Recent Updates on the Effect of Endocrine Disruptors on Male Reproductive Functions

Roshini Rajendran1, Latchoumycandane Calivarathan1, Premendu Prakash Mathur2, *
1 Molecular Pharmacology & Toxicology Laboratory, Department of Life Sciences, School of Life Sciences, Central University of Tamil Nadu, Neelakudi Campus, Thiruvarur – 610005, India
2 Department of Biochemistry & Molecular Biology, School of Life Sciences, Pondicherry University, Puducherry – 605014, India

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© 2022 Rajendran et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Department of Biochemistry & Molecular Biology, School of Life Sciences, Pondicherry University, Pondicherry – 605014, India; and Department of Life Sciences, School of Life Sciences, Central University of Tamil Nadu, Thiruvarur – 610005, Tamil Nadu, India; Tel/Fax: +91-674-7103001; E-mail:


Endocrine disruptors are man-made or naturally occurring chemical substances, upon exposure, alter the male reproductive health by interfering with hormonal homeostasis and spermatogenesis. Several studies have supported the hypothesis that a decrease in sperm count over the past few decades is due to exposure to environmental contaminants possessing estrogenic or anti-androgenic properties. Bisphenol A, phthalates, alkylphenols, and polychlorinated biphenyls are some of the endocrine-disrupting chemicals commonly present in our day-to-day products that have been shown to pose a significant threat to reproductive health. Many chemicals directly or indirectly affect the endocrine systems, altering metabolism, sex differentiation, growth, stress response, gender behavior, and reproduction. The endocrine pathway disruption is possible via membrane receptors or nuclear receptors and inhibition of enzymatic pathways. The declining male reproductive health has been linked to an increased presence of chemical contaminants in our environment in the form of pesticides and plastics. The effect of endocrine disruptors on reproductive health remains a real issue considering public health. This review gives a recent update on environmental chemicals that have endocrine-disrupting potential and their effect on the male reproductive system.

Keywords: Endocrine disruptors, Pesticide, Sperm Testicular function, Pesticides, Public health, Growth.


In recent decades, several chemical and biological agents have been shown to interfere with various metabolic pathways, leading to development, growth, and reproduction alterations. Endocrine disruptors are exogenous agents that can interfere with the production, release, transportation, metabolism, binding, action, or elimination of natural hormones in the body needed to maintain homeostasis and regulate the developmental processes of an organism [1]. Endocrine-disrupting chemicals (EDC) are a heterogeneous group of substances that have been under consideration for the past three decades due to their possible harmful effects on wildlife and human [2]. Humans and animals are exposed to a wide range of chemical substances from the environment, contributing to a complex exposure situation in our day-to-day lives. Most of the reported effects on wildlife are based on the observation of aquatic organisms and have been linked to the concentration of pollutants along the food chain. In humans, there is increasing evidence that the birth sex ratio is altered in areas close to industry and exposed to environmental and industrial chemicals [3]. Epidemiological studies support the hypothesis that human male reproductive disorders have been increasing over the past few decades in relation to the increase in endocrine disruptors in our environment [4, 5].

Exposure to EDC has been linked to several reproductive disorders, including infertility, testicular germ cell cancer (TGCC), one of the most prevalent cancers in young men, and congenital developmental defects such as cryptorchidism and hypospadias [6]. Interestingly, exposure to endocrine disruptors during fetal, neonatal, and adult life plays a significant role in perturbing normal reproductive function and development. Increased exposure to these chemicals has decreased reproductive function and the average sperm counts [7, 8]. The existence of specific receptors in target cells allows the hormone-mimicking effect of endocrine disruptors. Even though some toxic substances, such as polychlorinated biphenyls and polybrominated diphenyl ether, are banned in many countries, many of these substances can still be detected in considerable amounts in our environment [9]. Multigenerational and transgenerational effects on reproduction have been reported in both male and female rodents following exposure to endocrine-disrupting chemicals [10-12]. This brief review investigates the possible effects of environmental chemicals that have endocrine-disrupting potential and their effect on the male reproductive system.

1.1. Endocrine Disruptors (EDs)

The endocrine disruptors are a group of chemicals either occurring naturally or released into our environment due to man-made activities. EDs mimic or interfere with the endocrine system, thereby altering normal development and causing abnormalities in reproductive health. EDs are present in several products, and some of them are potentially hazardous. Unknowingly, we are exposed to these chemicals every day. The term EDs has been used to describe a highly heterogeneous group of substances that could be either toxicants or toxins that can disrupt the action of endogenous hormones. Some include industrial solvents, by-products of industrial processes, plasticizers, pesticides, pharmaceutical agents, phytoestrogens, and heavy metals. EDs are detected in air, soil, drinking water, food, cosmetics, household products, electronic devices, and textiles. Some EDs are highly persistent and lipophilic, so they accumulate in the body and appear in bodily fluids.

1.2. Human Exposure to Endocrine Disruptors

Some well-known examples of endocrine disruptors, similar to experimental rodents found in human bodily fluids, include bisphenol A, phthalates, PCBs, dioxins, alkylphenols, etc. Even though many chemicals possessing endocrine disrupting properties have been banned or restricted in some countries, they are still in use in other countries, and exposure occurs due to their presence in our environment at a considerable level. For example, even though the use of alkylphenols is restricted in the European Union and is still found in a considerable amount in our environment [13]. Several endocrine disruptors are detected in human urine, serum, amniotic fluid, breast milk, and semen [14-17]. Bisphenol A is one of the examples of endocrine-disrupting chemicals present in the bodily fluid of humans in several instances [18]. Men exposed to dioxins show a more significant number of morphologically abnormal sperm and low linear motility [19, 20]. Increased Exposure to polychlorinated biphenyls (PCBs) is associated with decreased sperm count, motility, and normal morphology [21, 22]. Exposure to organochlorine pesticides such as DDT has been shown to decrease normal sperm morphology, sperm count, volume, and motility [21, 23, 24], whereas organophosphate exposure has been shown to reduce the semen volume and increase pH [25, 26]. These findings in humans indicate that EDC exposure does affect human semen quality in a way that is similarly modeled by rodents in other studies.

