterioration of reproductive health observed in recent decades. Tobacco chewing and smoking have adverse effects on oral cavity or lung cancer predominantly. However, there are reports that tobacco smoking also affects reproduction. This may also be true for tobacco chewing.

Tobacco smoking and chewing
Mostafa (2010) pointed out that most of the reports showed that smoking reduces sperm production, normal forms, motility and fertilising capacity through increased DNA damage and seminal oxidative stress. He concluded that although some smokers may not experience reduced fertility, men with marginal semen quality can benefit from quitting smoking. Recently Lotti et al. (2015) suggested that smoking may negatively affect seminal vesicles, volume in an independent manner, as the difference between current smokers and non-smokers retained significance after adjusting confounders. Earlier Homan et al. (2007) mentioned that there is strong evidence that age, weight and tobacco smoking have adverse impact on general as well as reproductive health. Al-Matubsi et al. (2011) also reported that smokers had significantly lower sperm concentration and motility and higher serum testosterone and luteinizing hormone levels than non-smokers. Calogero et al. (2009) studied the effects of cigarettes smoke extract (CSE) on motility, chromatin integrity, mitochondrial membrane potential (MMP), and apoptosis in spermatozoa in vitro of non-smokers. CSE suppressed sperm motility and elevate the number of spermatozoa with low MMP, the leading source of energy for motility. In addition, CSE had a harmful effect on sperm chromatin condensation and apoptosis. It increased the number of spermatozoa with phosphatidylserine externalization and fragmented DNA, in a dose and duration dependent manner. Yu et al. (2014) investigated the relationship between smoking, the histone-to-protamine transition ratio in sperm and semen quality. Smoking is strongly linked with deformities in histone-toprotamine transition and with alteration of protamine mRNA expression in human sperm. The percentage of sperm DNA fragmentation index, sperm with abnormally high DNA stainability (HDS %) and round-head sperms are elevated in idiopathic infertile men; this escalation is related with cigarette smoking. These defects may be attributed to elevated oxidative stress and inadequate scavenging antioxidant enzymes in the seminal fluid (Elshal et al. 2009). Later Niu et al. (2010) also reported that smoking has adverse effects on the semen volume, sperm motility and morphology and decreases sperm DNA integrity and nuclear maturation of the smokers. Further, Ghaffari and Rostami (2013) reported that spermatozoa consume adenosine triphosphate (ATP) rapidly. Creatine kinase (CK), produced by creatine phosphate, is an energy reservoir for the regeneration of ATP which play an important role in sperm motility. They showed significantly lower sperm CK activity and motility in male smokers. Smoking, by diminishing sperm CK activity, may potentially impair sperm energy homeostasis which in turn affects sperm motility. This can be an important mechanism that may cause infertility in male smokers. Al-Matubsi et al. (2011) from Jordan also found that smokers had significantly lower sperm concentration, motility and higher serum testosterone and LH levels. Taha et al. (2012) observed that smoking (cigarettes/day and duration) has unfavourable effects on sperm motility, viability, DNA fragmentation, seminal zinc levels, and semen reactive oxygen species levels, and it is directly correlated with cigarette quantity and smoking duration. Smoking leads to a significant decline in semen quality and elevated number of leukocytes, thus smoking may affect the fertilization efficiency (Zhang et al. 2013). These data suggest that tobacco smoking is harmful to male reproductive health by reducing sperm count, concentration, motility, viability etc enhancing sperm DNA fragmentation, sperm head shape abnormality etc.

In addition to tobacco smoking, tobacco chewing may also affect the male reproduction. Sunanda et al. (2014) reported the adverse impact of tobacco chewing on semen parameters which was obvious even with mild chewers, but with the intensive chewing habits phenotypes of sperms, defects in the head and cytoplasmic residue were drastically affected. Recently, Patel et al. (2015) also observed an inverse dose–response relationship between tobacco chewing and semen volume, total sperm count, viable and motile sperm percentage. Heavy or long-term tobacco chewers had a lower sperm concentration. Kumar (2013) reviewed the data on tobacco and areca nut chewing with regards to and reproductive impairments and mentioned that that smokeless tobacco use is also harmful as smoking for reproduction and use of areca nut might have further compounded the problem. Recently Choksi et al. (2015) also reported that smoking and tobacco chewing deteriorate the sperm quality which in turn leads to infertility of the male partners. They concluded that lifestyle modification can help the couples to conceive spontaneously or improve conception with ART treatment. Kumar et al. (2014) studied the role of various lifestyle and environmental factors in male reproduction and their association with respect to semen quality, increased oxidative stress as well as sperm DNA damage. They found significant variation in semen quality parameter between lifestyle and environmental exposed and non-exposed subjects. Further, the levels of antioxidants were reduced, and sperm DNA damage was higher among the lifestyle and/or environmental exposed subjects, though the changes were not significant. They concluded that various lifestyle factors such as tobacco smoking, chewing and alcohol use as well as exposure to toxic agents might be attributed to the risk of deteriorating semen quality and elevation in oxidative stress and sperm DNA damage.

Alcohol/caffine
Alcohol is one of the top three addictives substances and humans are using extensively since long time in all over the world. La Vignera et al. (2013) mentioned that although alcohol is widely used, its impact on the male reproductive function is still controversial. They reviewed clinical studies and concluded that alcohol consumption is associated with a deterioration of sperm parameters which may be partially reversible after alcohol consumption discontinued. Earlier, Stutz et al. (2004) examined the effects of alcohol, tobacco, and drug use on plasma testosterone and seminal characteristic. Alcohol and tobacco use were associated significantly; subjects who used these substances exhibited a nonsignificant reduction in sperm concentration, viability, motility, and normal morphology. There was a significant decrease in sperm motility those used moderate amounts of aspirin. However, Jensen et al. (2014) found no consistent association between any semen variable and alcohol consumption, either for total consumption or consumption by type of alcohol. However, they found a linear association between total alcohol consumption and total or free testosterone level. Alcohol intake was not significantly associated with serum inhibin B, LH or FSH levels in either group. Gaur et al. (2010) reported that alcohol abuse targets sperm production and morphology and smoke-induced toxins mainly hamper sperm motility as well as seminal fluid quality. Progressive worsening in semen quality is related to quantity of alcohol intake and cigarettes smoked. Earlier, Kumar et al. (1992) reports adverse effects of smokedried meat extract (SME) on sperm morphology of Swiss mice which was dose dependent.

Caffeine is a widely consumed substance and consumption of caffeine is increasing in recent years among youth as an energetic drink. Drinking too much coffee can reduce a man’s ability to become father. Jensen et al.

(2010) reported that higher cola and/or caffeine intake was associated with reduced sperm concentration and total sperm count which was significant for cola. Recently Dias et al. (2015) hypothesized that caffeine changes human Sertoli cells (hSCs) metabolism as well as oxidative profile, which are vital for spermatogenesis. They reported that moderate consumption of caffeine appears to be safe to male reproductive health since it encourages lactate production by SCs, which can stimulate germ cells survival. Nevertheless, precaution should be taken by heavy consumers of beverages and food complemented with caffeine to avoid deleterious effects in hSCs functioning. Ramlau-Hansen et al. (2008) studied the relationship between prenatal and current caffeine exposure and semen quality. There was a tendency toward declining semen volume and mean testosterone and inhibin B concentrations with increasing maternal coffee drinking during pregnancy. Sons of mothers drinking (4-7 cups/day) had lower testosterone levels with respect to sons of mothers drinking 0-3 cups/day. They mentioned that the results are tentative, but they do not exclude a small to moderate effect of prenatal coffee consumption on semen volume and reproductive hormones. Present adult caffeine intake did not show any clear relations with semen quality, but high caffeine intake related to a higher testosterone concentration.

There are reports on the influence of caffeine on movement characteristics, fertilizing capacity of human spermatozoa. Earlier Aitken et al. (1983) reported that caffeine treatment to frozen-thawed human semen induced a significant rise in the number of motile spermatozoa but did not impact the quality of movement. Caffeine treatment of frozen-thawed human spermatozoa also augmented the percentage of spermatozoa penetrating cervical mucus membrane, by elevating the frequency rather than the accomplishment of collisions between spermatozoa and the cervical mucus interface. A preliminary report on the effect of the addition of caffeine to frozen sperms indicated that the addition of 7.2 mM caffeine proved optimal and resulted in 40% to 80% amplified sperm motility (Barkay et al., 1977). Later they carried out a study to determine the impact of caffeine on the fertilizing capacity of sperm cell. Sixty women underwent artificial insemination by donor with frozen/thawed semen, with or without addition of caffeine. Fourteen women became pregnant among caffeine-treated semen, whereas only seven pregnancies occurred among women received semen without caffeine during the six months period. Thus, they concluded that in vitro caffeine treatment of fertile donor semen does not damage the spermatozoa; however, it seems to improve the fertilizing capacity (Barkay et al., 1984). Further, Makler et al. (1980) also reported that caffeine increased the percentage of motile spermatozoa by 30% to 50% in approximately two-thirds of cases but no influence on sperm velocity was detected. Further, it was found that nonmotile live spermatozoa were activated by caffeine.

Obesity/ Physical activity/sedentary life
Obesity is a condition in which additional body fat gets accumulated and has been associated with an elevated risk of many diseases such as cardiovascular diseases, diabetes mellitus and certain types of cancer (Visscher and Seidell, 2001). The increasing prevalence of obesity around the world in recent decades can be explain by using high caloric foods, sedentary work, no or little exercise and even using vehicle for short distances, along with use of modern technologies that reduce the need for physical activity etc. It is gradually recognizing that obesity is one of the causes of sub fertility. The male infertility increased worldwide, which also coinciding with the high occurrence of obesity. There is a report which indicated that sperm concentration was significantly lower in the obese group as compared to the group with BMI 17-20, 20-25 and 25-30 kg/m2 (Koloszar et al., 2005). Kort et al. (2006) found that men with a BMI greater than 25 kg/m2 have fewer chromatin-intact normal-motile sperm cells per ejaculate as well as total number of normal-motile sperm cells. Therefore, to ensure maximum fertility potential, patients may be advised to reduce body weight. BMI was positively connected to estradiol levels and inversely to total testosterone and sex hormone-binding glogulin levels (Chavarro et al. 2009). They also reported a strong inverse relationship between BMI and inhibin B levels and a lower testosterone: LH ratio among subjects with a BMI ≥35 kg/m2. Further, BMI was unrelated to sperm motility, concentration, or morphology. In addition, there was steady decline in ejaculate volume with increasing BMI. Further, men with BMI ≥35 kg/m2 had a lower sperm count than normal weight men and sperm with high DNA damage were significantly more in obese men.

