Abstract
Infertility is a major health issue affecting human life. The most notable factors causing male infertility is exposure to environmental contaminants. Bisphenol A (BPA) is a common toxic environmental contaminant. Human population is exposed to bisphenol A through air, water, food and a variety of industrial products. Growing evidence from research on laboratory animals supports the hypothesis that bisphenol A is able to adversely affect male reproductive function. The specific mechanisms of action of bisphenol A are wide but not definite. Bisphenol A interferes with the hormonal metabolism and regulation, binding affinity or enzymatic activity, resulting in a deviation from a normal reproductive behaviour. Binding ability to androgen and oestrogen receptors, as well as other properties, is currently investigated. A decreased sperm count, inhibition of sperm motility and reduction of organ weights were observed and linked with oxidative stress after bisphenol A treatment. In addition, prenatal exposure to bisphenol A may lead to adverse effects in the offspring. In this review, we address the topic of BPA effects on male reproductive function and emphasize its effects on testicular steroidogenesis and spermatogenesis. A considerably more detailed and systematic research focusing on bisphenol A toxicology is required for a better understanding of risks associated with exposure to this endocrine disruptor.
Keywords
- reproduction
- male
- bisphenol A
- steroidogenesis
- spermatogenesis
1. Introduction
Over the last decade, research has focused on the potentially hazardous effects of a wide range of chemicals present in the human or wildlife environment. An increased occurrence of male reproductive and developmental disorders such as hypospadias, cryptorchidism and testicular cancer as well as a decreased semen quality have been related to the action of endocrine disruptors. Endocrine-disrupting effects of commercially available products have the potential to cause reproductive dysfunction alongside with adverse effects on development and sexual differentiation. The group of known endocrine disruptors is extremely heterogeneous. One of the most common environmental contaminants classified as endocrine disruptors is bisphenol A (BPA). Many studies have defined BPA as hazardous to the health of humans and animals, particularly to male reproduction [1]. BPA plays a key role in testicular disorders, due to its oestrogenic properties. Oestrogen biosynthesis takes place in the testicular cells; hence the absence of oestrogens causes negative effects on male reproduction [2]. Physiological levels of oestrogens are essential for a normal spermatogenesis; however, overage of oestrogens together with a deficiency of testosterone may cause infertility [3]. In addition, some reports have shown that BPA behaves as an androgen receptor antagonist, interrupting normal androgen receptor binding activity and interactions between androgen receptors and endogenous androgens. Such effects by BPA on the function of endogenous androgens could interfere with normal processes of spermatogenesis, which are controlled by numerous endogenous hormones [4, 5]. Moreover, androgens play characteristic roles in the expression of the male phenotype, development and maintenance of the secondary male characteristics and regulate the expression of an array of target genes that are important for a proper male fertility [6]. As such the chemical substances with antiandrogenic properties can react with male sexual functions and behaviour by blocking the binding of androgens to androgen receptors and a following induced expression of gene by androgen. It has been reported that BPA has adverse effects on the male reproductive system including a decreased sperm count, abnormal sperm motility and reduced reproductive organ weights [7]. One of the potential mechanisms of action of BPA on male reproductive functions and sperm quality has been also proposed to act through oxidative stress. Environmental contaminants such as BPA have been shown to induce reactive oxygen species overgeneration in both intracellular and extracellular spaces leading to cell death and tissue injury [8]. Sensitivity to BPA is not the same at all stages of life, and there are specific critical phases of male development that are more vulnerable to BPA exposure [9]. One such sensitive phase wherein organ differentiation and development take place is the prenatal and perinatal period. The cumulation of BPA in tissues of the male reproductive system is associated with different pathological consequences since low-level BPA exposure during embryonic phase of life has been observed in reduction of effectiveness