1.3. Mechanism of Action of Endocrine Disruptors on the Male Reproductive System

EDs can modify the action of endogenous hormones and deregulate hormonal balance through multiple mechanisms. Phthalates, BPA, dioxins, and PCBs are some of the well-known EDs shown to decrease semen quality [19-21, 23-27]. They behave as imperfect ligands, activating or inhibiting the nuclear hormone receptors’ functions, such as estrogen, androgen, progesterone, retinoid, and thyroid receptors. EDs can also act as transcriptional co-activators and inhibit enzymatic pathways of steroid biosynthesis. Monoethylhexyl phthalate (MEHP), the reactive metabolite of di (2-Ethylhexyl) phthalate (DEHP), activates the peroxisome proliferator-activated receptor (PPAR) α and PPARγ, leads to stimulation of retinoid x receptor (RXR) and PPAR to compete for binding sites on DNA and leads to inhibition of transcription of enzyme aromatase involved in sexual development. PPAR diminishes the steroidogenic proteins and leads to low sperm quality [28, 29]. Steroidogenic acute regulatory protein (StAR) is regulated by cAMP and mediates the rate-limiting step in steroidogenesis by the transportation of cholesterol into Leydig cells' mitochondria [30]. MEHP decreases the production of StAR protein and leads to a reduction in cholesterol transport. Apart from inducing oxidative stress in Leydig cells, exposure to a high level of MEHP inhibits the activities of steroidogenic enzymes such as 3β and 17β hydroxysteroid dehydrogenases, thereby altering testosterone biosynthesis [31, 32]. MEHP affects spermatogenesis by decreasing the number of Sertoli cells and its interaction with gonocytes and triggers testicular apoptosis by increasing Fas ligand expression [33-35]. The male reproductive system can be disturbed at different phases of a lifetime. Androgens are the essential hormones required for the normal development and differentiation of Wolffian ducts into the epididymis, vas deferens, and seminal vesicles. Dihydrotestosterone is produced from testosterone by 5α-reductase, an important hormone required for the masculinization of external genitalia and the prostate [36]. BPA affects sperm quality by the upregulation of the aryl hydrocarbon receptor mRNA level, which induces the expression of the CYP1 gene, which encodes the aromatase enzyme. Hence, a balanced hormonal environment is required for the normal development of the male reproductive system. Abnormal development of testes in fetal and neonatal life has long-term effects on sperm production [37]. Prepubertal exposure to endocrine-disrupting chemicals has negative consequences on reproductive function, as the blood-testis barrier in humans is developed just before puberty [38]. Thus, the effects of endocrine-disrupting chemicals mediated via activation or inhibition of androgen and estrogen receptors are the leading cause of adverse effects on male reproductive function. Estrogenic endocrine-disrupting chemicals exert more negative effects via the induction of oxidative stress. In addition, recently, possible negative actions on progeny through toxic epigenetic mechanisms have been found. Epigenetic modifications include heritable changes in gene expression without any change in DNA sequence. These changes include DNA methylation, histone modifications, and non-coding RNA expression. The early developmental period is susceptible to epigenetic mechanisms as the rate of DNA synthesis is maximum [39, 40]. The possible epigenetic action of EDs in humans is supported only by in vitro cell culture studies and more in vivo and human studies are needed to confirm it.

Table 1. Endocrine-disrupting chemicals and their impact on the male reproductive system.
Endocrine Disruptors Sources Effect on Male Reproduction
Bisphenol A Polycarbonate plastics and epoxy resins Reduced sperm concentration, motility, and normal morphology and arrest spermatogenesis at meiosis [83-86].
Phthalates Plasticizers, vinyl flooring, lubricating oils, and personal-care products (soaps, shampoos, hair sprays) Reduced fertility and semen quality parameters and reduced anogenital distance, reproductive abnormalities [33, 87-89]
Dioxins Incomplete combustion of organic material by forest fires or volcanic activity, emissions from municipal solid waste and industrial incinerators, chlorine bleaching process used by pulp and paper mills Reduced normal sperm morphology, lowered testosterone level, and limits prostate gland growth [90-93].
Pesticides Occupational Exposure as well as Exposure from gardens and lawns, agriculture, drift from spraying, and pesticide residues on certain fruits and vegetables Reduced sperm concentration, motility, and normal morphology alters Sertoli cell function and damages spermatozoa [94-97]
Triclosan a widely-used antimicrobial in personal care products Alters the morphology of sperm, and further research is necessary to conclude [98, 99]
Heavy metals like cadmium, lead Cigarette smoke, release from phosphate fertilizer, waste incineration process, paints, etc. Structural damage to seminiferous tubule hinders Leydig cell development and function, low sperm count, and motility [100-103].
Phytoestrogen Mainly from food Androgen insufficiency with under masculinization of the male urogenital tract and lowers sperm count [104-106]
Polychlorinated biphenyls Cutting oils, lubricants, and electrical insulators in transformers and capacitors Damages Sertoli cells, affects sperm motility and sperm count [107-109]
Alkylphenol Used as precursors to detergents, additives for fuels and lubricants, polymers, and as components in phenolic resins, emulsifiers Low sperm count, motility and reduced testosterone biosynthesis [110, 111].


Several endocrine-disrupting chemicals have been shown to alter male reproductive functions, either directly or indirectly competing for the same hormone receptors. Furthermore, they also inhibit the enzymes involved in steroidogenesis and the synthesis of other factors required for normal spermatogenesis. This review discusses some of the most common endocrine disruptors and their effects on male reproductive functions (Table 1).

2.1. Bisphenol A (BPA)

BPA is commonly used in the manufacturing of polycarbonate plastics and epoxy resins and is found in a variety of food containers such as hard, rigid plastics and the epoxy-based inner coating of canned foods. Exposure to BPA mainly via consuming contaminated food and drinking water, while exposure from the environment, domestic supplies, medical equipment, and occupational sources can also occur [41, 42]. BPA is one of the most extensively studied endocrine-disrupting chemicals that mimic natural estrogen. Estrogen plays a critical role in the development of the brain, mammary gland, and testis, interference of BPA with estrogen activity, especially during early development, results in permanent changes that affect reproductive functions later in life [43]. Even though they have a weak affinity to estrogen receptors (ERs), they can bind to and stimulate them. BPA acts primarily by mimicking the effect of estrogen, modifying DNA methylation [44] and modulating the activities of several enzymes, and subsequently induces metabolic diseases, spermatogenesis defects, and/or infertility in males [45]. It has also been observed that frequently exposed males to epoxy resins have higher urinary BPA concentrations and are associated with slightly lower FSH concentrations [46]. Increased BPA concentration is associated with lower sperm concentration, motility, morphology and higher levels of DNA damage [47]. BPA is a nonsteroidal estrogen that impedes nuclear estrogen receptors in different targets in the body [48]. Androgen level is inversely associated with urinary BPA concentration in men of proven fertility and has no association with semen quality [46]. BPA impairs Sertoli cell function by impeding the expression and localization of tight junction proteins [49-51] as well as indirect actions through the induction of epigenetic mechanisms and DNA hypermethylation. Exposure to BPA during prenatal, perinatal, and adult either through oral route or subcutaneous injections cause developmental abnormalities such as genitourinary anomalies, decreased epididymal weight, daily sperm production, or increased prostate weight [52-54]. Prenatal exposures to BPA increase the size of the preputial glands, reduce the size of the epididymides, and decrease the efficiency of sperm production in mice [54]. Perinatal exposure also causes infertility, daily sperm production and count reduction, and motility [55, 56]. Exposure to BPA prevents the action of anti-Müllerian hormone on Müllerian ducts of the developing fetus [57], leading to cause the failure of testicular descending [58]. The activities of steroidogenic enzymes such as 3β- and 17β-hydroxysteroid dehydrogenase decrease following BPA exposure, in both rat and human testicular microsomes, together with inhibition of 17α-hydroxylase/17, 20-lyase [59]. BPA induces Sertoli cell apoptosis [60] via induction of caspase-3 [61]. Sertoli cell plays a pivotal role in spermatogenesis under the influence of FSH; therefore, modulation of the Sertoli cells by BPA directly or indirectly via inhibition of FSH synthesis [46] may impair reproductive function in exposed males. Occupational exposure to high levels of BPA causes sexual dysfunction, characterized by reduced sexual desire and more significant erectile and ejaculatory difficulties [62]. A cross-sectional pilot study [63] has shown that workers exposed to BPA show altered sperm density and have a negative correlation between BPA concentration in blood and the percentage of normal sperm, suggesting the negative influence of BPA on semen quality. Male partners of subfertile couples seeking treatment from the Vincent Andrology Lab at Massachusetts General Hospital have shown a correlation between BPA exposure, increased DNA damage in spermatozoa, and reduced semen quality [47].

