Open access peer-reviewed chapter

The Role of Endocrine-Disrupting Chemicals in Male Fertility Decline

Written By

Magda Carvalho Henriques, Susana Loureiro, Margarida Fardilha and Maria Teresa Herdeiro

Submitted: 01 April 2019 Reviewed: 01 July 2019 Published: 13 December 2019

DOI: 10.5772/intechopen.88330

From the Edited Volume

Male Reproductive Health

Edited by Wei Wu, Francesco Ziglioli and Umberto Maestroni

Chapter metrics overview

1,007 Chapter Downloads

View Full Metrics

Abstract

Endocrine-disrupting chemicals (EDCs) are exogenous compounds with natural or anthropogenic origin omnipresent in the environment. These compounds disrupt endocrine function through interaction with hormone receptor or alteration of hormone synthesis. Humans are environmentally exposed to EDCs through the air, water, food and occupation. During the last decades, there has been a concern that exposure to EDCs may contribute to an impairment of human reproductive function. EDCs affect male fertility at multiple levels, from sperm production and quality to the morphology and histology of the male reproductive system. It has been proposed that exposure to EDCs may contribute to an impairment of sperm motility, concentration, volume and morphology and an increase in the sperm DNA damage. Moreover, EDCs exert reproductive toxicity inducing structural damage on the testis vasculature and blood-testis barrier and cytotoxicity on Sertoli and Leydig cells. This chapter will explore the effects of EDCs in male reproductive system and in the decline of male fertility.

Keywords

  • endocrine-disrupting chemicals
  • male infertility
  • lifestyle
  • environmental pollutants
  • body burden

1. Introduction

Endocrine-disrupting chemicals (EDCs) are exogenous substances or mixtures of chemicals that can disrupt male and female endocrine function through the interaction with hormone receptors. They lead to alterations in hormone action, synthesis, transport and metabolic processes [1]. Several compounds such as dioxins, plastic contaminants (e.g., bisphenols (BP)), triclosan (TCS), pesticides and herbicides (e.g., diphenyl-dichloro-trichloroethane (DDT)), metals and others are known EDCs [2].

Humans may be exposed to EDCs due to contamination of water and food chain, inhalation of contaminated house dust and through occupational exposure [2]. Although, in some westernized countries the use of certain EDCs has been banned, there are cases that human exposure to these chemicals is inevitable. Thus, during the past decades, human exposure to EDCs has received increased attention, and particular focus has been given to the harmful effects of EDCs to the male reproductive system. Evidences suggest that EDCs may have significant adverse effects on human health and are contributing to the trends in occurrence of male reproductive health problems and the decline in male fertility [3]. According to the literature, male reproductive decline may result from a combination of morphological, functional and molecular alterations in the reproductive organs, often due to exposure to EDCs. Most studies are focused either on the evaluation of basic seminal parameters or reproductive outcomes, but there are evidences that EDCs may impact at the level of the reproductive and endocrine systems. For example, there are evidences that TCS has a tendency to bioaccumulate in the epididymis [4]. Bisphenol A (BPA) has been reported to have both estrogenic and antiandrogenic effects [5, 6, 7]. It has been also negatively associated with sperm quality [8, 9, 10]. Toxicological studies showed that BPA caused adverse reproductive outcomes, namely, decreased epididymal weight, daily sperm production and testosterone (T) levels in rodents [11, 12, 13]. Recently, our group performed a systematic review regarding the effect of exposure to mercury (Hg) on human fertility [14]. Results revealed that higher levels of Hg in blood and hair were associated with male subfertility or infertility status.

This chapter summarizes the effects of male exposure to EDCs on markers of male fertility. The agents discussed here, which include TCS, BPA, metals (such as cadmium (Cd) and Hg), polychlorinated biphenyls (PCBs) and others were chosen based on their human exposure prevalence and adverse effects on human reproductive health.

Advertisement

2. EDCs induce reproductive system toxicity: ultrastructural, cellular and molecular changes

The male reproductive system is composed by two testes, a system of genital ducts, the accessory glands (seminal vesicles, prostate, Cowper and Littre glands) and the penis [15]. Testes, the male sexual glands, are ovoid organs localized outside the abdominal cavity within the scrotum. This localization maintains the temperature at 2–4°C lower than the body temperature, optimal for the testes function. Testes are surrounded by two different layers of protective tissue, the tunica albuginea and the tunica vaginalis. The testicular parenchyma is composed of one to three seminiferous tubules, the functional unit of the testis, and of interstitial tissue surrounding the tubules that contain the Leydig cells (LC), which are responsible for the production of T in the presence of luteinizing hormone (LH) (Figure 1) [16]. The seminiferous tubules are composed of male germ cells (spermatogonia, spermatocytes and spermatids) and Sertoli cells (SC). SC are involved in the mechanical support and nutrition of germ cells, regulation of male germ cell proliferation and differentiation, phagocytosis, steroid hormone synthesis and metabolism and maintenance of the integrity of seminiferous epithelium. The male reproductive system is responsible for the production of spermatozoa, for the synthesis and secretion of male sex hormones and for the delivery of male gametes into the female reproductive tract. The process of spermatogenesis is highly regulated by the hypothalamic-pituitary-gonadal (HPG) axis.

Figure 1.

Schematic representation of the effects of EDCs on HPG axis and testicular morphology.

Evidences suggest that the normal morphology and function of the male reproductive system are affected by several factors including environmental pollutants (Figure 1) (e.g., EDCs). In addition to altered testicular morphology and dysfunction, exposure to EDCs also increased the incidence of testicular pathologies. For instance, exposure to phthalates was associated with the development of testicular cancer, cryptorchidism and hypospadias [17]. This section discusses the current knowledge on reproductive system EDC toxicity in humans and other animals.