A negative association between BMI and neutral alpha-glucosidase levels, motility, rapid motility, and a positive relationship between BMI and seminal fructose levels was reported. No associations were found between BMI and sperm concentration. The study supports a deleterious effect of obesity on seminal quality, probably by alterations in the function of the epididymis (Martini et al. 2010). Later Hajshafiha et al. (2013) found that obese men were found to be 3.5 times more likely to have oligospermia. BMI was not connected with mean numeric values of the semen-analysis parameters, including sperm count, motility and morphology. BMI was not also significantly associated with hormone such as LH, prolactin, and LH/FSH ratio. However, a significant relationship was observed between BMI and estradiol, sex hormone-binding globulin, and the testosterone/estradiol ratio. Eisenberg et al. (2014) also reported that body size (measured by BMI or waist ircumference) is negatively related with semen parameters with little influence of physical activity. They further suggested that considering worldwide obesity prevalent, further study of the role of weight loss to improve semen quality is needed. Du Plessis et al. (2010) reviewed the data on obesity and male infertility and pointed to an augmented likelihood of abnormal semen quality among obese, and an elevated risk for subfertility among couples if male partner is obese. Several mechanisms might be resposible for the role of obesity on male infertility, by inducing sleep apnea, increased scrotal temperatures, alterations in hormonal profiles, decline sperm quality. They further, mentioned that neither the reversibility of obesity-associated male infertility with weight loss nor effective therapeutic interventions have been studied thoroughly. However, MacDonald et al. (2010) could not find evidence of an association between increased BMI and semen parameters based upon a systematic review with meta-analysis. They described limitation of the review was that data from most of the studies could not be aggregated for meta-analysis. Recently Shukla et al. (2014) mentioned that obesity has been linked to male fertility because of lifestyle changes, internal hormonal environment variations, and sperm genetic factors. They also mentioned that there are emerging evidences that obesity negatively affects male reproductive potential not only by decreasing sperm quality, but it affects the molecular structure of germ cells in the testes and eventually affects the sperm cells maturity and function. They also reported that the miRNA profile is changed in spermatozoa of obese; however, the effect of these alterations in fertilization and embryo health is not yet fully known.

Recently Chiu et al. (2014) studied the relationship between consumption of sugar-sweetened beverages (SSB) and semen quality. They found higher concentration of SSB was associated with lower sperm motility among healthy men. This might be associated with weight gain with respect to the high intake of SSB. Earlier studies have showed that high intake of SSBs cause weight gain and obesity (Ebbeling et al., 2012; Pan et al., 2013). Recently Guo et al. (2017) found standardized weighted mean differences (SMD) in sperm parameters (total sperm count, sperm concentration, and semen volume) of abnormal weight groups decreased to different degree compared to normal weight. Dose-response analysis found SMD of sperm count, sperm concentration and semen volume respectively fell 2.4%, 1.3% and 2.0% compared with normal weight for every 5-unit increase in BMI. This systematic review with meta-analysis has confirmed relationship between BMI and sperm quality, suggesting obesity may be a detrimental factor of male infertility.

Drugs use or Abuse
In addition to the illicit drug abuse, some of the other drugs may also affect human reproduction. Chronic medication can play a significant role in the pathogenesis of male reproductive health and some of the drugs/ compounds may reach to the seminal plasma affecting semen quality. The drugs that may distress male sexual health include drugs of abuse, central nervous system depressants, antihypertensives, anticholinergics, and psychotherapeutics agents (Wilson, 1991) and some anti-neoplastic drugs also. The immediate effects of some of drugs therapy and its reversibility are most readily observed in post-pubertal patients, but some antineoplastic treatments can bring permanent azoospermia. The probability of azoospermia is might be related to the agents and doses. The most hurtful are alkylating agents (chlorambucil, procarbazine, cyclophosphamide, melphalan, and busulfan), cisplatin and radiation (Meistrich, 2009). Later Fronczak et al. (2012) reviewed the literature on insults of illicit drug use on male fertility and reported that anabolic-androgenic steroids, marijuana, cocaine, methamphetamines, and opioid narcotics, negatively effect male fertility, and alterations in hypothalamic –pituitary-testicular axis, sperm function and testicular structure. Earlier Holma (1977) studied the effect of the oral administration of metandienone, an anabolic steroid, on spermatogenesis in male athletes. The sperm density declined 46% after 1 month of use and 73% declined after 2 months with highly pathologic sperms. The percentage of motile sperms diminished to about 30% after two months of use. Further, seminal acid phosphatase activity was markedly reduced after two months, while semen fructose was markedly changed after one month of use. The observed changes were reversable after discontinuation. Later, Turek et al. (1995) reported that a bodybuilder with a five-year of steroid use led to azoospermic and underwent successful gonadotropin replacement and conception was achieved three months after therapy was initiated.

Recently El Osta et al. (2016) reported that substance abuse, including anabolic-androgenic steroids (AAS), is commonly associated with impairment of male reproductive function, through different pathways. Earlier Moretti et al. (2007) also reported that azoospermia may be related to the use of androgenic anabolic steroids. They reported azoospermic case that had abused androgenic anabolic steroids and recovered spermatogenesis six months after cessation of abuse and on hormonal therapy. This endorses the recovery of spermatogenesis and suggests a possible relationship between altered meiotic segregation and androgenic anabolic steroids. Torres-Calleja et al. (2001) conducted a study to find out the effect of androgenic anabolic steroids (AAS) on endocrine and semen parameters of body builders. In subjects using AAS, eight had lower sperm counts, three had azoospermia, two polyzoospermia, and two had normal sperm counts. The percentage of morphologically normal sperm was declined significantly, only 17.7% had normal spermatozoa. Whereas, only one subject was found to be oligozoospermic in control group. Recently McBride and Coward (2016) reported that both AAS and testosterone replacement therapy (TRT) can depress the hypothalamicpituitary- gonadal axis resulting in diminution of spermatogenesis. TRT or AAS cessation may result in spontaneous recovery of normal spermatogenesis. However, some patients may not recover.

Psychosocial stress
Human feel different forms of stress, including psychological and work stress, these can affect male fertility and reproduction. The social and familial issues regarding reproduction are of great importance and unnecessaty causes the stress. Earlier McGrady (1984) reported that mildto- severe emotional stress depresses testosterone and perhaps interferes with spermatogenesis in the human male. It is difficult to attribute individual cases of infertility to psychological factors without evidence of psychopathology. In animals social stress, high altitude, immobilization stress and surgery, affect body weight, testosterone, copulatory behavior and testicular morphology. Stress applied to the pregnant rat also affects the sexual behavior and development of the male offspring. Hjollund et al. (2004a) collected prospective data on job strain, and coorelated with semen quality and probability of conceiving a clinical pregnancy and found psychologic job strain encountered in normal jobs does not seem to affect male reproductive function. Zorn et al. (2008) evaluated whether psychological factors in males affect semen quality and pregnancy. Possible depression in males is related to decreased sperm concentration, and poor managing with stress is associated with elevated occurrence of early miscarriage. Stress was correlated negatively with semen measures of volume and percent normal morphologic forms (Giblin et al., 1988). The data are consistent with the hypothesis that psychosocial stress contributes significantly to the etiology of some forms of infertility (Wasser et al., 1993). Gollenberg et al. (2010) examined the association between stressful life events and semen quality and found that stressful life events associated with diminishing semen quality in fertile men. The experience of psychosocial stress may be a modifiable factor to prevent the development of idiopathic infertility. Li et al. (2011) reviewed thirteen socio-psycho-behavioral factors in 57 cross-sectional studies with 29,914 participants from 26 countries/regions. They found that psychological stress can lower sperm density and sperm progressive motility and increase abnormal sperm. They further suggested that higher age, smoking, alcohol consumption, and psychological stress were the risk factors for semen quality. Further, health programs focusing on lifestyle and psychological health would be helpful for male reproductive health. Earlier, Schneid- Kofman and Sheiner (2005) also reviewed the relationship between psychological stress and male infertility. They mentioned that most of the studies rejected the theory of stress as a lone factor in infertility, but stress stands as an additional risk factor for infertility. Later Collodel et al. (2008) reported that stress seem to induce meiotic and structural alterations in sperm cells. The spermatogenic process was improved after a cycle of Conveyer of Modulating Radiance therapy showed that stress is an extra risk factor for idiopathic infertility.

Recently, Nargund (2015) mentioned that numerous clinical studies on psychological stress on male fertility have shown that stress is associated with reduced fatherhood and abnormal semen characrtersic. Adequate scientific evidence exists which suggest that psychological stress could affect spermatogenesis. The hypothalamic–pituitary–adrenal axis has a straight inhibitory action on the hypothalamic–pituitary–gonadal (HPG) axis and Leydig cells. Inhibition of the HPG axis results in a decrease of testosterone levels, which causes deviations in Sertoli cells and the blood– testis barrier, leading to the seizure of spermatogenesis. Germ cells also become vulnerable to gonadotoxins and oxidation. They concluded that even though some limitation stress as a causative factor in male infertility cannot be ignored. Earlier Wilson and Kopitzke (2002) concluded that there is a dearth of solid evidence that infertility patients demonstrate more psychopathology than controls, and that there is modest evidence for an association between distress during treatment and the outcome of the treatment itself. Hjollund et al. (2004b) also conducted a prospective study among Danish couples who were trying to become pregnant and found no consistent associations between stress and serum concentration of LH, FSH, inhibin B, testosterone, or estradiol. The effect of psychologic stress associated with man’s daily life on semen quality is minor or nonexistent. They reported that the effect of stress only on fecundability among men with lower sperm concentration. Later Janevic et al. (2014) evaluated associations between stressful life events, work-related stress and perceived stress and semen quality. They found an inverse association between perceived stress score and sperm concentration, motility, and morphology. Further, men who experienced two or more stressful life events had a lower percentage of motile sperm and morphologically normal sperm compared with no stressful events. However, job strain was not associated with semen quality.