2.2. Phthalates

Phthalates are used as plasticizers, and are present in hundreds of products, including vinyl flooring, lubricating oil, and personal care products. Due to endocrine-disrupting properties, phthalates are well-known to cause reproductive and developmental abnormalities [64]. They exert their anti-androgenic action by hindering testosterone synthesis in Leydig cells, resulting from cytochrome CYP17 dysfunction [65]. Exposure to di (n-butyl) phthalate alters gene expression patterns that regulate cholesterol and lipid homeostasis or insulin signaling, which is responsible for lower testosterone synthesis in fetal rat testis (Barlow et al., 2003). In a rodent study, prenatal exposure to phthalates induces specific developmental and reproductive abnormalities such as hypospadias, undescended testes, malformations of the epididymis, vas deferens, seminal vesicles, and prostate, reduced sperm counts and testicular cancer that have been identified as a ‘testicular dysgenesis syndrome’ or ‘phthalate syndrome’ [65, 66]. Dibutyl phthalate administered during pregnancy and lactation shows the reduced anogenital distance in male rodents [67]. Oral administration of di-(2-ethylhexyl) phthalate in pre-pubertal rats has been shown to increase testicular apoptosis and loss of seminiferous epithelium [34]. There is a strong correlation between anogenital distance and maternal urinary concentrations of phthalate metabolites, and prenatal exposure to phthalates has been shown to alter the anogenital distance in boys [67]. However, a Danish cohort (2010-2012) study has shown that there are no consistent associations between any prenatal phthalate exposure to anogenital distance or penile width in the infant [68]. A prospective Danish-Finnish cohort study on cryptorchidism from 1997 to 2001 has shown that the reproductive hormone profiles and phthalate exposures in newborn boys are in accordance with rodent data and suggests that the development of human Leydig cells and their function may also be susceptible to perinatal exposure to some phthalates [17]. Exposure to phthalates decreases male fertility [38], a short-term in vitro incubation of spermatozoa with the phthalates has been shown to decrease sperm motility, while extended incubation of 96 hr, causes sperm cytotoxicity [7]. An inverse association has been reported between increasing concentration of urinary mono (2-Ethylhexyl) phthalate (MEHP) and circulating levels of testosterone, estradiol, and free androgen index [69]. In the body, phthalates are rapidly hydrolyzed by the enzyme esterase in the gut and other tissues into monoesters, the active molecules. For example, DEHP metabolizes to its monoester metabolite, mono-(2-Ethylhexyl) phthalate (MEHP), and DBP is converted into mono-butyl phthalate, with a high concentration of phthalates reducing motility, whereas it is cytotoxic in long-term cultures [7]. DBP could repress steroidogenesis in testes of mice and rats; no effects have been displayed in human xenografts for a range of DBP concentrations [70, 71] shows significant individual variations. The concentration of phthalates in biological fluids in human phthalate exposure has also been positively correlated with reactive oxygen species (ROS) production and increased DNA sperm damage [72]. A few epidemiological studies examined the detection of phthalate metabolites and their association with human testicular function [73], and have shown that there is a weak correlation between urinary metabolites of phthalate and lower sperm concentration, motility, and morphology [73]. However, sperm DNA damage increases in accordance with the urinary levels of phthalate monoester and oxidative metabolites [74]. In utero exposure to phthalates has been shown to induce ‘testicular dysgenesis syndrome’ [75-77] and abnormal aggregation of the fetal Leydig cells [78], an occurrence of intratubular Leydig cells, a reduction of fetal testosterone production [75, 79] and Leydig cell Insl3 gene expression [80]. Furthermore, in utero exposure to phthalates induces increased Sertoli cell proliferation by altering the ubiquitination pathway [81]. In vitro exposure to metabolites of phthalates, MEHP significantly inhibits the proliferation and differentiation of stem Leydig cells [82]. Increased concentrations of phthalates and their metabolites alter sperm concentration, motility, and morphology by various mechanisms; however, further studies are warranted to correlate exposure to phthalates and male reproductive health.

2.3. Alkylphenols (AP)

Alkylphenols (AP) are present in our environment in the form of isomers, and it becomes challenging when identifying and quantifying each isomer. The consequences of endocrine disruption by AP have been studied substantially in laboratory rodents by subjecting them to 4-n-nonylphenol (NP) for up to the third generation [112]. Sub-acute exposure of juvenile rats to NP causes testicular damage and depletion in spermatogenesis [113], and a notable increase in the rate of Sertoli cell apoptosis has also been observed in vitro studies with NP [114]. Several isomers of NP have also hindered testosterone biosynthesis by inhibiting testicular steroidogenesis in rats [115]. Gestational Exposure to NP has been shown to alter the epididymal weight [116].

2.4. Persistent Organochlorine Pollutants (POPs)

POPs are a large group of chemicals that include polychlorinated biphenyls (PCB), polychlorinated dibenzofurans (PCDFs), and polychlorinated dibenzo-dioxins (PCDDs), and the pesticide dichlorodiphenyltrichloroethane (DDT). PCBs are very stable mixtures of organochlorine chemicals that are resistant to extreme temperature and pressure; therefore, they are used widely in electrical equipment like capacitors and transformers as well as in hydraulic fluids, heat transfer fluids, lubricants, and plasticizers. Upon Exposure, PCBs are generally metabolized to phenols along with the formation of intermediates such as arene oxide via the P450 microsomal monooxygenase system. Due to its electrophilic nature, arene oxide covalently binds to nucleophilic cellular macromolecules such as DNA, RNA, and proteins and induces DNA strand breaks. Most of the toxic effects caused by PCDDs and PCDFs are mediated by the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor. Dioxins are a class of chemicals (polychlorinated dibenzo-p-dioxins) formed as by-products of incomplete combustion of chlorinated waste and in contact with plastics with hot surfaces. TCDD is structurally similar to polychlorinated aromatic hydrocarbons that act through the Ah receptor mechanism [117, 118]. After binding with the cytosolic receptor, the dioxin-receptor complex undergoes dimerization with the AHR nuclear translocator protein.

Consequently, this complex binds to dioxin response elements (DREs) on DNA, resulting in the induction of target genes such as CYP1A1 transcription [119]. Apart from inducing general toxicity, TCDD is well known to cause reproductive toxicity [90]. Following maternal exposure, the fetal pituitary gonadotrophin is the initial target of dioxins and indirectly impacts testicular steroidogenesis [120]. Interestingly, exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in infancy has been shown to reduce sperm concentration and motility, but an opposite effect has been reported during puberty [121]. NIOSH cohort studies have shown that workers exposed to high concentrations of TCDD result in decreased testosterone and increased gonadotrophin concentrations [122], suggesting that persistent organochlorine pollutants negatively impact male reproductive health.

2.5. Perfluorinated Compounds (PFCs)

Perfluorinated compounds (PFCs), such as perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), are synthetic chemical substances with endocrine-disrupting properties. These substances are widely used as lubricants and surfactants in the industry and products like clothes, household utensils, and food wrapping. PFC has long half-lives, ranging from 3.5 to 7.3 years [123], and has been shown to bioaccumulate in animal tissues [124]. Epidemiological studies have confirmed the effects of PFCs exposure on testicular function [125]. High PFOS and PFOA serum levels have been shown to lower sperm concentration and also, in utero exposure of men to PFOA led to lower sperm numbers and higher levels of LH and FSH. PFCs also cause Leydig cell hyperplasia [126] and inhibits spermatogenesis in rats following pubertal exposure [127].

2.6. Pesticides

Despite its benefits in controlling agricultural pests, pesticide persists in soils and water bodies, moves up to the trophic chains, and affects predators. Several reproductive disorders have been connected to pesticide exposure, and more than one hundred of them have been listed as reproductive toxicants. Pesticides may act as endocrine disruptors by various mechanisms, including agonist receptors such as estrogen receptor, androgen receptor, estrogen-related receptor, pregnane X receptor, aryl-hydrocarbon receptor, and antagonist receptor by interfering with the synthesis, transport, metabolism, and excretion of natural hormones. The negative effect of pesticides includes abnormalities in reproductive and sexual development, gametogenesis, and early development of the fetus. Dichlorodiphenyltrichloroethane (DDT), a persistent organochlorine compound, was heavily used in the 1940s as a broad-spectrum insecticide. It was banned in the 1970s due to its estrogenic properties that have been shown to interfere with pubertal development [128]. Similar to DDT, organochlorine insecticides such as endosulfan and lindane have altered the testicular function in animal models [129-135]. Methoxychlor, an organochlorine pesticide introduced as an alternative to DDT, was also banned in the United States due to its endocrine-disrupting properties. It was detected in human adipose tissue and has impaired male reproduction [96, 97, 136]. We have also shown that methoxychlor induces apoptosis via mitochondria-and FasL medicated pathways in adult rat testis [137].