2.1 Changes in volume/weight of reproductive organs

The volume/weight of the male reproductive organs is an important indicator of the integrity of this system. Several animal studies showed a significant decrease in the weight of the testes and sex accessory tissues in animals exposed to EDCs [4, 18, 19, 20, 21, 22, 23]. For instance, male rats treated with 10 and 20 mg/(kg day) of TCS revealed a significant decrease in the weight of the testes, epididymis, ventral prostate, vas deferens and seminal vesicles [18]. However, an administration of 5 mg/(kg day) of TCS did not cause significant change in the testes and sex accessory tissues [18]. Recently, Lan et al. [4] showed that the absolute weights of testes and epididymis of rats treated with 10, 50 or 200 mg/kg of TCS were not significantly affected.

Rodents were exposed to BPA by the oral route or subcutaneous injections [24, 25]. A dose of 2 ng/g body weight induced a decrease in epididymal weight and an increase in prostate weight. Bisphenol S (BPS), considered a safe substitute for BPA, has chemical similarities with BPA and may act as an EDC. Thus, a recent work compared the effects of BPA and BPS on the morphology and physiology of the ventral prostate of adult gerbils [26]. Animals treated with BPA and BPS showed no alterations in prostate weight. Regarding histopathology, BPS-treated animals showed intense prostatic hyperplasia; increased relative frequency of epithelium, muscular stroma and non-muscular stroma; and decreased luminal compartment, and BPA-treated animals showed increased occurrence of hyperplastic growth. But, in general the authors found that BPS promoted more structural and histopathological changes than BPA.

Exposure to metals also induced effects on testes size. A dose of 5 mg/kg body weight of cadmium chloride (CdCl2) administered to rats by oral gavage caused a significant decrease in testes and epididymis weight [19]. Moreover, Hg and zinc (Zn) significantly decreased the absolute and relative testicular weights in murine, with Hg producing the highest reduction in weight [27]. Similar results were obtained by Narayana et al. [22] and Geng et al. [23] that showed a decrease in the weights of reproductive organs of rats exposed to pesticides.

Rats exposed to phthalates demonstrated reduced testicular weights and histologic changes in the seminiferous tubules [20, 21]. Moreover, rats exposed to phthalates during the prenatal period developed reproductive anomalies, namely, smaller testes and penis size [28].

Human studies related to the effects of exposure to EDCs on testicular volume/weight are limited but in accordance with animal studies. For instance, in a study in Croatian men, no occupational exposures were exposed to metals, and blood Cd was negatively correlated with testes size, suggesting that this metal exerts toxicity on human testes [29].

2.2 Alterations in testicular morphology

Experimental studies showed that exposure to EDCs had adverse effects on testes, resulting in testicular damage at structural and consequently functional level. Male rats treated with 20 mg/(kg day) of TCS exhibited several histopathological malformations in the testes and sex accessory tissues [18]. Lumen of vas deferens from the treated rats exhibited the presence of stereocilia detached from the epithelium and the presence of eosinophilic bodies. Moreover, the stereocilia were found to be thin, few or absent in the epithelium of TCS-treated rats. Rats treated with a high dose of TCS (200 mg/kg) showed changes in the cauda epididymis and in the testis compared with the control group [4]. In the cauda epididymis, the alterations included vacuolated and exfoliated epithelial cells. Moreover, these authors identified the absence of sperm tails in the seminiferous tubules in the TCS-treated groups.

Mice exposed to BPA showed the formation of morphologically multinucleated giant cells in testicular seminiferous tubules [30], disruption of the blood-testis barrier (BTB) and impaired spermatogenesis [31, 32]. Similar results were obtained by other study using pesticides that induced severe degenerative changes in seminiferous tubules [23]. Metals, such as Cd and Hg, also induced structural alterations in the testis structure, including damage in the vascular endothelium and in the BTB integrity and necrosis and disintegration of spermatocytes [27, 33]. In general, these animal studies showed that EDCs induced changes in testicular morphology, which may be a reason for the decline of male fertility. For instance, damage in epididymis compromise the transport of testicular sperm out of the testis, the acquisition of progressive spermatozoa motility and the sperm storage. Moreover, damage at SC and LC levels compromise the structure of the BTB and seminiferous tubules.

2.3 Testicular dysfunction due to EDC exposure

The two main functions of the testes are spermatogenesis (exocrine function) and steroidogenesis (endocrine function). In normal conditions the gonadotrophin-releasing hormone (GnRH) is secreted by the hypothalamus, stimulating the synthesis of LH and the follicle-stimulating hormone (FSH) [34]. LH is recognized by LH receptors in LC stimulating T biosynthesis (steroidogenesis). FSH is recognized by FSH receptors in SC having an important role in spermatozoa production (spermatogenesis). Several studies showed that these functions are affected by exposure to EDCs (Figure 1) [10, 18, 35, 36, 37, 38, 39]. Prenatal exposure to EDCs was associated with testicular anomalies later in life, which includes reduced semen volume and quality, increased incidence of cryptorchidism and hypospadias and increased incidence of testicular cancer [40]. EDCs reduced SC number and impaired LC development, inducing testicular anomalies at morphological and functional level [39]. This section presents the studies that assessed the relationship between animal and human exposure to EDCs and testicular dysfunction, including alterations in reproductive hormone levels.