There are few reports on psychological stress among men undergoing IVF. Clarke et al. (1999) assessed psychological variables, including selfreported stress, and sperm parameters. They demonstrated an inverse relationship between semen quality and psychological stress among subjects undergoing IVF. The emotional stress to a subject during IVF program negatively affects the quality of semen provide evidence for a significant decline in semen quality of male IVF patients at time of egg retrival (Ragni and Caccamo 1992). Earlier, Harrison et al. (1987) evaluated semen profiles of couples underwent IVF treatment. The semen sample was collected at the time of pre-IVF workup, and the second one was after ovum aspiration. The data revealed that total sperm count, sperm density, and sperm motility were significantly lower in the second sample compared to frist one for IVF.

Lifestyle factors such as tobacco smoking or chewing, alcohol, obesity, and some of the illicit drugs like cannabis, cocaine, etc and extreme heat, have harmful effects on male reproduction (Kumar et al., 2009). Further the data on other factors such as use of mobile phone and stress on reproductive health is also accumulated in recent decade. Some “negative lifestyle factors” may be contributing to the growing trends in male infertility. Further, occupational /environmental exposure to some of the organic solvents, pesticides, metals, plasticizers especially phthalates; ionizing and nonionizing radiations, extreme heat, stress etc. may be associated with declining semen quality. There may not be conclusive evidence for the entire lifestyle, occupational and environmental factors discussed above but adopting healthy lifestyle and prevention of the usage of reproductive toxicants may be beneficial at least in part in prevention of infertility as well in pregnancy outcome. Sub-fertile and/or even normal individuals have some control over their reproductive function by adopting healthy lifestyles.

Acknowledgements

One of the authors (SK) is thankful to ICMR, DST, DBT, New Delhi, for financial assistance in the form of adhoc research grants on various aspects of reproductive health with respect to occupational, environmental exposure and on smokeless tobacco use and health which form the author foundation on this important issue of human reproduction.