2.7. Phytoestrogens

Phytoestrogens are plant-derived substances possessing endocrine-disrupting effects; due to their consumption of foods and food products, it has been widely detected in human urine and blood samples across several countries [138, 139]. Perinatal exposure of rats to a dietarily relevant mixture of phytoestrogens has been shown to lower sperm quality by disrupting the hypothalamic-pituitary-gonadal axis and hormonal balance [140]. A higher soy food intake and isoflavone are associated with lower sperm concentration [141]. A case-control study has shown higher risks of male infertility following increasing exposure to phytoestrogens such as daidzein, genistein, and secoisolariciresinol [142]. Genistein is another well-studied phytoestrogen that acts as a tyrosine kinase inhibitor [143] and an antioxidant [144]. Phytoestrogen exposure interferes with the androgen receptor pathway and affects spermatogenesis's late steps [145]. In utero and neonatal exposure to genistein shows delayed spermatogenesis and a reduced number of epididymal sperm [146]. Since phytoestrogens are nonsteroidal compounds that mimic estrogen and act via estrogen receptors, once bound, they not only act as estrogen agonists but also behave as selective estrogen receptor modulators. Exposure to phytoestrogens shows detrimental effects on male reproductive health [104].

2.8. Cigarette Smoke and Endocrine Disruptors

Cigarette smoke contains numerous endocrine-disrupting chemicals that are noxious and toxic to the human body. Several studies have shown that exposure to nicotine decreases sperm motility and count and increases the percentage of sperm abnormality [147, 148] as well as decreases testosterone levels in rats [149-151]. Constituents in cigarette smoke such as benzo (a) pyrene and cadmium (Cd) are some of the well-known endocrine disruptors shown to alter male reproductive health. Smoking habits significantly correlate with Cd level in bodily fluids [152]. Further studies with an animal also confirm that Cd causes reproductive toxicity, including reducing sperm cell numbers and sperm motility with increases in DNA fragmentation and sperm abnormality [153]. Cd also interferes with steroidogenesis and may act as an estrogen-like factor by binding to ER. Benzo(a)pyrene alters sperm functional competence, evidenced by a reduced percentage of acrosome halo formation and sperm hyperactivation [154]. Prepubertal exposure to Benzo(a)pyrene alters the male reproductive parameters [155]. Even though the relationship between tobacco smoking and semen quality has remained controversial for the past several decades, most studies have reported significant changes in the conventional semen parameters, including semen volume, sperm density, motility, viability, and normal morphology in the smoking population and suggesting that smoking harms the male reproductive health [155, 156].


Exposure to endocrine-disrupting chemicals may lead to adverse health effects at different stages of life-based on the time and duration of exposure. The role of endocrine disruptors as genotoxic/ epigenotoxic agents raises the issue of epigenome altering that may influence the health of the actual and future population. The influence of EDCs on reproduction, development, growth, metabolic rate, and gender behavior converts into present health hazards. Also, a change in dietary intake is responsible for increasing consequences. Furthermore, there is an increasing amount of research to describe that male children are more likely to develop reproductive disorders in response to neonatal and especially prenatal exposure; such exposures are even more likely to occur now with the increasing Exposure to EDCs from general consumers goods. Reproductive health is decreasing, as evidenced by the increased number of infertility cases that correlate with environmental exposure to endocrine-disrupting chemicals and lifestyle changes. Several in vivo studies for a few decades with rats and mice strongly support exposure to chemicals having endocrine-disrupting chemicals adversely affecting both male and female reproductive systems and fertility. However, no direct study correlates human exposure to endocrine disruptors and reproductive health, but based on animal studies, these chemicals can pose a significant threat to human reproduction. Several endocrine disruptors have been found in the bodily fluid of humans, suggesting that further studies are needed to elucidate their reproductive and non-reproductive effects. Even though, many known endocrine-disrupting chemicals present in our environment, either alone or in combination, pose a great threat to organisms. Apart from known environmental contaminants having endocrine-disrupting properties, several unknown chemicals are also present in our environment, and their effect needs to be studied in the future to understand their effect on reproductive and non-reproductive health.


ED = Endocrine Disruptor
BPA = Bisphenol A
DDT = Dichlorodiphenyltrichloroethane
FSH = Follicle Stimulating Hormone
LH = Leutinizing Hormone
ER = Estrogen Receptor
EDC = Endocrine Disrupting Chemical


Not applicable.


CL greatly acknowledges the Science and Engineering Board, University Grants Commission and the Indian Council of Medical Research for the financial support in the form of Grants.


The authors declare no conflict of interest, financial or otherwise.


Declared none.