Evidences from animal studies suggest that TCS reduces the production of T in LC and disturbs the function of major steroidogenic enzymes [41, 42]. Male rats treated with TCS or pesticides showed a significant decrease in the levels of serum LH, FSH, cholesterol, pregnenolone and T compared to control [18, 23]. Regarding human studies, a case-control study showed that urinary levels of phthalates and TCS were negatively associated with inhibin B and positively with LH [39]. Additionally, an inverse association was found between urinary levels of phthalates or BPA and testosterone and estradiol (E2) [38, 39]. Similar results were obtained by Meeker et al. [35] that showed an inverse association between BPA concentrations in urine and serum levels of inhibin B and E2:T ratio in men recruited through an infertility clinic. Moreover, a positive association between BPA concentrations in urine and FSH and FSH:inhibin B ratio was found. Hanoaka et al. [36] did not found an association between exposure to BPA and free T and LH concentrations in men. However, a significant decrease in FSH concentrations was found in the BPA exposed men. Urinary levels of BPA were not associated with sperm quality in fertile men but were associated with markers of androgenic action [37]. A significant inverse association was found between urinary levels of BPA and free androgen index (FAI) levels and the FAI:LH ratio. Further, a significant positive association between BPA and sex hormone-binding globulin (SHBG) was found in fertile men. Recently, Lassen et al. [10] examined associations between urinary BPA concentration and reproductive hormones in young men from the general population. The authors found positive associations between urinary BPA concentrations and T, E2, LH and free T levels. BPA and BPS induced significant changes in T and estradiol [26].

Meeker et al. [38] demonstrated that exposure to phthalates may be associated with altered male endocrine function. Urinary concentrations of some phthalates were inversely associated with T, E2 and FAI.

Metals, namely, Cd, also affect the development of the male reproductive system and testis function. Mice prenatal exposed to Cd showed defects on the development of gonads, depletion of germ cells and impairment of spermatozoa maturation [43]. Cd also induces testicular dysfunction, which results of the functional impairment of SC and LC. Regarding human studies, the effect of Cd exposure to male endocrine function was assessed by several authors (as reviewed by de Angelis et al. [33]). The results obtained are controversial; some authors found that Cd concentrations were positively correlated with FSH, T, E2, LH and inhibin B and negatively correlated with prolactin [29, 44]. However, other authors did not find significant correlations between Cd concentrations and serum hormone levels [45, 46]. In general, these results suggest that exposure to EDCs may be associated with alterations in circulating hormone levels in men. Additionally, Yang et al. [47] showed that levels of GnRH and LH were significantly higher in occupationally manganese (Mn)-exposed group compared with the non-exposed men. The levels of T were lower in the exposed group. However, this study demonstrated that there was no association between exposure to Mn and E2 and FSH and prolactin levels.

2.4 Molecular effects of EDCs

The effects of EDCs on the morphology and function of the male reproductive system may be attributed to the interactions of these chemicals with several molecules. Male rats treated with 20 mg/(kg day) of TCS showed a significant reduction in the testicular levels of mRNA for cholesterol side-chain cleavage enzyme (Cyp11a1), 25-hydroxyvitamin D-1 alpha hydroxylase (Cyp27b1), 3β-hydroxysteroid dehydrogenase (Hsd3b1), 17β-hydroxysteroid dehydrogenase (Hsd17b6), steroidogenic acute regulatory protein (Star) and androgen receptor (Ar) as compared to control [18]. Moreover, the authors found that there was a decreased localization of StAR protein in testicular LC as determined by immunolocalization indicating a reduced expression of this protein in animals treated with TCS as compared to control. These results could be correlated to the reduction in LC number.

In vitro studies investigated the effect of BPA on steroidogenesis [48, 49]. The authors found that BPA inhibited the production of testosterone in a concentration-dependent manner over the course of the 24 h incubation [48]. Moreover, the concentrations of E2 were greater in the presence of BPA. The decrease in the concentrations of T is related with the inhibition of activities of some enzymes, such as 3β-hydroxysteroid dehydrogenase (HSD3B1) and 17α-hydroxylase (CYP17A). However, the activity of aromatase was not altered by BPA treatment. More recently, additional results in MA-10 Leydig cell line showed that BPA affects steroidogenic genes, for instance, induces the upregulation of CYP11A1 and CYP19 genes [49]. Moreover, the authors found that BPA treatment induced the phosphorylation levels of c-Jun and the levels of protein expression of SF-1, suggesting that the JNK/c-Jun pathway may be involved in BPA toxicity. Similar results were observed in an animal study [49].

The testes from male Sprague-Dawley rats treated with CdCl2 showed a significant increase in the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) [19]. Geng et al. [23] found that pesticides altered the testicular protein expression of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax). Moreover, these authors showed that the activities of testicular enzymes including acyl carrier protein (ACP), lactate dehydrogenase (LDH) and gamma-glutamyltransferase (γ-GT) were significantly altered by exposure to pesticides.

Advertisement

3. Spermatozoa

Sperm motility, together with concentration and morphology, is considered as one of the important predictors of male fertility in vivo. Declining human sperm quality has been demonstrated in several recent studies. Age, lifestyle, environmental pollutants and nutritional factors can affect semen quality [14, 50, 51, 52]. The present section focuses on studies of environmental exposure to EDCs and male reproductive function, as measured by declines in semen quality parameters or increased sperm DNA damage/fragmentation.

3.1 Effects of EDCs on sperm production, morphology, motility and velocity

Several studies have been published regarding the association of exposure to phenols and human semen quality [53, 54, 55]. A case–control study was conducted to evaluate the association between exposure to phenols and idiopathic male infertility [55]. For that, the authors recruited idiopathic infertile men and fertile controls and measured urinary levels of BPA, benzophenone-3, pentachlorophenol, TCS, 4-tert-octylphenol (4-t-OP), 4-n-octylphenol (4-n-OP) and 4-n-nonylphenol (4-n-NP) and semen parameters. The authors found that exposure to 4-t-OP, 4-n-OP and 4-n-NP was associated with idiopathic male infertility, and exposure to 4-t-OP and 4-n-NP was also associated with abnormal semen quality parameters. However, in this study the authors did not find more relationships between exposure to other phenols and idiopathic male infertility. In another study, urinary BPA concentrations were associated with declines in sperm concentration, motility and morphology [53]. An increasing urine BPA level was associated with lower semen concentration, lower total sperm count, lower sperm vitality and lower sperm motility [54]. Moreover, the authors demonstrated a dose–response relationship between increasing urine BPA level and reduction in semen quality. Lassen et al. [10] also found an inverse association between BPA concentrations and progressive motility, but in this study, BPA excretion was not associated with semen volume, sperm concentration, total sperm count or percentage morphologically normal forms. However, some authors did not find any association between urinary BPA concentrations and some semen parameters, such as semen volume or sperm morphology [8, 54].