(Images of child and man adapted from 'Pixabay-Stunning free images' http://www.pixabay.com)
Figure 1: Possible environmental, occupational and life style factors associated with male infertility
References
  1. Agarwal A,  Deepinder F, Sharma RK,  Geetha R and Jianbo L. Effect of cell phone usage on semen analysis in men attending infertility clinic: an observational study. Fertil Steril. 2008;89(1):124–128. DOI: 10.1016/j.fertnstert.2007.01.166.
  2. Agarwal A, Desai NR, Makker K, Varghese A, Mouradi R, Sabanegh E, et al. Effects of radiofrequency electromagnetic waves (RF-EMW) from cellular phones on human ejaculated semen: an in vitro pilot study. Fertil Steril. 2009;92:1318–1325. DOI: 10.1016/j.fertnstert.2008.08.022.
  3. Aitken RJ, Best F, Richardson DW, Schats R and Simm G. Influence of caffeine on movement characteristics, fertilizing capacity and ability to penetrate cervical mucus of human spermatozoa. J Reprod Fertil. 1983;67(1):19-27.
  4. Akinloye O, Arowojolu AO, Shittu OB and Anetor JI. Cadmium toxicity: a possible cause of male infertility in Nigeria. Reprod Biol. 2006;6(1):17-30.
  5. Alexander BH, Checkoway H, Faustman EM, van Netten C, Muller CH and Ewers TG.  Contrasting associations of blood and semen lead concentrations with semen quality among lead smelter workers. Am J Ind Med. 1998;34(5):464-469.
  6. Al-Matubsi H, Kanaan RA, Hamdan F, Salim M, Oriquat GA, and Al-Hanbali O. Smoking practices in Jordanian people and their impact on semen quality and hormonal levels among adult men. Central European J Public Health. 2011;19(1):54-59.
  7. Aneck-Hahn NH, Schulenburg GW, Bornman MS, Farias P and Jager deC. Impaired semen quality associated with environmental DDT exposure in young men living in a malaria area in the Limpopo Province. South Africa J Androl. 2007;28(3):423-434. DOI: 10.2164/jandrol.106.001701.
  8. Apostoli P, Kiss P, Porru S, Bonde JP and Vanhoorne M (1998) Male reproductive toxicity of lead in animals and humans. ASCLEPIOS Study Group. Occup Environ Med. 1998;55(6):364–374.
  9. Aruldhas MM, Subramanian S, Sekar P, Vengatesh G, Chandrahasan G, Govindarajulu P and Akbarsha MA. Chronic chromium exposure-induced changes in testicular histoarchitecture are associated with oxidative stress: study in a non-human primate (Macacaradiata Geoffroy). Human Reprod. 2005;20(10):2801–2813. DOI: 10.1093/humrep/dei148.
  10. Assennato G, Paci C, Baser ME, Molinini R, Candela RG, Altamura BM and Giorgino R. Sperm count suppression without endocrine dysfunction in lead-exposed men. Arch Environ Health. 1986;41(6):387-390. DOI: 10.1080/00039896.1986.9935784.
  11. Awadalla NJ, El-Helaly M, Gouida M, Mandour R and Mansou M. Sperm chromatin structure, semen quality and lead in blood and seminal fluid of infertile men. Int J Occup Environ Med. 2011;2(1):27-36.
  12. Barkay J, Zuckerman H, Sklan D and Gordon S. Effect of caffeine on increasing the motility of frozen human sperm. Fertility and Sterility. 1977;28(2):175-177.
  13. Barkay J, Bartoov B, Ben-Ezra S, Langsam J, Feldman E, Gordon S and Zuckerman H. The influence of in vitro caffeine treatment on human sperm morphology and fertilizing capacity. Fertility and Sterility. 1984;41(6):913-918.
  14. Barreto G, Madureira D, Capani F, Aon-Bertolino L, Saraceno E and Alvarez-Giraldez LD. The role of catechols and free radicals in benzene toxicity: an oxidative DNA damage pathway. Environ Mol Mutagen. 2009;50(9):771-780. DOI: 10.1002/em.20500.
  15. Bedwal RS and Bahuguna A. Zinc, copper and selenium in reproduction. Experientia. 1994;50(7):626-640.
  16. Benoff S, Hurley IR, Barcia M, Mandel FS, Cooper GW and Hershlag A. A potential role for cadmium in the etiology of varicocele-associated infertility. Fertil Steril. 1997;67(2):336–347. DOI: 10.1016/S0015-0282(97)81921-8.
  17. Berihu BA. Histological and functional effect of aluminium on male reproductive system. Int J Pharma Sci Res. 2015;6: 1122-1132.
  18. Birnbaum LS. Endocrine effects of prenatal exposure to PCBs, dioxins, and other xenobiotics: implications for policy and future research. Environ Health Perspect. 1994;102(8):676–679.
  19. Bolt HM, Başaran N, Duydu Y (2012) Human environmental and occupational exposures to boric acid: reconciliation with experimental reproductive toxicity data. J Toxicol Environ Health A. 2012;75(8-10):508-514. doi: 10.1080/15287394.2012.675301.
  20. Bonde J P. Semen quality in welders exposed to radiant heat. Br J Ind Med. 1992;49(1):5–10.
  21. Burdoff A, Talamanaca IF, Jensen TK and Thulstrup AM. Effects of occupational exposure on the reproductive system: core evidence and practical implications. Occup Med. 2006;56:516-520. DOI: 10.1093/occmed/kql113.
  22. Bustamante LP, Waliszewski S , Hernández-Valero M , Sanín-Aguirre L , Infanzón- RM and Jañas AG. Prenatal exposure to organochlorine pesticides and cryptorchidism. Ciencia & Saude Coletiva. 2010;15(1):1169-1174. 
  23. Calogero A, Polosa R, Perdichizzi A, Guarino F, La Vignera S, Scarfia A, et al. Cigarette smoke extract immobilizes human spermatozoa and induces sperm apoptosis. Reprod Biomed online. 2009;19(4):564-571.
  24. Carlsen E, Giwercman A, Keiding N and Skakkebxk NE. Evidence for decreasing quality of semen during past 50 years. Br Med J. 1992;305:609-613.
  25. Chavarro JE, Toth TL, Wright DL, Meeker JD and Hauser R. Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic. Fertil Steril. 2010;93(7):2222-2231. DOI: 10.1016/j.fertnstert.2009.01.100.
  26. Cheburakov lulu and Cheburakova OP. Disorders of spermatogenesis in people working at the clean-up of the Chernobyl nuclear power plant accident. Radiats Biol Radioecol. 1993;33(6):771-774.
  27. Cheng CY, Wong EW, Lie PP, Li MW, Su L, Siu ER and Murk DD. Environmental toxicants and male reproductive function. Spermatogenesis. 2011;1(1):2–13. DOI: 10.4161/spmg.1.1.13971.
  28. Cherry N, Labreche F, Collins J and Tulandi T. Occupational exposure to solvents and male infertility. Occup Environ Med. 2001;58(10):635–640.
  29. Chia SE. Endocrine disruptors and male reproductive function-a short review. Int J Androl. 2000;23(S2):45-46.
  30. Chia SE, Ong CN, Lee ST and Tsakok FH. Blood concentrations of lead, cadmium, mercury, zinc, and copper and human semen parameters. Arch Androl. 1992;29:177–183.
  31. Chia SE, Ong CN, Tsakok MF and Ho A. Semen parameters in workers exposed to trichloroethylene.  Reprod Toxicol. 1996;10(4):295-299.
  32. Chiu YH, Afeiche MC, Gaskins AJ, Williams PL, Mendiola J, Jørgensen N, et al. Sugar-sweetened beverage intake in relation to semen quality and reproductive hormone levels in young men. Human Reprod 2014;29(7):1575-1584. DOI: 10.1093/humrep/deu102.
  33. Choksi T, Patel A, Shrivastav A and Agnihotri AS. Semen analysis: Study of hundred samples of semen, in association with different epidemiological parameters, from cases of male infertility. J Res Med Dental Sci. 2015;3(3):232-234.
  34. Chowdhury AR. Recent advances in heavy metals induced effect on male reproductive function—A retrospective. Al Ameen J Med Sci. 2009;2:37-42.
  35. Chowdhury AR, Chinoy NJ, Gautam AK, Rao RV, Parikh DJ, Shah GM, et al. Effect of lead on human semen. Adv Contracept Deliv Syst. 1986;2(2-3):208-210.
  36. Clarke RN, Klock SC, Geoghegan A and Travassos DE. Relationship between psychological stress and semen quality among in-vitro fertilization patients. Human Reprod. 1999;14(3):753-758.
  37. Clifton DK and Bremner WJ. The effect of testicular x-irradiation on spermatogenesis in man. A comparison with the mouse. J Androl. 1983;4(6):387-392.
  38. Collodel G, Moretti E, Fontani V, Rinaldi S, Aravagli L, Saragò G, et al. Effect of emotional stress on sperm quality. Indian J Med Res. 2008;128(3):254-261.
  39. Cullen MR, Kayne RD and Robins JM. Endocrine and reproductive dysfunction in men associated with occupational inorganic lead intoxication. Arch Environ Health. 1984;39:431–440;
  40. Danadevi K, Rozati R, Reddy PP and Grover P. Semen quality of Indian welders occupationally exposed to Nickle and Chromium. Reprod Toxicol. 2003;17(3):451-456.
  41. Danielsson BRG, Dencker L, Lindgren A and Tjälve H. Accumulation of toxic metals in male reproduction organs. Disease, Metabolism and Reproduction in the Toxic Response to Drugs and Other Chemicals. Archieves Toxicol 1984;7:177-180.
  42. De Celis R, Feria-Velasco A, González-Unzaga M, Torres-Calleja J and Pedrón-Nuevo N. Semen quality of workers occupationally exposed to hydrocarbons. Fertility and sterility. 2000;73(2):221-228.
  43. De Iuliis GN, Newey RJ, King BV and Aitken RJ (2009) Mobile phone radiation induces reactive oxygen species production and DNA damage in human spermatozoa In Vitro. PLoS One. 2009;4(7):e6446. DOI: 10.1371/journal.pone.0006446.
  44. Desdoits-Lethimonier C, Albert O, Bizec B Le, Perdu E, Zalko D, Courant F, et al. Human testis steroidogenesis is inhibited by phthalates. Human Reprod. 2012;27(5):1451-1459. DOI: 10.1093/humrep/des069.
  45. Dias T R, Alvesa MG, Bernardino RL, Martins AD, Moreira AC, Silva J, et al. Dose-dependent effects of caffeine in human Sertoli cells metabolism and oxidative profile: Relevance for male fertility. Toxicology. 2015;328:12–20. DOI: 10.1016/j.tox.2014.12.003.
  46. Dickman MD, Leung CK and Leong MK. Hong Kong male subfertility links to mercury in human hair and fish. Sci Total Environ. 1998;214:165-174.
  47. Du Plessis SS, Cabler S, McAlister DA, Sabanegh E and Agarwal A. The effect of obesity on sperm disorders and male infertility. Nat Rev Urol. 2010;7(3):153-61. DOI: 10.1038/nrurol.2010.6.
  48. Duty SM , Calafat AM, Silva MJ, Ryan L and Hauser R. Phthalate exposure and reproductive hormones in adult men. Human Reprod. 2005;20(3):604-610. DOI: 10.1093/humrep/deh656.