[1] La Merrill MA, Vandenberg LN, Smith MT, et al. Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification. Nat Rev Endocrinol 2020; 16(1): 45-57.
[2] Colborn T, vom Saal FS, Soto AM. Developmental effects of endocrine-disrupting chemicals in wildlife and humans. Environ Health Perspect 1993; 101(5): 378-84.
[3] Mackenzie CA, Lockridge A, Keith M. Declining sex ratio in a first nation community. Environ Health Perspect 2005; 113(10): 1295-8.
[4] Stukenborg JB, Mitchell RT, Söder O. Endocrine disruptors and the male reproductive system. Best Pract Res Clin Endocrinol Metab 2021; 35(5): 101567.
[5] Bonde JP, te Velde E. Declining sperm counts — the never-ending story. Nat Rev Urol 2017; 14(11): 645-6.
[6] Weidner IS, Møller H, Jensen TK, Skakkebaek NE. Cryptorchidism and hypospadias in sons of gardeners and farmers. Environ Health Perspect 1998; 106(12): 793-6.
[7] Pant N, Pant AB, Shukla M, Mathur N, Gupta YK, Saxena DK. Environmental and experimental exposure of phthalate esters: The toxicological consequence on human sperm. Hum Exp Toxicol 2011; 30(6): 507-14.
[8] Knapke ET, Magalhaes DP, Dalvie MA, Mandrioli D, Perry MJ. Environmental and occupational pesticide exposure and human sperm parameters: A Navigation Guide review. Toxicology 2022; 465: 153017.
[9] Rudel RA, Perovich LJ. Endocrine disrupting chemicals in indoor and outdoor air. Atmos Environ 2009; 43(1): 170-81.
[10] Zhou C, Gao L, Flaws JA. Exposure to an environmentally relevant phthalate mixture causes transgenerational effects on female reproduction in mice. Endocrinology 2017; 158(6): 1739-54.
[11] Manikkam M, Guerrero-Bosagna C, Tracey R, Haque MM, Skinner MK. Transgenerational actions of environmental compounds on reproductive disease and identification of epigenetic biomarkers of ancestral exposures. PLoS One 2012; 7(2): e31901.
[12] Anwer H, Morris MJ, Noble DWA, Nakagawa S, Lagisz M. Transgenerational effects of obesogenic diets in rodents: A meta-analysis. Obes Rev 2022; 23(1): e13342.
[13] Soares A, Guieysse B, Jefferson B, Cartmell E, Lester JN. Nonylphenol in the environment: A critical review on occurrence, fate, toxicity and treatment in wastewaters. Environ Int 2008; 34(7): 1033-49.
[14] Calafat AM, Kuklenyik Z, Reidy JA, Caudill SP, Ekong J, Needham LL. Urinary concentrations of bisphenol A and 4-nonylphenol in a human reference population. Environ Health Perspect 2005; 113(4): 391-5.
[15] Guenther K, Heinke V, Thiele B, Kleist E, Prast H, Raecker T. Endocrine disrupting nonylphenols are ubiquitous in food. Environ Sci Technol 2002; 36(8): 1676-80.
[16] Huang P, Kuo P, Chou Y, Lin S, Lee C. Association between prenatal exposure to phthalates and the health of newborns. Environ Int 2009; 35(1): 14-20.
[17] Main KM, Mortensen GK, Kaleva MM, et al. Human breast milk contamination with phthalates and alterations of endogenous reproductive hormones in infants three months of age. Environ Health Perspect 2006; 114(2): 270-6.
[18] Genuis SJ, Beesoon S, Birkholz D, Lobo RA. Human excretion of bisphenol A: blood, urine, and sweat (BUS) study. J Environ Public Health 2012; 2012: 1-10.
[19] Faure AC, Viel JF, Bailly A, Blagosklonov O, Amiot C, Roux C. Evolution of sperm quality in men living in the vicinity of a municipal solid waste incinerator possibly correlated with decreasing dioxins emission levels. Andrologia 2014; 46(7): 744-52.
[20] Mai X, Dong Y, Xiang L, Er Z. Maternal exposure to 2,3,7,8-tetrachlorodibenzo -p -dioxin suppresses male reproductive functions in their adulthood. Hum Exp Toxicol 2020; 39(7): 890-905.
[21] Jurewicz J, Hanke W, Radwan M, Bonde J. Environmental factors and semen quality. Int J Occup Med Environ Health 2009; 22(4): 305-29.
[22] Petersen M, Halling J, Jørgensen N, et al. Reproductive function in a population of young faroese men with elevated exposure to Polychlorinated Biphenyls (PCBs) and perfluorinated alkylate substances (PFAS). Int J Environ Res Public Health 2018; 15(9): 1880.
[23] Aneck-Hahn NH, Schulenburg GW, Bornman MS, Farias P, De Jager C. Impaired semen quality associated with environmental DDT exposure in young men living in a malaria area in the Limpopo Province, South Africa. J Androl 2006; 28(3): 423-34.
[24] Sadler-Riggleman I, Klukovich R, Nilsson E, et al. Epigenetic transgenerational inheritance of testis pathology and Sertoli cell epimutations: generational origins of male infertility. Environ Epigenet 2019; 5(3): dvz013.
[25] Recio-Vega R, Ocampo-Gómez G, Borja-Aburto VH, Moran-Martínez J, Cebrian-Garcia ME. Organophosphorus pesticide exposure decreases sperm quality: Association between sperm parameters and urinary pesticide levels. J Appl Toxicol 2008; 28(5): 674-80.
[26] Giulioni C, Maurizi V, Scarcella S, et al. Do environmental and occupational exposure to pyrethroids and organophosphates affect human semen parameters? Results of a systematic review and meta-analysis. Andrologia 2021; 53(11): e14215.
[27] Istvan M, Rahban R, Dananche B, et al. Maternal occupational exposure to endocrine-disrupting chemicals during pregnancy and semen parameters in adulthood: Results of a nationwide cross-sectional study among Swiss conscripts. Hum Reprod 2021; 36(7): 1948-58.
[28] Akingbemi BT, Ge R, Klinefelter GR, Zirkin BR, Hardy MP. Phthalate-induced Leydig cell hyperplasia is associated with multiple endocrine disturbances. Proc Natl Acad Sci USA 2004; 101(3): 775-80.
[29] Maradonna F, Carnevali O. Lipid metabolism alteration by endocrine disruptors in animal models: An overview. Front Endocrinol (Lausanne) 2018; 9: 654.
[30] Gunnarsson D, Leffler P, Ekwurtzel E, Martinsson G, Liu K, Selstam G. Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes. Reproduction 2008; 135(5): 693-703.
[31] Zhao Y, Ao H, Chen L, et al. Mono-(2-ethylhexyl) phthalate affects the steroidogenesis in rat Leydig cells through provoking ROS perturbation. Toxicology in vitro An international journal published in association with BIBRA 2012; 26(6): 950-5.
[32] Enangue Njembele AN, Tremblay JJ. Mechanisms of MEHP Inhibitory Action and Analysis of Potential Replacement Plasticizers on Leydig Cell Steroidogenesis. Int J Mol Sci 2021; 22(21): 11456.
[33] Yao PL, Lin YC, Richburg JH. Mono-(2-ethylhexyl) phthalate-induced disruption of junctional complexes in the seminiferous epithelium of the rodent testis is mediated by MMP2. Biol Reprod 2010; 82(3): 516-27.
[34] Park JD, Habeebu SSM, Klaassen CD. Testicular toxicity of di-(2-ethylhexyl)phthalate in young Sprague–Dawley rats. Toxicology 2002; 171(2-3): 105-15.
[35] Chiba K, Kondo Y, Yamaguchi K, Miyake H, Fujisawa M. Inhibition of claudin-11 and occludin expression in rat Sertoli cells by mono-(2-ethylhexyl) phthalate through p44/42 mitogen-activated protein kinase pathway. J Androl 2012; 33(3): 368-74.
[36] Fisher JS. Environmental anti-androgens and male reproductive health: focus on phthalates and testicular dysgenesis syndrome. Reproduction 2004; 127(3): 305-15.
[37] Sharpe RM. Environmental/lifestyle effects on spermatogenesis. Philos Trans R Soc Lond B Biol Sci 2010; 365(1546): 1697-712.
[38] Latini G, Del Vecchio A, Massaro M, Verrotti A, De Felice C. Phthalate exposure and male infertility. Toxicology 2006; 226(2-3): 90-8.