TCS has been shown to decrease sperm density probably due to reduced testicular spermatogenesis [18]. A reduced sperm density was observed in the lumina of epididymal tubule from the treated rats. Rats treated with high doses of TCS (50 and 200 mg/kg) showed a significant decrease in the daily sperm production and an increase in the percentage of sperm abnormalities, which included elevated ratios of abnormal sperm head and tails [4]. Zhu et al. [56] performed a cross-sectional study to evaluate the association between exposure to TCS measured by urinary TCS concentration and semen quality in humans. The authors found an association between urinary TCS concentrations and poor semen quality parameters; namely, the authors found an inverse association between urinary TCS concentrations and percentage of sperm motility, sperm count, sperm concentration and percentage of normal morphology, suggesting that environmental exposure to TCS may have impact on semen quality.

Regarding exposure to PCBs, several studies showed an inverse association between exposure to PCB 153 and sperm motility, while relationships with sperm concentration or total sperm count were inconsistent [57, 58, 59]. Additionally, Hauser et al. [60] found an inverse dose–response relationship between PCB 138 and sperm concentration, motility and morphology.

The correlation between exposure to metals and adverse consequences for human and animal fertility is not completely established. Several studies determined the effects of exposure to metals on male gametes. In vitro studies, using bovine sperm, determined the effect of direct exposure to Hg on male gametes [61, 62]. Arabi et al. [61] showed that exposure to Hg (50, 100, 200, and 300 μmol/l) induced LPO (lipid peroxidation), decreased the glutathione (GSH) content and decreased the percentage of viable spermatozoa. Additionally, a more recent study showed that bovine sperm exposed to Hg at 8 nM and 8 μM have less motility and have impaired sperm membrane integrity, increasing levels of reactive oxygen species (ROS) and LPO and decreasing the antioxidant activity and diminished fertility ability [62]. Regarding human fertility, in a cross-sectional study, participants with high blood Hg level had lower sperm with a normal morphology [63]. Cd is another male reproductive toxicant that exerts effects even at low levels of exposure by several mechanisms [64]. In vitro studies on human spermatozoa obtained through ejaculation allow to evaluate the effect of Cd treatment in semen parameters [65, 66]. Cd decreased sperm motility and sperm viability and induced detrimental effects on spermatozoa metabolism by inhibition of the activity of glycogen phosphorylase, glucose-6-phosphatase, fructose-1,6-diphosphatase, glucose-6-phosphate isomerase, amylase, Mg2+−dependent ATPase and lactic and succinic acid dehydrogenases. As reviewed by de Angelis et al. [33], significant negative correlations were found between Cd levels and semen parameters, including total sperm count, concentration, motility and morphology. Results from a meta-analysis indicate that men with low fertility had higher semen Pb and Cd levels and lower semen Zn levels [67]. Sperm motility was significantly decreased in men occupationally exposed to Mn [47].

Occupational exposure to pesticides increased the risk of morphological abnormalities in sperm in addition with a decline in sperm count and a decreased percentage of viable spermatozoa. For instance, the exposure to pesticides reduced the seminal volume, sperm motility and concentration and increased the seminal pH and the abnormal sperm head morphology [68, 69, 70]. A study showed that young Swedish men exposed to phthalates presented a decrease in progressive sperm motility [71]. Additionally, levels of urinary phthalates and insecticides were also associated with lower sperm concentration, lower motility and increased percentage of sperm with abnormal morphology [72, 73, 74, 75]. These results confirmed the results obtained by in vitro and in vivo studies [76, 77].

3.2 Sperm DNA damage

Sperm DNA integrity is essential for the correct transmission of genetic information [78]. Damage at sperm DNA level may result in male infertility. Sperm DNA damage is caused by oxidative stress that causes impairment in the sperm membrane [79]. It is well-known that some EDCs may induce oxidative stress and decrease the cellular levels of GSH and protein-sulfhydryl groups. Preclinical studies with male rats showed that exposure to BPA was associated with a significant increase in sperm DNA damage [80]. A statistically significant positive association between urinary concentrations of parabens and BPA and sperm DNA damage was found in male partners of subfertile couples [53, 81]. Contrary results were obtained by Goldstone et al. [8] that found a negative relationship between BPA and DNA fragmentations.

Additionally, other EDCs such as heavy metals (e.g., Hg), PCBs and insecticides induce sperm DNA damage [59, 61, 73, 75, 82, 83, 84]. Urinary levels of Hg and nickel in infertile men were associated with increasing trends for tail length, and the levels of Mn were associated with increasing trend for tail distributed moment [82]. The adverse effects of phthalates on sperm DNA were assessed by several studies among infertile men [75, 84]. Urinary concentrations of phthalate metabolites were associated with sperm DNA damage. These studies suggest that environmental and occupational exposure to EDCs may be associated with increased sperm DNA damage.