  49. Duty SM, Silva MJ, Barr DB, Brock JW, Louise R, Chen Z, et al. Phthalate exposure and human semen parameters. Epidemiol. 2003;14:269-277.
  50. Duty SM, Singh NP, Silva MJ, Barr DB, Brock JW, Ryan L, et al. The relationship between environmental exposures to phthalates and DNA damage in human sperm using the neutral comet assay. Environ Health Perspect. 2003;111(9):1164-1169.
  51. Easley CA, Bradner JM, Moser A, Rickman CA, McEachin ZT, Merritt MM, et al. Assessing reproductive toxicity of two environmental toxicants with a novel in vitro human spermatogenic model. Stem Cell Research. 2015;14(3):347-355. DOI: 10.1016/j.scr.2015.03.002.
  52. Ebbeling CB, Feldman HA, Chomitz VR, Antonelli TA, Gortmaker SL, Osganian SK, et al. A randomized trial of sugar-sweetened beverages and adolescent body weight. New England J Med. 2012;367(15):1407-1416.
  53. Eisenberg ML, Kim S, Chen Z, Sundaram R, Schisterman EF and Louis GM. The relationship between male BMI and waist circumference on semen quality: data from the LIFE study. Human Reprod. 2014;29(2):193-200. DOI: 10.1093/humrep/det428.
  54. El Osta R, Almont T, Diligent C, Hubert N, Eschwège P and Hubert J. Anabolic steroids abuse and male infertility. Basic Clin Androl.  2016;6:26:2. DOI: 10.1186/s12610-016-0029-4.
  55. Eldesouki MA, Sharaf NE, Abdel Shakour AA, Mohamed MS, Hussein AS and Hasani IW. Study of the effect of occupational exposure to volatile organic compounds (VOC's) on male reproductive hormones. World J Med Sci. 2013;8(1): 6-12.
  56. Elshal MF, El-Sayed IH, Elsaied MA, El-Masry SA and Kumosani TA. Sperm head defects and disturbances in spermatozoal chromatin and DNA integrities in idiopathic infertile subjects: association with cigarette smoking. Clinical biochemistry. 2009;42(7):589-594. DOI: 10.1016/j.clinbiochem.2008.11.012.
  57. Emokpae MA, Christian A and Ibadin K. Seminal plasma levels of lead and mercury in infertile males in Benin city, Nigeria. Int J Med Res & Health Sci. 2016;5(1):1-6.
  58. Erfurth EM, Gerhardsson L, Nilsson A, Rylander L, Schutz A, Skerfving S, et al. Effects of lead on the endocrine system in lead smelter workers, Archives of Environ Health-An Int Journal. 2011;56(5):449-455. DOI: 10.1080/00039890109604481.
  59. Ernst E and Lauritsen JG. Effect of organic and inorganic mercury on human sperm motility. Pharmacol Toxicol. 1991;68(6):440-444.
  60. Erogul O, Oztas E, Yildirim I, Kir T, Aydur E, Komesli G, et al. Effects of electromagnetic radiation from a cellular phone on human sperm motility: an in vitro study. Archives of Med Res. 2006;37(7):840-843. DOI: 10.1016/j.arcmed.2006.05.003.
  61. Eskenazi B, Wyrobek AJ, Fenster L, Katz DF, Sadler M, Lee J, et al. A study of the effect of perchloroethylene exposure on semen quality in dry cleaning workers. Am J Ind Med. 1991;20(5):575-591.
  62. Falzone N, Huyser C, Becker P, Leszczynski D and Franken DR (2011) The effect of pulsed 900-MHz GSM mobile phone radiation on the acrosome reaction, head morphometry and zona binding of human spermatozoa. Int J Androl. 2011;34(1):20-26. DOI: 10.1111/j.1365-2605.2010.01054.x.
  63. Fejes I, Zavaczki Z, Szollosi J, Koloszar S, Daru J, Kovacs L, et al. Is there a relationship between cell phone use and semen quality? Arch Androl. 2005;51(5):385-393. DOI: 10.1080/014850190924520.
  64. Figà-Talamanca I, Cini C, Varricchio GC, Dondero F, Gandini L, Lenzi A, et al. Effects of prolonged autovehicle driving on male reproduction function: a study among taxi drivers. Am J Ind Med. 1996;30(6):750-758. DOI: 10.1002/(SICI)1097-0274(199612)30:6<750::AID-AJIM12>3.0.CO;2-1.
  65. Figa-Talamanca I, Valerio A P, Franco W, Gandini L, Lenzi A, Lombardo F, et al. Fertility and semen quality of workers exposed to high temperatures in the ceramics industry. Reprod Toxicol. 1992;6(6):517-523.
  66. Fischbein A, Zabludovsky N, Eltes F, Grischenko V and Bartoov B. Ultra morphological sperm characteristics in the risk assessment of health effects after radiation exposure among salvage workers in Chernobyl. Environ Health Perspect. 1997;105 (Suppl 6):1445-1449.
  67. Fisher BE. Most unwanted persistent organic pollutants. Environ Health Perspect. 1999;107:A18-A23.
  68. Frazier LM. Reproductive Disorders Associated with Pesticide Exposure. J Agromed. 2007;12(1):27-37. DOI: 10.1300/J096v12n01_04.
  69. Fredricsson Bengt, Lennart Möller, Pousette Åke and Westerholm Roger. Human sperm motility is affected by plasticizers and diesel particle extracts. Basic & Clinical Pharmacol & Toxicol. 1993;72(2):128–133.
  70. Fronczak CM, Edward DK and Barqawi AB. The insults of illicit drug use on male fertility. J Androl.  2012;33(4) 515–528. DOI: 10.2164/jandrol.110.011874.
  71. Garolla A, Torino M, Miola P, Caretta N, Pizzol D, Menegazzo M, et al. Twenty-four-hour monitoring of scrotal temperature in obese men and men with a varicocele as a mirror of spermatogenic function. Human Reprod. 2015;30(5):1006 –1013. DOI: 10.1093/humrep/dev057.
  72. Gaur DS, Talekar MS and Pathak VP. Alcohol intake and cigarette smoking: impact of two major lifestyle factors on male fertility. Indian J Pathol Microbiol. 2010;53(1):35-40. doi: 10.4103/0377-4929.59180.
  73. Gennart JP, Buchet JP, Roels H, Ghyselen P, Ceulemans E and Lauwerys R. Fertility of male workers exposed to cadmium, lead, or manganese. Am J of Epidemiol. 1992;135(11):1208-1219.
  74. Ghaffari MA and Rostami M. The effect of cigarette smoking on human sperm creatine kinase activity: as an ATP buffering system in sperm. Int J Fertil Steril. 2013;6(4):258-265.
  75. Giblin PT, Poland ML, Moghissi KS, Ager JW and Olson JM. Effects of stress and characteristic adaptability on semen quality in healthy men. Fertil Steril. 1998;49(1):127-132.
  76. Gollenberg AL, Liu F, Brazil C, Drobnis EZ, Guzick D, Overstreet JW, et al. Semen quality in fertile men in relation to psychosocial stress. Fertil Steril. 2010;93(4):1104-1111. DOI: 10.1016/j.fertnstert.2008.12.018.
  77. Goncharov NP, Katsiya GV, Kolesnikova GS, Dobracheva GA, Todua TN, Vax VV, et al. Endocrine and reproductive health status of men who had experienced short-term radiation exposure at Chernobyl. Int J Androl 1998;21(5):271-276.
  78. Gorpinchenko I, Nikitin O, Banyra O and Shulyak A. The influence of direct mobile phone radiation on sperm quality. Cent European J Urol. 2014;67(1):65-71. DOI:  10.5173/ceju.2014.01.art14.
  79. Guo D, Wu W, Tang Q, Qiao S, Chen Y, Chen M, et al. The impact of BMI on sperm parameters and the metabolite changes of seminal plasma concomitantly. Oncotarget. 2017;8(30):48619-48634. DOI: 10.18632/oncotarget.14950.
  80. Gye MC and Park CJ. Effect of electromagnetic field exposure on the reproductive system. Clin Exp Reprod Med 2012;39(1):1-9. DOI: 10.5653/cerm.2012.39.1.1.
  81. Hajshafiha M, Ghareaghaji R, Salemi S, Sadegh-Asadi N and Sadeghi-Bazargani H. Association of body mass index with some fertility markers among male partners of infertile couples. Int J Gen Med. 2013;6:447-451. doi: 10.2147/IJGM.S41341. Print 2013.
  82. Hanf V, Forstmann A, Costea JE, Schieferstein G, Fischer I and Schweinsberg F. Mercury in urine and ejaculate in husbands of barren couples. Toxicology Letters. 1996;88 (1-3):227-231.
  83. Harrison KL, Callan VJ and Hennessey JF. Stress and semen quality in an in vitro fertilization program. Fertil Steril. 1987;48(4):633-636.
  84. Hernandez-Ochoa I, Garcia-Vargas G, Lopez-Carrillo L, Rubio-Andrade M, Moran-Martinez J, Cebrian ME, et al. Low lead environmental exposure alters semen quality and sperm chromatin condensation in northern Mexico. Reprod Toxicol. 2005;20(2):221-228. DOI: 10.1016/j.reprotox.2005.01.007.
  85. Hjollund NH, Bonde JP, Henriksen TB, Giwercman A, Olsen J; Danish First Pregnancy Planner Study Team.  Job strain and male fertility. Epidemiology. 2004;15(1):114-117. DOI: 10.1097/01.ede.0000100290.90888.4a.
  86. Hjollund NH, Bonde JP, Henriksen TB, Giwercman A, Olsen J. Danish First Pregnancy Planner Study Team. Reproductive effects of male psychologic stress. Epidemiology. 2004;15 (1):21-27.
  87. Hjollund NH, Skotte JH, Kolstad HA, and Bonde JP. Extremely low frequency magnetic fields and fertility: a follow up study of couples planning first pregnancies. The Danish first pregnancy planner study team. Occup Environ Med. 1999;56(4):253–255.
  88. Hjollund NH, Storgaard L, Ernst E, Bonde JP and Olsen J. The relation between daily activities and scrotal temperature. Reprod Toxicol . 2002;16(3):209-214.
  89. Hjollund NH, Storgaard L, Ernst E, Bonde JP and Olsen J. Impact of diurnal scrotal temperature on semen quality. Reprod Toxicol. 2002;16(3):215-221.
  90. Holma PK. Effects of an anabolic steroid (metandienone) on spermatogenesis. Contraception. 1977;15(2):151-162.
  91. Homan GF, Davies M and Norman R. The impact of lifestyle factors on reproductive performance in the general population and those undergoing infertility treatment: a review. Human Reprod update. 2007;13(3):209-223. DOI: 10.1093/humupd/dml056.
  92. Hosni H, Selim O, Abbas M and Fathy A. Semen quality and reproductive endocrinal function related to blood lead levels in infertile painters. Andrologia. 2013;45(2):120-127. DOI: 10.1111/j.1439-0272.2012.01322.x.
  93. Hovatta O, Venäläinen ER, Kuusimäki L, Heikkilä J, Hirvi T, Reima I. Aluminium, lead and cadmium concentrations in seminal plasma and spermatozoa, and semen quality in Finnish men. Human Reprod. 1998;13(1):115-119.  
  94. Hsu PC, Guo YL, Smith DR, Lin YS, Tseng LH, Lee CW et al. Airborne persistent organic pollutants and male reproductive health. Aerosol Air Qual. Res. 2014;14:1292-1298.
  95. Huang LP, Lee CC, Hsu PC and Shih TS. The association between semen quality in workers and the concentration of di(2-ethylhexyl) phthalate in polyvinyl chloride pellet plant air. Fertil Steril. 2011;96(1):90–94. DOI: 10.1016/j.fertnstert.2011.04.093.