[39] Bollati V, Baccarelli A. Environmental epigenetics. Heredity 2010; 105(1): 105-12.
[40] Singh S, Li SSL. Epigenetic effects of environmental chemicals bisphenol A and phthalates. Int J Mol Sci 2012; 13(8): 10143-53.
[41] Toppari J, Larsen JC, Christiansen P, et al. Male reproductive health and environmental xenoestrogens. Environ Health Perspect 1996; 104(Suppl. 4): 741-803.
[42] Demierre AL, Peter R, Oberli A, Bourqui-Pittet M. Dermal penetration of bisphenol A in human skin contributes marginally to total exposure. Toxicol Lett 2012; 213(3): 305-8.
[43] Acconcia F, Pallottini V, Marino M. Molecular Mechanisms of Action of BPA. Dose Response 2015; 13(4)
[44] Cimmino I, Fiory F, Perruolo G, et al. Potential Mechanisms of Bisphenol A (BPA) Contributing to Human Disease. Int J Mol Sci 2020; 21(16): 5761.
[45] Chitra K, Latchoumycandane C, Mathur PP. Induction of oxidative stress by bisphenol A in the epididymal sperm of rats. Toxicology 2003; 185(1-2): 119-27.
[46] Hanaoka T, Kawamura N, Hara K, Tsugane S. Urinary bisphenol A and plasma hormone concentrations in male workers exposed to bisphenol A diglycidyl ether and mixed organic solvents. Occup Environ Med 2002; 59(9): 625-8.
[47] Meeker JD, Ehrlich S, Toth TL, et al. Semen quality and sperm DNA damage in relation to urinary bisphenol A among men from an infertility clinic. Reprod Toxicol 2010; 30(4): 532-9.
[48] Welshons WV, Thayer KA, Judy BM, Taylor JA, Curran EM, vom Saal FS. Large effects from small exposures. I. Mechanisms for endocrine-disrupting chemicals with estrogenic activity. Environ Health Perspect 2003; 111(8): 994-1006.
[49] Fiorini C, Tilloy-Ellul A, Chevalier S, Charuel C, Pointis G. Sertoli cell junctional proteins as early targets for different classes of reproductive toxicants. Reprod Toxicol 2004; 18(3): 413-21.
[50] Li YJ, Song TB, Cai YY, Zhou JS, Song X, Zhao X, et al. (2009) Bisphenol A exposure induces apoptosis and upregulation of Fas/FasL and caspase-3 expression in the testes of mice. Toxicol sci 2009; 108(2): 427-36.
[51] Salian S, Doshi T, Vanage G. Neonatal exposure of male rats to Bisphenol A impairs fertility and expression of sertoli cell junctional proteins in the testis. Toxicology 2009; 265(1-2): 56-67.
[52] Richter CA, Birnbaum LS, Farabollini F, et al. In vivo effects of bisphenol A in laboratory rodent studies. Reprod Toxicol 2007; 24(2): 199-224.
[53] Rahman MS, Pang WK, Ryu DY, Park YJ, Pang MG. Multigenerational and transgenerational impact of paternal bisphenol A exposure on male fertility in a mouse model. Hum Reprod 2020; 35(8): 1740-52.
[54] Vom Saal FS, Cooke PS, Buchanan DL, et al. A physiologically based approach to the study of bisphenol A and other estrogenic chemicals on the size of reproductive organs, daily sperm production, and behavior. Toxicol Ind Health 1998; 14(1-2): 239-60.
[55] Salian S, Doshi T, Vanage G. Perinatal exposure of rats to Bisphenol A affects the fertility of male offspring. Life Sci 2009; 85(21-22): 742-52.
[56] Salian S, Doshi T, Vanage G. Perinatal exposure of rats to Bisphenol A affects fertility of male offspring—An overview. Reprod Toxicol 2011; 31(3): 359-62.
[57] Pryor JL, Hughes C, Foster W, Hales BF, Robaire B. Critical windows of exposure for children’s health: the reproductive system in animals and humans. Environ Health Perspect 2000; 108(Suppl. 3): 491-503.
[58] Hutson JM, Baker M, Terada M, Zhou B, Paxton G. Hormonal control of testicular descent and the cause of cryptorchidism. Reprod Fertil Dev 1994; 6(2): 151-6.
[59] Ye L, Zhao B, Hu G, Chu Y, Ge RS. Inhibition of human and rat testicular steroidogenic enzyme activities by bisphenol A. Toxicol Lett 2011; 207(2): 137-42.
[60] Iida H, Maehara K, Doiguchi M, Mōri T, Yamada F. Bisphenol A-induced apoptosis of cultured rat Sertoli cells. Reprod Toxicol 2003; 17(4): 457-64.
[61] Mørck TJ, Sorda G, Bechi N, et al. Placental transport and in vitro effects of Bisphenol A. Reprod Toxicol 2010; 30(1): 131-7.
[62] Li D, Zhou Z, Qing D, et al. Occupational exposure to bisphenol-A (BPA) and the risk of Self-Reported Male Sexual Dysfunction. Hum Reprod 2010; 25(2): 519-27.
[63] Xiao GB, Wang RY, Cai YZ, He GH, Zhou ZJ. Effect of bisphenol A on semen quality of exposed workers: A pilot study. j indust hyg occup dis 2009; 27(12): 741-3.
[64] Grady R, Sathyanarayana S. An update on phthalates and male reproductive development and function. Curr Urol Rep 2012; 13(4): 307-10.
[65] Foster PMD. Disruption of reproductive development in male rat offspring following in utero exposure to phthalate esters. Int J Androl 2006; 29(1): 140-7.
[66] Welsh M, Saunders PTK, Fisken M, et al. Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest 2008; 118(4): 1479-90.
[67] Swan SH, Main KM, Liu F, et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect 2005; 113(8): 1056-61.
[68] Jensen TK, Frederiksen H, Kyhl HB, et al. Prenatal exposure to phthalates and anogenital distance in male infants from a low-exposed danish cohort (2010–2012). Environ Health Perspect 2016; 124(7): 1107-13.
[69] Meeker JD, Calafat AM, Hauser R. Urinary metabolites of di(2-ethylhexyl) phthalate are associated with decreased steroid hormone levels in adult men. J Androl 2009; 30(3): 287-97.
[70] Heger NE, Hall SJ, Sandrof MA, et al. Human fetal testis xenografts are resistant to phthalate-induced endocrine disruption. Environ Health Perspect 2012; 120(8): 1137-43.
[71] Mitchell RT, Childs AJ, Anderson RA, et al. Do phthalates affect steroidogenesis by the human fetal testis? Exposure of human fetal testis xenografts to di-n-butyl phthalate. J Clin Endocrinol Metab 2012; 97(3): E341-8.
[72] Khasin LG, Della Rosa J, Petersen N, Moeller J, Kriegsfeld LJ, Lishko PV. The impact of Di-2-Ethylhexyl phthalate on sperm fertility. Front Cell Dev Biol 2020; 8: 426.
[73] Hauser R, Meeker JD, Duty S, Silva MJ, Calafat AM. Altered semen quality in relation to urinary concentrations of phthalate monoester and oxidative metabolites. Epidemiology 2006; 17(6): 682-91.
[74] Hauser R, Meeker JD, Singh NP, et al. DNA damage in human sperm is related to urinary levels of phthalate monoester and oxidative metabolites. Hum Reprod 2007; 22(3): 688-95.
[75] Fisher JS, Macpherson S, Marchetti N, Sharpe RM. Human ‘testicular dysgenesis syndrome’: a possible model using in-utero exposure of the rat to dibutyl phthalate. Hum Reprod 2003; 18(7): 1383-94.
[76] Ema M, Miyawaki E, Kawashima K. Further evaluation of developmental toxicity of di-n-butyl phthalate following administration during late pregnancy in rats. Toxicol Lett 1998; 98(1-2): 87-93.
[77] Barlow NJ, Foster PM. Pathogenesis of male reproductive tract lesions from gestation through adulthood following in utero exposure to Di(n-butyl) phthalate. Toxicol Pathol 2003; 31(4): 397-410.
[78] Mahood IK, Hallmark N, McKinnell C, Walker M, Fisher JS, Sharpe RM. Abnormal Leydig Cell aggregation in the fetal testis of rats exposed to di (n-butyl) phthalate and its possible role in testicular dysgenesis. Endocrinology 2005; 146(2): 613-23.
[79] Parks LG, Ostby JS, Lambright CR, et al. The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male rat. Toxicol sci 2000; 58(2): 339-49.