Advertisement

4. Conclusions

The results yielded in this chapter showed that both environmental and occupational exposures to EDCs affect male reproductive function at multiple levels. In human populations, the majority of studies point toward an association between exposure to EDCs and male reproduction system disorders, such as infertility, testicular cancer, poor sperm quality and/or function. Exposure to EDCs was associated with declined semen quality, increased sperm DNA damage, alterations in testis morphology and endocrine function. However, there are studies exploring the effect of EDCs on male reproductive health including semen quality, reproductive hormones and male fertility that produced inconsistent results probably due to small-sized study populations and lack of control for potential confounding variables. These contrary results highlight the need to discuss and investigate the effect of environmental pollutants in the male reproductive health. Moreover, the identification of the sequence of events and mechanisms might be important to better understand the effect of exposure to EDCs on male reproductive system and their contribution to male fertility decline.

Advertisement

Acknowledgments

Thanks are due to the support of iBiMED (UID/BIM/04501/2013, UID/BIM/04501/2019 and POCI-01-0145-FEDER-007628), CESAM (UID/ AMB/50017/2019 and POCI-01-0145-FEDER-007638) and FCT/MEC through national funds. We are also thankful to FCT of the Portuguese Ministry of Science and Higher Education by an individual grant to M.C.H. (SFRH/BD/131846/2017).

Advertisement

Conflict of interest

The authors declare no conflicts of interest.

Advertisement

Abbreviations

ACPacyl carrier protein
ALTalanine aminotransferase
ARandrogen receptor
ASTaspartate aminotransferase
BaxBcl-2-associated X protein
Bcl-2B-cell lymphoma 2
BPbisphenols
BPAbisphenol A
BPSbisphenol S
BTBblood-testis barrier
Cdcadmium
CdCl2cadmium chloride
DDTdiphenyl-dichloro-trichloroethane
E2estradiol
EDCsendocrine-disrupting chemicals
FAIfree androgen index
FSHfollicle-stimulating hormone
GnRHgonadotropin-releasing hormone
GSHglutathione
Hgmercury
LCLeydig cells
LDHlactate dehydrogenase
LHluteinizing hormone
Mnmanganese
PCBspolychlorinated biphenyls
ROSreactive oxygen species
SCSertoli cells
SHBGsex hormone-binding globulin
StARsteroidogenic acute regulatory protein
Ttestosterone
TCStriclosan
Znzinc
γ-GTgamma-glutamyltransferase