  96. IARC, 2012. Arsenic and Arsenic compound.
  97. Jacques A, Kunstmann JM, Czyglik F and Jouannet P. Decline in semen quality among fertile men in Paris during the past 20 years. N Engl J Med. 1995;332(50):281-285. DOI: 10.1056/NEJM199502023320501.
  98. Janevic T, Kahn LG, Landsbergis P, Cirillo PM, Cohn BA, Liu X, et al. Effects of work and life stress on semen quality. Fertility Sterility. 2014;102(2):530–538. DOI: 10.1016/j.fertnstert.2014.04.021.
  99. Jeng HA. Exposure to Endocrine Disrupting Chemicals and Male Reproductive Health. Frontiers in Public Health. 2014;2:55.
  100. Jensen TK, Swan S, Jørgensen N, Toppari J, Redmon B, Punab M, et al. Alcohol and male reproductive health: a cross-sectional study of 8344 healthy men from Europe and the USA. Human Reprod 2014;29(8):1801-1809. DOI: 10.1093/humrep/deu118.
  101. Jensen TK, Swan SH, Skakkebaek NE, Rasmussen S, Jorgensen N. Caffeine intake and semen quality in a population of 2,554 young Danish men. Am J Epidemiol. 2010;171(8):883-891. DOI: 10.1093/aje/kwq007.
  102. Jönsson BA, Richthoff J, Rylander L, Giwercman A and Hagmar L. Urinary phthalate metabolites and biomarkers of reproductive function in young men. Epidemiol. 2005;16(4):487-493.
  103. Jung A and Schuppe HC. Influence of genital heat stress on semen quality in humans. Andrologia. 2007;39(6):203–215. DOI: 10.1111/j.1439-0272.2007.00794.x.
  104. Jurasovic J, Cvitkovic P, Pizent A, Colak B and Telisman S. Semen quality and reproductive endocrine function with regard to blood cadmium in Croatian male subjects. Biometals. 2004;17(6):735–743.
  105. Jurewicz J, Hanke W, Radwan M and Bonde JP. Environmental factors and semen quality. Int J Occup Med Environ Health. 2009;22(4):305-329. DOI: 10.2478/v10001-009-0036-1.
  106. Kasperczyk A, Dobrakowski M, Czuba ZP, Horak S and Kasperczyk S. Environmental exposure to lead induces oxidative stress and modulates the function of the antioxidant defence system and the immune system in the semen of males with normal semen profile. Toxicol Applied Pharmacol. 2015;284(3):339-344. DOI: 10.1016/j.taap.2015.03.001.
  107. Katukam V, Kulakarni M, Syed R, Alharbi K and Naik J. Effect of benzene exposure on fertility of male workers employed in bulk drug industries. Genet Test Mol Biomarkers. 2012;16(6):592-597. DOI: 10.1089/gtmb.2011.0241.
  108. Kavlock RJ, Daston GP, DeRosa C, Fenner-Crisp P, Gray LE, Kaattari S, et al. Research needs for the risk assessment of health and environmental effects of endocrine disruptors: a report of the U.S. EPA-sponsored workshop. Environ Health Persp. 1996;104 (Suppl 4):715–740.
  109. Kim YJ and Kim JM. Arsenic Toxicity in Male Reproduction and Development. Dev Reprod. 2015;19(4):167-180.
  110. Klein JP, Mold M, Mery L, Cottier M and Exley C. Aluminum content of human semen: Implications for semen quality. Reprod Toxicol. 2014;50:43-48. DOI: 10.1016/j.reprotox.2014.10.001.
  111. Knez J. Endocrine-disrupting chemicals and male reproductive health. Reproductive biomedicine online. 2013;26(5):440-448. DOI: 10.1016/j.rbmo.2013.02.005.
  112. Koloszar S, Fejes I, Zavaczki Z, Daru J, Szöllősi J and Pal A. Effect of body weight on sperm concentration in normozoospermic males. Archives of andrology. 2005;51(4):299-304. DOI: 10.1080/01485010590919701.
  113. Kolstad HA. Bonde JP, Spano M, Giwercman A, Zschiesche W, Kaae D, et al. Change in semen quality and sperm chromatin structure following occupational styrene exposure. ASCLEPIOS. Int Archives of Occup and Environ Health. 1999;72(3):135–141.
  114. Kort HI, Massey JB, Elsner CW, Mitchell-Leef D, Shapiro DB, Witt MA Roudebush WE. Impact of body mass index values on sperm quantity and quality. J Androl. 2006;27(3):450-452. DOI: 10.2164/jandrol.05124.
  115. Kumar S. Occupational exposure associated reproductive dysfunction. J Occup Health. 2004;46(1):1-19.
  116. Kumar S. Tobacco and areca nut chewing--reproductive impairments: an overview. Reprod Toxicol. 2013;36:12-17. DOI: 10.1016/j.reprotox.2012.11.007.
  117. Kumar S, Murarka S, Mishra VV and Gautam AK. Environmental & lifestyle factors in deterioration of male reproductive health. Indian J Med Res. 2014;140(7):29-35.
  118. Kumar S, Sathwara NG, Gautam AK, Agarwal K, Shah B, Kulkarni PK, et al. Semen quality of industrial workers occupationally exposed to Chromium. J of Occup Hlth. 2005;47:424-430.
  119. Kumar S, Zaidi SSA, Gautam AK, Dave LM & Saiyed HN. Semen quality and reproductive hormones among welders—A preliminary study. Environ Health Prev Med. 2003;8(2):64-67. DOI: 10.1007/BF02897929.
  120. Kumar S, Zinyu R, Chetia M, Dutta LP. Genotoxic effect of smoke-dried meat extract in Swiss albino mice using sperm head shape abnormality test. Cancer letters. 1992;64(1):51-53.
  121. Kumar S, Kumari Archana and Murarka S. Lifestyle factors in deteriorating male reproductive health. Ind J Exp Biol. 2009;47(8):615-624.
  122. La Vignera S, Condorelli RA, Balercia G, Vicari E and Calogero AE. Does alcohol have any effect on male reproductive function? A review of literature. Asian journal of andrology. 2015;15(2):221-225.
  123. Lancranjan I, Popescu HI, O GA, Klepsch I and Serbanescu M. Reproductive ability of workmen occupationally exposed to lead. Arch Environ Health. 1975;30:396–401.
  124. Leung TY, Choy CM, Yim SF, Lam CW and Haines CJ. Whole blood mercury concentrations in sub-fertile men in Hong Kong. Aust N Z J Obstet Gynaecol. 2001;41(1):75-77.
  125. Li H, Chen Q, Li S, Yao W, Li L, Shi X, et al. Effect of CrVI exposure on sperm quality: human and animal studies. Ann Occup Hyg. 2001;45(7):505–511.
  126. Li Y, Lin H, Li  Y and Cao J. Association between socio-psycho-behavioral factors and male semen : systematic review and meta-analyses. Fertil Steril. 2011;95(1):116-123. DOI: 10.1016/j.fertnstert.2010.06.031.
  127. Lin S, Hwang SA, Marshall EG, Stone R and Chen J. Fertility rates among lead workers and professional bus drivers: a comparative study. Annals of Epidemiol. 1996;6(3):201-208.
  128. Liu L, Bao H, Liu F, Zhang J and Heqing S. Phthalates exposure of Chinese reproductive age couples and its effect on male semen quality, a primary study. Environ Int. 2012;42:78-83. DOI: 10.1016/j.envint.2011.04.005.
  129. Liu XX, Tang GH, Yuan YX, Deng LX, Zhang Q and Zheng LK. Detection of the frequencies of numerical and structural chromosome aberrations in spermof benzene series-exposed workers by multi-color fluorescence in situ hybridization. Yi Chuan Xue Bao. 2003;30(12):1177-1182.
  130. Lotti F, Corona G, Vitale P, Maseroli E, Rossi M, Fino MG, et al. Current smoking is associated with lower seminal vesicles and ejaculate volume, despite higher testosterone levels, in male subjects of infertile couples. Human Reprod 2015;30(3):590-602. DOI: 10.1093/humrep/deu347.
  131. Lottrup G, Andersson AM, Leffers H, Mortensen GK, Toppari J, Skakkeaek NE, et al. Possible impact of phthalates on infant reproductive health. Int J Androl. 2006;29(1):172–180. DOI: 10.1111/j.1365-2605.2005.00642.x.
  132. MacDonald AA, Herbison GP, Showell M and Farquhar CM. The impact of body mass index on semen parameters and reproductive hormones in human males: a systematic review with meta-analysis. Human Reprod Update. 2010;16(3):293-311. DOI: 10.1093/humupd/dmp047.
  133. Maffini MV, Rubin BS, Sonnenschein C and Soto A M. Endocrine disruptors and reproductive health: the case of bisphenol-A. Molecular Cellular Endocrinol. 2006;254-255:179-186.DOI: 10.1016/j.mce.2006.04.033.
  134. Makler A, Makler E, Joseph Itzkovitz J, Brandes M. Factors Affecting Sperm Motility. IV. Incubation of human semen with caffeine, kallikrein, and other metabolically active compounds. Fertility and Sterility. 1980;33(6):624-630.
  135. Mansour NA. Occupational and environmental exposure versus reproductive health. Egyptian J Occup Med. 2014; 38(2):181-195.
  136. Marchetti F, Eskenazi B, Weldon Rosana H, Li G, Zhang L, Rappaport SM, et al. Occupational exposure to benzene and chromosomal structural aberrations in the sperm of Chinese men. Environ Health Perspect. 2012;120(2):229-234. doi: 10.1289/ehp.1103921.
  137. Martini AC, Tissera A, Estofán D, Molina RI, Mangeaud A, de Cuneo MF, et al. Overweight and seminal quality: a study of 794 patients. Fertil Steril. 2010;94(5):1739-43. DOI: 10.1016/j.fertnstert.2009.11.017.
  138. Mattison DR, Plowchlk DR, Meadows MJ, Aljuburi AZ, Gandy J and Malek A. Reproductive toxicity: Male and female reproductive systems as target for chemical injury. Med Clin N Am. 1990;74(2):391– 411.
  139. McBride JA and Coward RM. Recovery of spermatogenesis following testosterone replacement therapy or anabolic-androgenic steroid use. Asian J Androl. 2016;18(3):373-380. DOI: 10.4103/1008-682X.173938.
  140. McGrady AV. Effects of psychological stress on male reproduction: a review. Arch Androl. 1984;13(1):1-7.
  141. Meeker JD, Calafat AM and Hauser R. Urinary metabolites of Di(2-ethylhexyl) Phthalate are associated with decreased steroid hormone levels in adult men. J of Androl. 2009;30(3):287-297. DOI: 10.2164/jandrol.108.006403.
  142. Meeker JD, Rossano MG, Protas B, Diamond MP, Puscheck E, Daly D, et al. Cadmium, Lead, and other metals in relation to semen quality: Human evidence for molybdenum as a male reproductive toxicant. Environ Health Perspect. 2008;116(11):1473-1479. DOI: 10.1289/ehp.11490.
  143. Meeker JD, Ryan L, Barr DB, Herrick R F, Bennett DH, Bravo R, et al. The relationship of urinary metabolites of Carbaryl/Naphthalene and Chlorpyrifos with human semen quality. Environ Health Perspect. 2004;112(17):1665-1670.
  144. Meeker JD, Singh NP, Ryan L, Duty SM, Barr DB, Herrick RF, et al. Urinary levels of insecticide metabolites and DNA damage in human sperm.  Human Reprod. 2004;19(11):2573-2580. DOI: 10.1093/humrep/deh444.