[80] Wilson VS, Lambright C, Furr J, et al. Phthalate ester-induced gubernacular lesions are associated with reduced insl3 gene expression in the fetal rat testis. Toxicol Lett 2004; 146(3): 207-15.
[81] Ma T, Hou J, Zhou Y, Chen Y, Qiu J, Wu J, et al. (2020) Dibutyl phthalate promotes juvenile Sertoli cell proliferation by decreasing the levels of the E3 ubiquitin ligase Pellino 2. Environmental health: a global access science source 19 (1): 87.
[82] Hao X, Guan X, Zhao X, et al. Phthalate inhibits Leydig cell differentiation and promotes adipocyte differentiation. Chemosphere 2021; 262: 127855.
[83] Dobrzyńska MM, Radzikowska J. Genotoxicity and reproductive toxicity of bisphenol A and X-ray/bisphenol A combination in male mice. Drug Chem Toxicol 2013; 36(1): 19-26.
[84] Tiwari D, Vanage G. Mutagenic effect of Bisphenol A on adult rat male germ cells and their fertility. Reprod Toxicol 2013; 40: 60-8.
[85] Liu C, Duan W, Li R, et al. Exposure to bisphenol A disrupts meiotic progression during spermatogenesis in adult rats through estrogen-like activity. Cell Death Dis 2013; 4(6): e676.
[86] Liu X, Wang Z, Liu F. Chronic exposure of BPA impairs male germ cell proliferation and induces lower sperm quality in male mice. Chemosphere 2021; 262: 127880.
[87] Wang YX, You L, Zeng Q, et al. Phthalate exposure and human semen quality: Results from an infertility clinic in China. Environ Res 2015; 142: 1-9.
[88] Conley JM, Lambright CS, Evans N, et al. A mixture of 15 phthalates and pesticides below individual chemical no observed adverse effect levels (NOAELs) produces reproductive tract malformations in the male rat. Environ Int 2021; 156: 106615.
[89] Yi WEI, Xiang-Liang T, Yu Z, et al. DEHP exposure destroys blood-testis barrier (BTB) integrity of immature testes through excessive ROS-mediated autophagy. Genes Dis 2018; 5(3): 263-74.
[90] Latchoumycandane C, Chitra KC, Mathur PP. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces oxidative stress in the epididymis and epididymal sperm of adult rats. Arch Toxicol 2003; 77(5): 280-4.
[91] Bjerke DL, Peterson RE. Reproductive toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in male rats: different effects of in utero versus lactational exposure. Toxicol Appl Pharmacol 1994; 127(2): 241-9.
[92] Johnson KJ, Passage J, Lin H, Sriram S, Budinsky RA. Dioxin male rat reproductive toxicity mode of action and relative potency of 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,3,7,8-tetrachlorodibenzofuran characterized by fetal pituitary and testis transcriptome profiling. Reprod Toxicol 2020; 93: 146-62.
[93] Jin M, Lou J, Yu H, et al. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin promotes inflammation in mouse testes: The critical role of Klotho in Sertoli cells. Toxicol Lett 2018; 295: 134-43.
[94] Dou L, Mou F, Li J, Wang S. The endocrine disruptor hexachlorobenzene can cause oxidative damage in the testis of mice. Andrologia 2021; 53(10): e14195.
[95] Wu K, Li Y, Pan P, et al. Gestational vinclozolin exposure suppresses fetal testis development in rats. Ecotoxicol Environ Saf 2020; 203: 111053.
[96] Latchoumycandane C, Chitra KC, Mathur PP. The effect of methoxychlor on the epididymal antioxidant system of adult rats. Reprod Toxicol 2002; 16(2): 161-72.
[97] Latchoumycandane C, Mathur P. Induction of oxidative stress in the rat testis after short-term exposure to the organochlorine pesticide methoxychlor. Arch Toxicol 2002; 76(12): 692-8.
[98] Jurewicz J, Radwan M, Wielgomas B, et al. Environmental levels of triclosan and male fertility. Environ Sci Pollut Res Int 2018; 25(6): 5484-90.
[99] Nassan FL, Mínguez-Alarcón L, Williams PL, et al. Urinary triclosan concentrations and semen quality among men from a fertility clinic. Environ Res 2019; 177: 108633.
[100] Kumar S, Sharma A. Cadmium toxicity: effects on human reproduction and fertility. Rev Environ Health 2019; 34(4): 327-38.
[101] Wu HM, Lin-Tan DT, Wang ML, et al. Lead level in seminal plasma may affect semen quality for men without occupational exposure to lead. Reprod Biol Endocrinol 2012; 10(1): 91.
[102] Bhardwaj JK, Paliwal A, Saraf P. Effects of heavy metals on reproduction owing to infertility. J Biochem Mol Toxicol 2021; 35(8): e22823.
[103] Chinyere Nsonwu-Anyanwu A, Raymond Ekong E, Jeremiah Offor S, et al. Heavy metals, biomarkers of oxidative stress and changes in sperm function: A case-control study. Int J Reprod Biomed (Yazd) 2019; 17(3): ijrm.v17i3.4515.
[104] Cederroth CR, Zimmermann C, Beny JL, et al. Potential detrimental effects of a phytoestrogen-rich diet on male fertility in mice. Mol Cell Endocrinol 2010; 321(2): 152-60.
[105] Meena R, Supriya C, Pratap Reddy K, Sreenivasula Reddy P. (2017) Altered spermatogenesis, steroidogenesis and suppressed fertility in adult male rats exposed to genistein, a non-steroidal phytoestrogen during embryonic development. Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 99: 70-7.
[106] Yuan G, Liu Y, Liu G, et al. Associations between semen phytoestrogens concentrations and semen quality in Chinese men. Environ Int 2019; 129: 136-44.
[107] Cai J, Wang C, Wu T, et al. Disruption of spermatogenesis and differential regulation of testicular estrogen receptor expression in mice after polychlorinated biphenyl exposure. Toxicology 2011; 287(1-3): 21-8.
[108] Raychoudhury SS, Flowers AF, Millette CF, Finlay MF. Toxic effects of polychlorinated biphenyls on cultured rat Sertoli cells. J Androl 2000; 21(6): 964-73.
[109] Rignell-Hydbom A, Rylander L, Giwercman A, et al. Exposure to PCBs and p,p′-DDE and human sperm chromatin integrity. Environ Health Perspect 2005; 113(2): 175-9.
[110] Gong YI, Han XD. Effect of nonylphenol on steroidogenesis of rat Leydig cells. J Environ Sci Health B 2006; 41(5): 705-15.
[111] Duan P, Hu C, Butler HJ, et al. Effects of 4-nonylphenol on spermatogenesis and induction of testicular apoptosis through oxidative stress-related pathways. Reprod Toxicol 2016; 62: 27-38.
[112] Tyl RW, Myers CB, Marr MC, Castillo NP, Seely JC, Sloan CS, et al. (2006) Three-generation evaluation of dietary para-nonylphenol in CD (Sprague-Dawley) rats. Toxicol sci 2006; 92(1): 295-310.
[113] Tan BLL, Kassim NM, Mohd MA. Assessment of pubertal development in juvenile male rats after sub-acute exposure to bisphenol A and nonylphenol. Toxicol Lett 2003; 143(3): 261-70.
[114] Wang X, Han X, Hou Y, Yao G, Wang Y. Effect of nonylphenol on apoptosis of Sertoli cells in vitro. Bull Environ Contam Toxicol 2003; 70(5): 898-904.
[115] Laurenzana EM, Balasubramanian G, Weis C, Blaydes B, Newbold RR, Delclos KB. Effect of nonylphenol on serum testosterone levels and testicular steroidogenic enzyme activity in neonatal, pubertal, and adult rats. Chem Biol Interact 2002; 139(1): 23-41.
[116] Hossaini A, Dalgaard M, Vinggaard AM, Frandsen H, Larsen JJ. In utero reproductive study in rats exposed to nonylphenol. Reprod Toxicol 2001; 15(5): 537-43.
[117] Poland A, Knutson JC. 2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Annu Rev Pharmacol Toxicol 1982; 22(1): 517-54.