References

  1. 1. Gore AC, Chappell VA, Fenton SE, Flaws JA, Nadal A, Prins GS, et al. EDC-2: The Endocrine Society’s second scientific statement on endocrine-disrupting chemicals. Endocrine Reviews. 2015;36(6):E1-E150
  2. 2. Frye C, Bo E, Calamandrei G, Calzà L, Dessì-Fulgheri F, Fernández M, et al. Endocrine disrupters: A review of some sources, effects, and mechanisms of actions on behaviour and neuroendocrine systems. Journal of Neuroendocrinology. 2012;24:144-159
  3. 3. Meeker JD. Exposure to environmental endocrine disrupting compounds and men’s health. Maturitas. 2010;66(3):236-241
  4. 4. Lan Z, Hyung Kim T, Shun Bi K, Hui Chen X, Sik KH. Triclosan exhibits a tendency to accumulate in the epididymis and shows sperm toxicity in male Sprague-dawley rats. Environmental Toxicology. 2015;30(1):83-91. DOI: 10.1002/tox.21897
  5. 5. Wetherill YB, Akingbemi BT, Kanno J, McLachlan JA, Nadal A, Sonnenschein C, et al. In vitro molecular mechanisms of bisphenol A action. Reproductive Toxicology. 2007;24(2):178-198
  6. 6. Lee HJ, Chattopadhyay S, Gong E-Y, Ahn RS, Lee K. Antiandrogenic effects of bisphenol A and nonylphenol on the function of androgen receptor. Toxicological Sciences. 2003;75(1):40-46
  7. 7. Akingbemi BT, Sottas CM, Koulova AI, Klinefelter GR, Hardy MP. Inhibition of testicular steroidogenesis by the xenoestrogen bisphenol A is associated with reduced pituitary luteinizing hormone secretion and decreased steroidogenic enzyme gene expression in rat Leydig cells. Endocrinology. 2004;145(2):592-603
  8. 8. Goldstone AE, Chen Z, Perry MJ, Kannan K, Louis GMB. Urinary bisphenol a and semen quality, the LIFE study. Reproductive Toxicology. 2015;51:7-13
  9. 9. Knez J, Kranvogl R, Breznik BP, Vončina E, Vlaisavljević V. Are urinary bisphenol a levels in men related to semen quality and embryo development after medically assisted reproduction? Fertility and Sterility. 2014;101(1):215-221.e5
  10. 10. Lassen TH, Frederiksen H, Jensen TK, Petersen JH, Joensen UN, Main KM, et al. Urinary bisphenol a levels in young men: Association with reproductive hormones and semen quality. Environmental Health Perspectives. 2014;122(5):478-484
  11. 11. Herath CB, Jin W, Watanabe G, Arai K, Suzuki AK, Taya K. Adverse effects of environmental toxicants, octylphenol and bisphenol a, on male reproductive functions in pubertal rats. Endocrine. 2004;25(2):163-172
  12. 12. Salian S, Doshi T, Vanage G. Perinatal exposure of rats to bisphenol A affects the fertility of male offspring. Life Sciences. 2009;85(21-22):742-752
  13. 13. 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
  14. 14. Henriques MC, Loureiro S, Fardilha M, Herdeiro MT. Exposure to mercury and human reproductive health: A systematic review. Reproductive Toxicology. 2019 Apr;85:93-103
  15. 15. Netter FH. Atlas of Human Anatomy. 6th ed. Philadelphia: Elsevier; 2014
  16. 16. Ilacqua A, Francomano D, Aversa A. The physiology of the testis. In: Belfiore A, LeRoith D, editors. Principles of Endocrinology and Hormone Action. Cham, Switzerland: Springer; 2018. pp. 455-491. DOI: 10.1007/978-3-319-44675-2_17
  17. 17. Nordkap L, Joensen UN, Blomberg Jensen M, Jørgensen N. Regional differences and temporal trends in male reproductive health disorders: Semen quality may be a sensitive marker of environmental exposures. Molecular and Cellular Endocrinology. 2012;355:221-230
  18. 18. Kumar V, Chakraborty A, Kural MR, Roy P. Alteration of testicular steroidogenesis and histopathology of reproductive system in male rats treated with triclosan. Reproductive Toxicology. 2009;27(2):177-185
  19. 19. El-Demerdash FM, Yousef MI, Kedwany FS, Baghdadi HH. Cadmium-induced changes in lipid peroxidation, blood hematology, biochemical parameters and semen quality of male rats: Protective role of vitamin E and β-carotene. Food and Chemical Toxicology. 2004;42(10):1563-1571
  20. 20. Gangolli SD. Testicular effects of phthalate esters. Environmental Health Perspectives. 1982;45:77-84. DOI: 10.1289/ehp.824577
  21. 21. Wolf C, Lambright C, Mann P, Price M, Cooper RL, Ostby J, et al. Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p′-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual difference. Toxicology and Industrial Health. 1999;15(1-2):94-118. DOI: 10.1177/074823379901500109
  22. 22. Narayana K, Prashanthi N, Nayanatara A, Kumar HHC, Abhilash K, Bairy KL. Neonatal methyl parathion exposure affects the growth and functions of the male reproductive system in the adult rat. Folia Morphologica. 2006;65(1):26-33
  23. 23. Geng X, Shao H, Zhang Z, Ng JC, Peng C. Malathion-induced testicular toxicity is associated with spermatogenic apoptosis and alterations in testicular enzymes and hormone levels in male Wistar rats. Environmental Toxicology and Pharmacology. 2015;39(2):659-667
  24. 24. Richter CA, Birnbaum LS, Farabollini F, Newbold RR, Rubin BS, Talsness CE, et al. In vivo effects of bisphenol A in laboratory rodent studies. Reproductive Toxicology. 2007;24(2):199-224
  25. 25. Vom Saal FS, Cooke PS, Buchanan DL, Palanza P, Thayer KA, Nagel SC, 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. Toxicology and Industrial Health. 1998;14(1-2):239-260. DOI: 10.1177/074823379801400115
  26. 26. Silva JPA, Ramos JG, Campos MS,da Silva LD, de Azevedo Brito PV, Mendes EP, et al. Bisphenol-S promotes endocrine-disrupting effects similar to those promoted by bisphenol-A in the prostate of adult gerbils. Reproductive Toxicology. 2019;85:83-92
  27. 27. Orisakwe OE, Afonne OJ, Nwobodo E, Asomugha L, Dioka CE. Low-dose mercury induces testicular damage protected by zinc in mice. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2001;95(1):92-96
  28. 28. Foster PMD, Gray E, Leffers H, Skakkebæk NE. Disruption of reproductive development in male rat offspring following in utero exposure to phthalate esters. International Journal of Andrology. 2006;29(1):140-147. DOI: 10.1111/j.1365-2605.2005.00563.x