  145. Mehrpour O, Karrari P, Zamani N, Saatsakis AM and Abdollahi M. Occupational exposure to pesticides and consequences on male semen and fertility: A review. Toxicol Letters. 2014;230(2):146-156. DOI: 10.1016/j.toxlet.2014.01.029.
  146. Meistrich ML. Male gonadal toxicity. Pediatric blood & cancer. 2009;53(2):261-266. DOI: 10.1002/pbc.22004.
  147. Meistrich ML. The effects of chemotherapy and radiotherapy on spermatogenesis in humans. Fertil Steril. 2013;100(5): 1180-1186.
  148. Mendiola J, Moreno JM, Roca M, Vergara-Juárez N, Martínez-García MJ, García-Sánchez A, et al. Relationship between heavy metals concentrations in three different body fluids and male reproductive parameters: a pilot study. Environ Health 2011;10(1):6. DOI: 10.1186/1476-069X-10-6.
  149. Mendiola J, Jorgensen N, Andersson AM, Calafat AM, Xiaoyun Ye, Redmon JB, et al. Are environmental levels of Bisphenol A associated with reproductive function in fertile men? Environ Health Perspect. 2010;118(9):1286-1291. DOI: 10.1289/ehp.1002037.
  150. Migliore L, Naccarati A, Zanello A, Scarpato R, Bramanti L and Mariani M. Assessment of sperm DNA integrity in workers exposed to styrene. Human Reprod. 2002;17(11):2912–2918.
  151. Mínguez-Alarcón L, Afeiche MC, Williams PL, Arvizu M, Tanrikut C, Amarasiriwardena CJ, et al. Hair mercury (Hg) levels, fish consumption and semen parameters among men attending a fertility center. Int J Hyg Environ Health 2018;221(2):174-182. DOI: 10.1016/j.ijheh.2017.10.014.
  152. Mocevic E, Specht IO, Marott JL, Giwercman A, Jönsson BA, Toft G, et al. Environmental mercury exposure, semen quality and reproductive hormones in Greenlandic Inuit and European men: a cross-sectional study.  Asian J Androl. 2013;15(1):97-104. DOI: 10.1038/aja.2012.121.
  153. Moretti E, Collodel G, La Marca A, Piomboni P, Scapigliati G and Baccetti B. Structural sperm and aneuploidies studies in a case of spermatogenesis recovery after the use of androgenic anabolic steroids. J Assist Reprod Genet. 2007;24(5):195-198. DOI: 10.1007/s10815-005-9002-4.
  154. Mostafa T. Cigarette smoking and male infertility. J Adv Res. 2010;1(3):179-186.
  155. Murature DA, Tang SY, Steinhardt G and Dougherty RC. Phthalate esters and semen quality parameters. Biomed Environ Mass Spectrom. 1987;14 (8):473–477. DOI: 10.1002/bms.1200140815.
  156. Murray TJ, Lea RG, Abramovich DR, Haites NE and Fowler PA. Endocrine disrupting chemicals: effects on human male reproductive health. Early pregnancy. 2001;5(2):80-112.
  157. Nakai N, Murata M, Nagahama, M, Hirase T, Tanaka M, Fujikawa T, et al. Oxidative DNA damage induced by toluene is involved in its male reproductive toxicity. Free radical research. 2003;37(1):69-76.
  158. Nargund VH. Effects of psychological stress on male fertility. Nature Reviews Urology 2015;12(7):373-382. DOI: 10.1038/nrurol.2015.112.
  159. Ni Z, Hou S, Barton CH and Vaziri ND. Lead exposure raises superoxide and hydrogen peroxide in human endothelial and vascular smooth muscle cells. Kidney Int. 2004;66(6):2329–2336. DOI: 10.1111/j.1523-1755.2004.66032.x.
  160. Niu ZH, Liu JB, Shi TY, Yuan Y and Shi HJ. Impact of cigarette smoking on human sperm DNA integrity. Zhonghua nan ke xue. 2010;16(4):300-304.
  161. Nobles CJ, Schisterman EF, Ha S, Kim K, Mumford SL, Buck Louis GM, et al. Ambient air pollution and semen quality. Environ Res. 2018;163:228-236. DOI: 10.1016/j.envres.2018.02.004.
  162. Océane A and Bernard J. A critical assessment of the endocrine susceptibility of the human testis to phthalates from fetal life to adulthood. Human Reprod. 2014;20(2):231-249. DOI: 10.1093/humupd/dmt050.
  163. Ogilvy-Stuart AL and Shalet SM. Effect of radiation on the human reproductive system. Environ Health Perspect. 1993;101 Suppl 2:109-16.
  164. Pan A, Malik VS, Hao T, Willett WC, Mozaffarian D and Hu FB. Changes in water and beverage intake and long-term weight changes: results from three prospective cohort studies. Int J Obesity. 2013;37(10):1378-1385.
  165. Pandey G and Jain G. A review on toxic effects of aluminium exposure on male reproductive system and probable mechanisms of toxicity. Int J Toxicol and Applied Pharmacol. 2013;3(3):48-57.
  166. Pant N, Upadhyay G, Pandey S, Mathur N, Saxena DK and Srivastava SP. Lead and cadmium concentration in the seminal plasma of men in the general population: correlation with sperm quality. Reprod Toxicol. 2003;17(4):447-450.
  167. Pant N, Manju S, Patel DK, Shukla Y, Mathur N, Gupta YK, et al. Correlation of phthalate exposures with semen quality. Toxicol Applied Pharmacol. 2008;231(1):112-116. DOI: 10.1016/j.taap.2008.04.001.
  168. Patel K, Mehta N and Mehta AU. A study on effects of tobacco chewing on various semen parameters. Indian J Applied Basic Med Sci. 2015;17(24):67-74.
  169. Petrelli G and Figà-Talamanca I. Reduction in fertility in male greenhouse workers exposed to pesticides. Eur J Epidemiol. 2001;17:675-677.
  170. Petrelli G, Figà-Talamanca I, Tropeano R, Tangucci M, Cini C, Aquilani S, et al. Reproductive male-mediated risk: Spontaneous abortion among wives of pesticide applicators. Eur J Epidemiol. 2000;16:391–393.
  171. Potashnik G, Aderet NB, Israeli R, Yanai-Inbar I and Sober I. Suppressive effect of 1,2-dibromo-3- chloropropane on human spermatogenesis. Fertil Steril1978;30(4):444–447.
  172. Queiroz EK and Waissmann W. Occupational exposure and effects on the male reproductive system. Cad Saúde Pública. 2006;22(3):485-493. DOI: /S0102-311X2006000300003.
  173. Radwan M, Jurewicz J, Polańska K, Sobala W, Radwan P, Bochenek M, et al. Exposure to ambient air pollution-does it affect semen quality and the level of reproductive hormones? Annals of human biology. 2016;43(1):50-6. DOI: 10.3109/03014460.2015.1013986.
  174. Ragni G and Caccamo A. Negative effect of stress of in vitro fertilization program on quality of semen. Acta Eur Fertil. 1992;23(1):21-23.
  175. Ramlau-Hansen CH, Thulstrup AM, Bonde JP, Olsen J and Bech BH. Semen quality according to prenatal coffee and present caffeine exposure: two decades of follow-up of a pregnancy cohort. Hum Reprod. 2008;23(12):2799-2805. DOI: 10.1093/humrep/den331.
  176. Ratcliffe JM, Schrader SM, Steenland K, Clapp DE, Turner T and Hornung RW. Semen quality in papaya workers with long term exposure to ethylene dibromide. Br J Ind Med. 1987;44(5):317-326.
  177. Rice KM, Walker EM, Wu M, Gillette C and Blough ER. Environmental mercury and its toxic effects. J Prev Med Public Health. 2014;47(2):74-83. DOI: 10.3961/jpmph.2014.47.2.74.
  178. Rignell-Hydbom A, Rylander L, Giwercman A, Jönsson BA, Lindh C, Eleuteri P, et al. Exposure to PCBs and p,p′-DDE and human sperm chromatin ntegrity. Environ Health Perspect. 2005:113:175-179.
  179. Robbins WA, Wei F, Elashoff DA, Wu G, Xun L and Jia J. Y: X Sperm ratio in boron exposed men. J Androl 2008;29(1):115-121. DOI: 10.2164/jandrol.107.003541.
  180. Robins TG, Bornman MS, Ehrlich RI, Cantrell AC, Pienaar E, Vallabh J, et al. Semen quality and fertility of men employed in a South African lead acid battery plant. Am J Ind Med. 1997;32(4):369-376.
  181. M Hooiveld, W Haveman, K Roskes, R Bretveld, I Burstyn, Roeleveld N. Adverse reproductive outcomes among male painters with occupational exposure to organic solvents. Occup and Environ Med. 2006;63(8):538-544.
  182. Rogan WJ and Chen A. Health risks and benefits of bis(4-chlorophenyl)-1,1,1-trichloroethane (DDT). Lancet. 2005;366(9487):763-773. DOI: 10.1016/S0140-6736(05)67182-6.
  183. Roychoudhury S, Nath S, Massanyi P, Stawarz R, Kacaniova M and Kolesarova A. Copper-induced changes in reproductive functions: in vivo and in vitro effects. Physiological Research. 2016;65(1):11.
  184. Rupa DS, Reddy PP and Reddy OS. Reproductive performance in population exposed to pesticides in cotton fields in India. Environ Res. 199155(2):123–128.
  185. Rzymski P, Tomczyk K, Rzymski P, Poniedziałek B, Opala T and Wilczak M. Impact of heavy metals on the female reproductive system. Annals of Agricultural and Environ Med. 2015;22(2):259-264. DOI: 10.5604/12321966.1152077.
  186. Sadighi MA, Aminian O and Dehghan F. Occupational exposure frequency in men with idiopathic abnormal spermatozoa visiting Royan Institute in 1998-2001. J Reprod Infertil. 2003;4(3):203.
  187. Safe SH. Endocrine disruptors and human health--is there a problem? An update. Environ Health Perspect. 2000;108(6):487–493.
  188. Schneid-Kofman N and Sheiner E. Does stress effect male infertility?--a debate. Med Sci Monit. 2005;11(8):SR11-3.
  189. Scialli AR, Bonde JP, Brüske-Hohlfeld I, Culver BD, Li Y and Sullivan FM. An overview of male reproductive studies of boron with an emphasis on studies of highly exposed Chinese workers. Reprod Toxicol. 2010;29(1):10-24. DOI: 10.1016/j.reprotox.2009.10.006.
  190. Sengupta M, Deb I, Sharma GD and Kar KK. Human sperm and other seminal constituents in male infertile patients from arsenic and cadmium rich areas of Southern Assam. Syst Biol Reprod Med. 2013;59(4):199-209. DOI: 10.3109/19396368.2013.783143.
  191. Sharma T, Banerjee BD, Yadav CS, Gupta P and Sharma S. Heavy metal levels in adolescent and maternal blood: Association with risk of hypospadias. ISRN Pediatrics, vol. 2014, Article ID 714234, 5 pages.
  192. Shen H, Xu W, Zhang J, Chen M, Martin FL, Xia Y, et al. Urinary metabolic biomarkers link oxidative stress indicators associated with general arsenic exposure to male infertility in a han Chinese population. Environ. Sci. Techno 2013;47(15):8843–8851.
  193. Sheykin Y, JungM, Yoo Peter, Schulsinger D and Komaroff E. Increase in scrotal temperature in laptop computer users. Human Reprod. 2005;20(2):452-455. DOI: 10.1093/humrep/deh616.