[118] Whitlock JP Jr. Mechanistic aspects of dioxin action. Chem Res Toxicol 1993; 6(6): 754-63.
[119] Watson AJ, Hankinson O. Dioxin- and Ah receptor-dependent protein binding to xenobiotic responsive elements and G-rich DNA studied by in vivo footprinting. J Biol Chem 1992; 267(10): 6874-8.
[120] Mutoh J, Taketoh J, Okamura K, et al. Fetal pituitary gonadotropin as an initial target of dioxin in its impairment of cholesterol transportation and steroidogenesis in rats. Endocrinology 2006; 147(2): 927-36.
[121] Mocarelli P, Gerthoux PM, Patterson DG Jr, et al. Dioxin exposure, from infancy through puberty, produces endocrine disruption and affects human semen quality. Environ Health Perspect 2008; 116(1): 70-7.
[122] Egeland GM, Sweeney MH, Fingerhut MA, Wille KK, Schnorr TM, Halperin WE. Total serum testosterone and gonadotropins in workers exposed to dioxin. Am J Epidemiol 1994; 139(3): 272-81.
[123] Olsen GW, Burris JM, Ehresman DJ, et al. Half-life of serum elimination of perfluorooctanesulfonate,perfluorohexanesulfonate, and perfluorooctanoate in retired fluorochemical production workers. Environ Health Perspect 2007; 115(9): 1298-305.
[124] Kelly BC, Ikonomou MG, Blair JD, Morin AE, Gobas FAPC. Food web-specific biomagnification of persistent organic pollutants. Science 2007; 317(5835): 236-9.
[125] Cui Q, Pan Y, Wang J, Liu H, Yao B, Dai J. Exposure to per- and polyfluoroalkyl substances (PFASs) in serum versus semen and their association with male reproductive hormones. Environ Pollut 2020; 266(Pt 2): 115330.
[126] Biegel LB, Liu RCM, Hurtt ME, Cook JC. Effects of ammonium perfluorooctanoate on Leydig cell function: in vitro, in vivo, and ex vivo studies. Toxicol Appl Pharmacol 1995; 134(1): 18-25.
[127] Li Z, Li C, Wen Z, et al. Perfluoroheptanoic acid induces Leydig cell hyperplasia but inhibits spermatogenesis in rats after pubertal exposure. Toxicology 2021; 448: 152633.
[128] Lam T, Williams PL, Lee MM, et al. Prepubertal organochlorine pesticide concentrations and age of pubertal onset among Russian boys. Environ Int 2014; 73: 135-42.
[129] Chitra KC, Latchoumycandane C, Mathur PP. Chronic effect of endosulfan on the testicular functions of rat. Asian J Androl 1999; 1(4): 203-6.
[130] Chitra KC, Sujatha R, Latchoumycandane C, Mathur PP. Effect of lindane on antioxidant enzymes in epididymis and epididymal sperm of adult rats. Asian J Androl 2001; 3(3): 205-8.
[131] Saradha B, Mathur PP. Induction of oxidative stress by lindane in epididymis of adult male rats. Environ Toxicol Pharmacol 2006; 22(1): 90-6.
[132] Saradha B, Vaithinathan S, Mathur PP. Single exposure to low dose of lindane causes transient decrease in testicular steroidogenesis in adult male Wistar rats. Toxicology 2008; 244(2-3): 190-7.
[133] Saradha B, Vaithinathan S, Mathur PP. Lindane alters the levels of HSP70 and clusterin in adult rat testis. Toxicology 2008; 243(1-2): 116-23.
[134] Saradha B, Vaithinathan S, Mathur PP. Lindane induces testicular apoptosis in adult Wistar rats through the involvement of Fas–FasL and mitochondria-dependent pathways. Toxicology 2009; 255(3): 131-9.
[135] Sujatha R, Chitra KC, Latchoumycandane C, Mathur PP. Effect of lindane on testicular antioxidant system and steroidogenic enzymes in adult rats. Asian J Androl 2001; 3(2): 135-8.
[136] Latchoumycandane C, Mathur PP. Effect of methoxychlor on the antioxidant system in mitochondrial and microsome-rich fractions of rat testis. Toxicology 2002; 176(1-2): 67-75.
[137] Vaithinathan S, Saradha B, Mathur PP. Methoxychlor induces apoptosis via mitochondria- and FasL-mediated pathways in adult rat testis. Chem Biol Interact 2010; 185(2): 110-8.
[138] Kunisue T, Tanabe S, Isobe T, Aldous KM, Kannan K. Profiles of phytoestrogens in human urine from several Asian countries. J Agric Food Chem 2010; 58(17): 9838-46.
[139] Valentín-Blasini L, Sadowski MA, Walden D, Caltabiano L, Needham LL, Barr DB. Urinary phytoestrogen concentrations in the U.S. population (1999–2000). J Expo Sci Environ Epidemiol 2005; 15(6): 509-23.
[140] Boberg J, Mandrup KR, Jacobsen PR, et al. Endocrine disrupting effects in rats perinatally exposed to a dietary relevant mixture of phytoestrogens. Reprod Toxicol 2013; 40: 41-51.
[141] Chavarro JE, Toth TL, Sadio SM, Hauser R. Soy food and isoflavone intake in relation to semen quality parameters among men from an infertility clinic. Hum Reprod 2008; 23(11): 2584-90.
[142] Xia Y, Chen M, Zhu P, et al. Urinary phytoestrogen levels related to idiopathic male infertility in Chinese men. Environ Int 2013; 59: 161-7.
[143] Akiyama T, Ishida J, Nakagawa S, et al. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 1987; 262(12): 5592-5.
[144] Vedavanam K, Srijayanta S, O’Reilly J, Raman A, Wiseman H. Antioxidant action and potential antidiabetic properties of an isoflavonoid-containing soyabean phytochemical extract (SPE). Phytother Res 1999; 13(7): 601-8.
[145] Cederroth CR, Auger J, Zimmermann C, Eustache F, Nef S. Soy, phyto-oestrogens and male reproductive function: a review. Int J Androl 2010; 33(2): 304-16.
[146] Delclos KB, Bucci TJ, Lomax LG, et al. Effects of dietary genistein exposure during development on male and female CD (Sprague-Dawley) rats. Reprod Toxicol 2001; 15(6): 647-63.
[147] Oyeyipo IP, Raji Y, Emikpe BO, Bolarinwa AF. Effects of nicotine on sperm characteristics and fertility profile in adult male rats: a possible role of cessation. J Reprod Infertil 2011; 12(3): 201-7.
[148] Ezzatabadipour M, Azizollahi S, Sarvazad A, Mirkahnooj Z, Mahdinia Z, Nematollahi-Mahani SN. Effects of concurrent chronic administration of alcohol and nicotine on rat sperm parameters. Andrologia 2012; 44(5): 330-6.
[149] Oyeyipo I, Raji Y, Bolarinwa A. Nicotine alters male reproductive hormones in male albino rats: The role of cessation. J Hum Reprod Sci 2013; 6(1): 40-4.
[150] Axelsson J, Lindh CH, Giwercman A. Exposure to polycyclic aromatic hydrocarbons and nicotine, and associations with sperm DNA fragmentation. Andrology 2022; 10(4): 740-8.
[151] Altıntaş A, Liu J, Fabre O, et al. Perinatal exposure to nicotine alters spermatozoal DNA methylation near genes controlling nicotine action. FASEB J 2021; 35(7): e21702.
[152] Mendiola J, Moreno JM, Roca M, Vergara-Juarez N, Martinez-Garcia MJ, Garcia-Sanchez A, et al. (2011) Relationships between heavy metal concentrations in three different body fluids and male reproductive parameters: A pilot study. Envir health 2011; 10(1): 6.
[153] Oliveira H, Spanò M, Santos C, Pereira ML. Adverse effects of cadmium exposure on mouse sperm. Reprod Toxicol 2009; 28(4): 550-5.
[154] Mukhopadhyay D, Nandi P, Varghese AC, Gutgutia R, Banerjee S, Bhattacharyya AK. The in vitro effect of benzo[a]pyrene on human sperm hyperactivation and acrosome reaction. Fertil Steril 2010; 94(2): 595-8.
[155] Jorge BC, Reis ACC, Sterde ÉT, et al. Exposure to benzo(a)pyrene from juvenile period to peripubertal impairs male reproductive parameters in adult rats. Chemosphere 2021; 263: 128016.
[156] Antoniassi MP, Intasqui P, Camargo M, et al. Analysis of the functional aspects and seminal plasma proteomic profile of sperm from smokers. BJU Int 2016; 118(5): 814-22.