  29. 29. Jurasović J, Cvitković P, Pizent A, Čolak B, Telišman S. Semen quality and reproductive endocrine function with regard to blood cadmium in Croatian male subjects. Biometals. 2004;17(6):735-743. DOI: 10.1007/s10534-004-1689-7
  30. 30. Takao T, Nanamiya W, Nagano I, Asaba K, Kawabata K, Hashimoto K. Exposure with the environmental estrogen bisphenol a disrupts the male reproductive tract in young mice. Life Sciences. 1999;65(22):2351-2357
  31. 31. Cheng CY, Wong EWP, Lie PPY, Li MWM, Su L, Siu ER, et al. Environmental toxicants and male reproductive function. Spermatogenesis. 2011;1(1):2-13. DOI: 10.4161/spmg.1.1.13971
  32. 32. Su L, Mruk DD, Cheng CY. Drug transporters, the blood-testis barrier and spermatogenesis. The Journal of Endocrinology. 2010;208(3):207-223. DOI: 10.1677/JOE-10-0363
  33. 33. de Angelis C, Galdiero M, Pivonello C, Salzano C, Gianfrilli D, Piscitelli P, et al. The environment and male reproduction: The effect of cadmium exposure on reproductive functions and its implication in fertility. Reproductive Toxicology. 2017;73:105-127
  34. 34. Corradi PF, Corradi RB, Greene LW. Physiology of the hypothalamic pituitary gonadal axis in the male. The Urologic Clinics of North America. 2016;43(2):151-162
  35. 35. Meeker JD, Calafat AM, Hauser R. Urinary bisphenol a concentrations in relation to serum thyroid and reproductive hormone levels in men from an infertility clinic. Environmental Science & Technology. 2010;44(4):1458-1463. DOI: 10.1021/es9028292
  36. 36. 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. Occupational and Environmental Medicine. 2002;59(9):625-628
  37. 37. Mendiola J, Jørgensen N, Andersson A-M, Calafat AM, Ye X, Redmon JB, et al. Are environmental levels of bisphenol A associated with reproductive function in fertile men? Environmental Health Perspectives. 2010;118(9):1286-1291. DOI: 10.1289/ehp.1002037
  38. 38. Meeker JD, Calafat AM, Hauser R. Urinary metabolites of di(2-ethylhexyl) phthalate are associated with decreased steroid hormone levels in adult men. Journal of Andrology. 2009;30(3):287-297
  39. 39. Den Hond E, Tournaye H, De Sutter P, Ombelet W, Baeyens W, Covaci A, et al. Human exposure to endocrine disrupting chemicals and fertility: A case–control study in male subfertility patients. Environment International. 2015;84:154-160
  40. 40. Sharpe RM, Skakkebaek NE. Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet. 1993;341(8857):1392-1395
  41. 41. Forgacs AL, Ding Q , Jaremba RG, Huhtaniemi IT, Rahman NA, Zacharewski TR. BLTK1 murine leydig cells: A novel steroidogenic model for evaluating the effects of reproductive and developmental toxicants. Toxicological Sciences. 2012;127(2):391-402. DOI: 10.1093/toxsci/kfs121
  42. 42. Kumar V, Balomajumder C, Roy P. Disruption of LH-induced testosterone biosynthesis in testicular Leydig cells by triclosan: Probable mechanism of action. Toxicology. 2008;250(2-3):124-131
  43. 43. Tam PPL, Liu WK. Gonadal development and fertility of mice treated prenatally with cadmium during the early organogenesis stages. Teratology. 1985;32(3):453-462. DOI: 10.1002/tera.1420320314
  44. 44. Akinloye O, Arowojolu AO, Shittu OB, Anetor JI. Cadmium toxicity: A possible cause of male infertility in Nigeria. Reproductive Biology. 2006;6(1):17-30
  45. 45. 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. Environmental Research. 2004;96(3):338-344
  46. 46. Mendiola J, Moreno JM, Roca M, Vergara-Juárez N, Martínez-García MJ, García-Sánchez A, et al. Relationships between heavy metal concentrations in three different body fluids and male reproductive parameters: A pilot study. Environmental Health. 2011;10(1):6
  47. 47. Yang H, Wang J, Yang X, Wu F, Qi Z, Xu B, et al. Occupational manganese exposure, reproductive hormones, and semen quality in male workers: A cross-sectional study. Toxicology and Industrial Health. 2019;35(1):53-62
  48. 48. Zhang X, Chang H, Wiseman S, He Y, Higley E, Jones P, et al. Bisphenol A disrupts steroidogenesis in human H295R cells. Toxicological Sciences. 2011;121(2):320-327
  49. 49. Lan H-C, Wu K-Y, Lin I-W, Yang Z-J, Chang A-A, Hu M-C. Bisphenol A disrupts steroidogenesis and induces a sex hormone imbalance through c-Jun phosphorylation in Leydig cells. Chemosphere. 2017;185:237-246
  50. 50. Mínguez-Alarcón L, Afeiche MC, Williams PL, Arvizu M, Tanrikut C, Amarasiriwardena CJ, et al., Earth Study Team. Hair mercury (Hg) levels, fish consumption and semen parameters among men attending a fertility center. International Journal of Hygiene and Environmental Health. 2018;221(2):174-182
  51. 51. Ilacqua A, Izzo G, Pietro EG, Baldari C, Aversa A. Lifestyle and fertility: The influence of stress and quality of life on male fertility. Reproductive Biology and Endocrinology. 2018;16(1):115. DOI: 10.1186/s12958-018-0436-9
  52. 52. Silva JV, Cruz D, Gomes M, Correia BR, Freitas MJ, Sousa L, et al. Study on the short-term effects of increased alcohol and cigarette consumption in healthy young men’s seminal quality. Scientific Reports. 2017;7(1):45457
  53. 53. Meeker JD, Ehrlich S, Toth TL, Wright DL, Calafat AM, Trisini AT, et al. Semen quality and sperm DNA damage in relation to urinary bisphenol A among men from an infertility clinic. Reproductive Toxicology. 2010;30(4):532-539
  54. 54. Li D-K, Zhou Z, Miao M, He Y, Wang J, Ferber J, et al. Urine bisphenol-A (BPA) level in relation to semen quality. Fertility and Sterility. 2011;95(2):625-630.e4
  55. 55. Chen M, Tang R, Fu G, Xu B, Zhu P, Qiao S, et al. Association of exposure to phenols and idiopathic male infertility. Journal of Hazardous Materials. 2013;250-251:115-121
  56. 56. Zhu W, Zhang H, Tong C, Xie C, Fan G, Zhao S, et al. Environmental exposure to triclosan and semen quality. International Journal of Environmental Research and Public Health. 2016;13(2):224
  57. 57. Richthoff J, Rylander L, Jönsson BAG, Akesson H, Hagmar L, Nilsson-Ehle P, et al. Serum levels of 2,2′,4,4′,5,5′-hexachlorobiphenyl (CB-153) in relation to markers of reproductive function in young males from the general Swedish population. Environmental Health Perspectives. 2003;111(4):409-413. DOI: 10.1289/ehp.5767