  194. Shukla KK, Chambial S, Dwivedi S, Misra S and Sharma P. Recent scenario of obesity and male fertility. Androl. 2014;2(6):809-818.
  195. Sikka SC and Wang R. Endocrine disruptors and estrogenic effects on male reproductive axis. Asian J Andrology. 2008;10(1):134-145. DOI: 10.1111/j.1745-7262.2008.00370.x.
  196. Skakkebaek NE, Rajpert-De ME, Buck Louis GM, Toppari J, Andersson AM, Eisenberg ML, et al. Male reproductive disorders and fertility trends: Influences of environment and genetic susceptibility. Physiol Reviews. 2016;96(1):55-97. doi: 10.1152/physrev.00017.2015.
  197. Song B, Cai ZM, Li X, Deng LX and Zheng LK. Effect of benzene on sperm DNA. Zhonghua Nan Ke Xue. 2005;11(1):53-55.
  198. Srinivasa J, Maxim P, Urban J and D’Souza A. Effects of pesticides on male reproductive functions. Iran J Med Sci 2005;30(4):153-159.
  199. Støy J, Hjøllund NH, Mortensen JT, Burr H and Bonde JP. Semen quality and sedentary work position. Int J Androl. 2004;27(1):5-11.
  200. Streffer C. Radiation effects of exposure during prenatal development. Radiologe 1995;35(3):141-7. [Article in German]
  201. Stutz G, Zamudio J, Santillán ME, Vincenti L, De Cuneo MF and Ruiz RD. The effect of alcohol, tobacco, and aspirin consumption on seminal quality among healthy young men. Archives of Environ Health: An Int J. 2004;59(11):548-552. DOI: 10.1080/00039890409603432.
  202. Sunanda P, Panda B, Dash C, Ray PK, Padhy RN and Routray P. Prevalence of abnormal spermatozoa in tobacco chewing sub-fertile males. J Human Reprod Sci. 2014;7(2):136-142.
  203. Swan SH. Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans. Environ Res. 2008;108(2):177–184.
  204. Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, Calafat AM, et al. Decrease in Anogenital Distance among Male Infants with Prenatal Phthalate Exposure. Environ Health Perspect. 2005;113(8):1056-1061.
  205. Taha EA, Ez-Aldin AM, Sayed SK, Ghandour NM and Mostafa T. Effect of smoking on sperm vitality, DNA integrity, seminal oxidative stress, zinc in fertile men. Urol. 2012;80(4):822-825. DOI: 10.1016/j.urology.2012.07.002.
  206. Tavares RS, Mansell S, Barratt CL, Wilson SM, Publicover SJ and Ramalho-Santos J. p,p'-DDE activates CatSper and compromises human sperm function at environmentally relevant concentrations. Human Reprod. 2013;28(12):3167-3177. DOI: 10.1093/humrep/det372.
  207. Telisman S, Cvitkovic P, Jurasovic J, Pizent A, Gavella M and Rocic B. Semen quality and reproductive endocrine function in relation to biomarkers of lead, cadmium, zinc, and copper in men. Environ Health Perspect. 2000;108(1):45–53.
  208. Ten J, Mendiola J, Torres-Cantero AM, Moreno-Grau JM, Moreno-Grau S, Roca M, et al. occupational and lifestyle exposures on male Infertility: A mini review. The Open Reprod Sci J. 2008;1:16-21.
  209. Thakur JS, Prinja S, Singh D, Rajwanshi A, Prasad R, Parwana HK. Adverse reproductive and child health outcomes among people living near highly toxic waste water drains in Punjab. India J Epidemiol Commun Health 2010;64(2):148-154. DOI: 10.1136/jech.2008.078568.
  210. Thonneau P, Bujan L, Multigner L and Mieusset R. Occupational heat exposure and male fertility: a review. Human Reprod. 1998;13(8):2122-2125.
  211. Toppari J, Larsen JC, Christiansen P, Giwercman A, Grandjean P,  Guillette LJ, et al. Male reproductive health and environmental xenoestrogens. Environ Health Perspect. 1996;104 (Suppl 4):741–803.
  212. Torres-Calleja J, González-Unzaga M, DeCelis-Carrillo R, Calzada-Sánchez L and Pedrón N. Effect of androgenic anabolic steroids on sperm quality and serum hormone levels in adult male bodybuilders. Life Sci. 2001;68(15):1769-1774.
  213. Turek PJ, Williams RH, Gilbaugh JH 3rd and Lipshultz LI. The reversibility of anabolic steroid-induced azoospermia. J Urol. 1995;153(5):1628-1630.
  214. Turusov V, Rakitsky V and Tomatis L. Dichlorodiphenyltrichloroethane (DDT): Ubiquity, persistence, and risks. Environ Health Perspect. 2002;110(2):125-128.
  215. Tvrda E, Peer R, Sikka SC and Agarwal A. Iron and copper in male reproduction: a double-edged sword. J Assisted Reprod and Genetics. 2015;32(1):3-16. DOI: 10.1007/s10815-014-0344-7.
  216. Vaziri MH, Sadighi MA, Kavousi A, Firoozeh M, Jazani RK, Dizaj AV, et al. The Relationship between Occupation and Semen Quality. Int J Fertil Steril. 2011;5(2):66–71.
  217. Vaziri ND and Khan M. Interplay of reactive oxygen species and nitric oxide in the pathogenesis of experimental lead-induced hypertension. Clin Exp Pharmacol Physiol. 2007;34:920–925. DOI: 10.1111/j.1440-1681.2007.04644.x.
  218. Veras MM, Caldini EG, Dolhnikoff M and Saldiva PH. Air pollution and effects on reproductive-system functions globally with particular emphasis on the Brazilian population. J Toxicol Environ Health, Part B. 2010;13(1):1-15. DOI: 10.1080/10937401003673800.
  219. Vignera S La, Condorelli RA, Vicari E, D'Agata R and Calogero AE. Effects of the Exposure to Mobile Phones on Male Reproduction: A Review of the Literature. J Androl. 2012;33(3):350-356. DOI: 10.2164/jandrol.111.014373.
  220. Visscher TL and Seidell JC. The public health impact of obesity. Annu Rev Public Health. 2001;22:355-375. DOI: 10.1146/annurev.publhealth.22.1.355.
  221. Waliszewski SM, Infanzon RM, Arroyo SG, Pietrini RV, Carvajal O, Trujillo P, et al. Persistent organochlorine pesticides levels in blood serum lipids in women bearing babies with undescended testis. Bull Environ Contam Toxicol. 2005; 75(5):952-959.  DOI: 10.1007/s00128-005-0842-5.
  222. Wasser SK, Sewall G and Soules MR (1993) Psychosocial stress as a cause of infertility. Fertil Steril. 1993;59(3):685-689.
  223. Welch LS, Schrader SM, Turner TW and Cullen MR. Effects of exposure to ethylene glycol ethers on shipyard painters: II. Male reproduction. Am J Industrial Med. 1988;14(5):509-526.
  224. WHO (1973) Safe use of pesticides. WHO technical report series Geneva: World Health Organization. 513.
  225. Whorton D, Krauss RM, Marshall S and Milby TH. Infertility in male pesticide workers. Lancet. 1977;310(8051):1259–1261.
  226. Wilson B. The effect of drugs on male sexual function and fertility, Nurse Pract. 1991;16(9):12-7, 21-4.
  227. Wilson JF and Kopitzke EJ. Stress and infertility. Curr Womens Health Rep. 2002;2(3):194-199.
  228. World Health Organization (2001) International code of conduct on the distribution and use of pesticides by Food and Agricultural Organization of the United Nations, Rome.
  229. Wu L, Jin L, Shi T, Zhang B, Zhou Y, Zhou T, et al. Association between ambient particulate matter exposure and semen quality in Wuhan, China. Environ Int. 2017;98:219-228.  
  230. Wyrobek AJ, Watchmaker G, Gordon L, Wong K, Moore D and Whorton D. Sperm shape abnormalities in carbaryl-exposed employees. Environ Health Perspect. 1981;40:255-265.
  231. Xia Y, Cheng S, Bian Q, Xu L, Collins MD, Chang HC, et al. Genotoxic effects on spermatozoa of Carbaryl-exposed workers. Toxicol Sci. 2004;85(1):615-623.
  232. Xiao GB, Pan C, Cai Y, Lin H and Fu Z. Effect of benzene, toluene, xylene on the semen quality and the function of accessory gonad of exposed workers. Industrial Health. 2001;39(2):206–210.
  233. Xing C, Marchetti F, Li G, Weldon RH, Kurtovich E, Young S, et al. Benzene exposure near the U.S. permissible limit is associated with sperm aneuploidy. Environ Health Persp. 2010;118(6):833-839. DOI: 10.1289/ehp.0901531.
  234. Wang YX, You L, Zeng Q, Sun Y, Huang YH, Wang C, et al. Phthalate exposure and human semen quality: Results from an infertility clinic in China. Environ Res. 2015;142:1-9. DOI: 10.1016/j.envres.2015.06.010.
  235. Xu DX, Shen HM, Zhu QX, Chua L, Wang QN, Chia SE, et al. The associations among semen quality, oxidative DNA damage in human spermatozoa and concentrations of cadmium, lead and selenium in seminal plasma. Mutat Res. 2003;534:155–163.
  236. Xu W, Bao H, Liu F, Liu L, Zhu YG, She J, et al. Environmental exposure to arsenic may reduce human semen quality: associations derived from a Chinese cross-sectional study. Environ Health. 2012;11:46. DOI: 10.1186/1476-069X-11-46.
  237. Xuezhi J, Youxin L and Yilan W. Studies of lead exposure on reproductive system: a review of work in China. Biomed Environ Sci. 1992;5(3):266-275.
  238. Yu B, Qi Y, Liu D, Gao X, Chen H, Bai C, et al. Cigarette smoking is associated with abnormal histone-to-protamine transition in human sperm. Fertil Steril. 2014;101(1):51-57.e1. DOI: 10.1016/j.fertnstert.2013.09.001.
  239. Yuan B, Wu W, Chen M, Gu H, Tang Q, Guo D, et al. From the Cover: Metabolomics reveals a role of Betaine in prenatal DBP exposure-induced epigenetic transgenerational failure of spermatogenesis in rats. Toxicol Sci. 2017;158(2):356-366. DOI: 10.1093/toxsci/kfx092.
  240. Zeng X, Jin T, Buchet JP, Jiang X, Kong Q, Ye T, et al. Impact of cadmium exposure on male sex hormones: a population-based study in China. Environ Res. 2004;96(3):338-344. DOI: 10.1016/j.envres.2004.02.004.
  241. Zhang YH, Zheng LX and Chen BH Phthalate exposure and human semen quality in Shanghai: a cross-sectional study. Biomed Environ Sci. 2006;19(3):205-209.
  242. Zhang ZH, Li LL, Yu Y, Zhang HG and Liu RZ. Decline of semen quality and increase of leukocytes with cigarette smoking in infertile men. Int J Reprod BioMed. 2013;11(7):589-596.
  243. Zhou N, Jiang C, Chen Q, Yang H, Wang X, Zou P, et al. Exposures to atmospheric PM10 and PM10-2.5 affect male semen quality: Results of MARHCSs Study. Environ Sci & Technol. 2018;52(3):1571-1581. DOI: 10.1021/acs.est.7b05206.
  244. Zorn B, Auger J, Velikonja V, Kolbezen M and Meden-Vrtovec H. Psychological factors in male partners of infertile couples: relationship with semen quality and early miscarriage. Int J Androl. 2008;31(6):557-564. DOI: 10.1111/j.1365-2605.2007.00806.x.