  58. 58. Rignell-Hydbom A, Rylander L, Giwercman A, Jönsson BAG, Nilsson-Ehle P, Hagmar L. Exposure to CB-153 and p,p′-DDE and male reproductive function. Human Reproduction. 2004;19(9):2066-2075
  59. 59. Rignell-Hydbom A, Rylander L, Giwercman A, Jönsson BAG, Lindh C, Eleuteri P, et al. Exposure to PCBs and p,p’-DDE and human sperm chromatin integrity. Environmental Health Perspectives. 2005;113(2):175-179
  60. 60. Hauser R, Chen Z, Pothier L, Ryan L, Altshul L. The relationship between human semen parameters and environmental exposure to polychlorinated biphenyls and p,p’-DDE. Environmental Health Perspectives. 2003;111(12):1505-1511
  61. 61. Arabi M. Bull spermatozoa under mercury stress. Reproduction in Domestic Animals. 2005;40(5):454-459
  62. 62. Silva EFSJD, Missio D, Martinez CS, Vassallo DV, Peçanha FM, Leivas FG, et al. Mercury at environmental relevant levels affects spermatozoa function and fertility capacity in bovine sperm. Journal of Toxicology and Environmental Health, Part A. Current Issues. 2019;82(4):268-278
  63. 63. Ai C-E, Li C-J, Tsou M-C, Chen J-L, Hsi H-C, Chien L-C. Blood and seminal plasma mercury levels and predatory fish intake in relation to low semen quality. Environmental Science and Pollution Research. 2019;26(19):19425-19433
  64. 64. Thompson J, Bannigan J. Cadmium: Toxic effects on the reproductive system and the embryo. Reproductive Toxicology. 2008;25(3):304-315
  65. 65. Pant N, Pant AB, Chaturvedi PK, Shukla M, Mathur N, Gupta YK, et al. Semen quality of environmentally exposed human population: The toxicological consequence. Environmental Science and Pollution Research. 2013;20(11):8274-8281. DOI: 10.1007/s11356-013-1813-8
  66. 66. Kanwar U, Chadha S, Batla A, Sanyal SN, Sandhu R. Effect of selected metal ions on the motility and carbohydrate metabolism of ejaculated human spermatozoa. Indian Journal of Physiology and Pharmacology. 1988;32(3):195-201
  67. 67. Sun J, Yu G, Zhang Y, Liu X, Du C, Wang L, et al. Heavy metal level in human semen with different fertility: A meta-analysis. Biological Trace Element Research. 2017;176(1):27-36
  68. 68. Yucra S, Rubio J, Gasco M, Gonzales C, Steenland K, Gonzales GF. Semen quality and reproductive sex hormone levels in peruvian pesticide sprayers. International Journal of Occupational and Environmental Health. 2006;12(4):355-361. DOI: 10.1179/oeh.2006.12.4.355
  69. 69. Lifeng T, Shoulin W, Junmin J, Xuezhao S, Yannan L, Qianli W, et al. Effects of fenvalerate exposure on semen quality among occupational workers. Contraception. 2006;73(1):92-96
  70. 70. Hossain F, Ali O, D’Souza UJA, Naing DKS. Effects of pesticide use on semen quality among farmers in rural areas of Sabah, Malaysia. Journal of Occupational Health. 2010;52(6):353-360
  71. 71. Axelsson J, Rylander L, Rignell-Hydbom A, Jönsson BAG, Lindh CH, Giwercman A. Phthalate exposure and reproductive parameters in young men from the general Swedish population. Environment International. 2015;85:54-60
  72. 72. Duty SM, Silva MJ, Barr DB, Brock JW, Ryan L, Chen Z, et al. Phthalate exposure and human parameters. Epidemiology. 2003;14(3):269-277
  73. 73. Meeker JD, Barr DB, Hauser R. Human semen quality and sperm DNA damage in relation to urinary metabolites of pyrethroid insecticides. Human Reproduction. 2008;23(8):1932-1940. DOI: 10.1093/humrep/den242
  74. 74. Duty SM, Calafat AM, Silva MJ, Brock JW, Ryan L, Chen Z, et al. The relationship between environmental exposure to phthalates and computer-aided sperm analysis motion parameters. Journal of Andrology. 2004;25(2):293-302
  75. 75. Duty SM, Silva MJ, Barr DB, Brock JW, Ryan L, Chen Z, et al. Phthalate exposure and human semen parameters. Epidemiology. 2003;14(3):269-277
  76. 76. Pant N, Pant A, Shukla M, Mathur N, Gupta Y, Saxena D. Environmental and experimental exposure of phthalate esters: The toxicological consequence on human sperm. Human & Experimental Toxicology. 2011;30(6):507-514. DOI: 10.1177/0960327110374205
  77. 77. Barakat R, Lin P-CP, Rattan S, Brehm E, Canisso IF, Abosalum ME, et al. Prenatal exposure to DEHP induces premature reproductive senescence in male mice. Toxicological Sciences. 2017;156(1):96-108. DOI: 10.1093/toxsci/kfw248
  78. 78. Agarwal A. Role of sperm chromatin abnormalities and DNA damage in male infertility. Human Reproduction Update. 2003;9(4):331-345. DOI: 10.1093/humupd/dmg027
  79. 79. Wright C, Milne S, Leeson H. Sperm DNA damage caused by oxidative stress: Modifiable clinical, lifestyle and nutritional factors in male infertility. Reproductive Biomedicine Online. 2014;28(6):684-703
  80. 80. Tiwari D, Vanage G. Mutagenic effect of bisphenol a on adult rat male germ cells and their fertility. Reproductive Toxicology. 2013;40:60-68
  81. 81. Meeker JD, Yang T, Ye X, Calafat AM, Hauser R. Urinary concentrations of parabens and serum hormone levels, semen quality parameters, and sperm DNA damage. Environmental Health Perspectives. 2011;119(2):252-257
  82. 82. Zhou Y, Fu XM, He DL, Zou XM, Wu CQ , Guo WZ, et al. Evaluation of urinary metal concentrations and sperm DNA damage in infertile men from an infertility clinic. Environmental Toxicology and Pharmacology. 2016;45:68-73. DOI: 10.1016/j.etap.2016.05.020
  83. 83. Rignell-Hydbom A, Axmon A, Lundh T, Jönsson BA, Tiido T, Spano M. Dietary exposure to methyl mercury and PCB and the associations with semen parameters among Swedish fishermen. Environmental Health. 2007;6(1):14. DOI: 10.1186/1476-069X-6-14
  84. 84. Hauser R, Meeker JD, Singh NP, Silva MJ, Ryan L, Duty S, et al. DNA damage in human sperm is related to urinary levels of phthalate monoester and oxidative metabolites. Human Reproduction. 2007;22(3):688-695

Written By

Magda Carvalho Henriques, Susana Loureiro, Margarida Fardilha and Maria Teresa Herdeiro

Submitted: 01 April 2019 Reviewed: 01 July 2019 Published: 13 December 2019