of spermatogenesis in male descendants [44]. Many experiments have examined the effect of prenatal, neonatal and lactational exposure to low BPA doses. Such studies examined the impact of small dosage of this endocrine disruptor throughout crucial stages of development in various cells and organs. These crucial stages continue throughout reaching of sexual maturity, the physiological phase of modification to fertility [10]. In relation to male reproductive functions, sexual dysfunction in animal studies is difficult to conduct. However, changes in sexual behaviour including a reduced performance in latency and frequency of intromission among rodents exposed to BPA have also been reported [10, 11]. Even results from a human study involving workers of BPA manufactures in China from 2004 to 2008 provide important evidence that occupational exposure to BPA significantly increases the risk of male sexual dysfunction [12]. Another issue that is becoming increasingly debated in the context of male reproductive function and endocrine-disrupting compounds, such as BPA is their ability to modify the epigenome. Hormone cascade pathway is usually returnable and activates constant modulations of cell processes. Throughout sexual development, sex steroids are able to initiate persistent impact on activities of gene that induce developmental changes of cells and genes to react to another hormonal impulse during life. This hormonal imprinting or gene programming probably include mechanisms of epigenetics related to DNA methylation, which can be transmitted from mother cell to daughter cells and cause permanent changes [13]. Multiple evidence from
2. Potential impact of BPA on the steroidogenesis
There is overwhelming evidence about the potential ability of BPA to affect cellular processes, such as steroidogenesis and spermatogenesis. The testicular compartments responsible for steroidogenesis and spermatogenesis are the seminiferous tubules and interstitium. Both are morphologically distinct but functionally connected. Steroidogenesis and spermatogenesis are two vital, high energy demanding processes which are exceptionally vulnerable to damage caused by BPA [17]. Steroidogenesis is a process underway in the Leydig cells. Testosterone as a product of the steroidogenic pathway is released from the Leydig cells under the control of the luteinizing hormone (LH). LH binds to the LH receptor to induce the dissociation of the α subunit of the G protein. Gsα then activates the cyclic adenosine monophosphate (cAMP). cAMP binds to protein kinase A (PKA). The active PKA phosphorylates certain cytoplasmic proteins, which, in turn, will increase the transportation rate of cholesterol into the inner mitochondrial membrane. Cholesterol is then catalyzed by the P450SCC enzyme into pregnenolone. Pregnenolone is delivered to the smooth endoplasmic reticulum and subsequently converted into testosterone. Depending on the species, this conversion can occur via progesterone, 17α-OH progesterone and androstenedione through delta-4 intermediates or via 17α-hydroxypregnenolone, dehydroepiandrosterone and androstenediol as delta-5 intermediates by the actions of enzymes, 3β-hydroxysteroid dehydrogenase (3β-HSD), 17α-hydroxylase and 17β-hydroxysteroid dehydrogenase (17β-HSD) [18]. BPA can alter the level of endogenous steroids at a particular site by altering its synthesis, metabolism, distribution or clearance. Alternatively, the chemicals may interact directly with the steroid receptor to either mimic or block steroid actions [19, 33]. Hormonal activity is mediated by binding to steroid receptors. Specific hormone-receptor complex is translocated to the DNA molecule. After this step alterations in the expression of steroid—responsive genes—are observed [20]. BPA is able to inhibit the steroidogenic process through specific mechanisms such as binding to the receptors and damage to the steroidogenic enzymes.
2.1. Estrogenic and antiandrogenic affinity of BPA
Although there are different mechanisms through which endocrine disruptors are able to modify the endocrine response, chemical substances that might simulate the effect of steroid hormones by a reaction with their respective receptors continue to receive considerable attention. The initial step in the mechanism of action of steroid hormones is the binding of the steroid to its receptor or binding protein. BPA has been shown to be able to bind to the oestrogen receptor and initiate transcription of the oestrogen receptor—regulated genes
2.2. Interaction of BPA and steroidogenic enzymes
There are mechanisms other than ER- or AR-mediated effects through which BPA could affect physiological functions, including modulation of steroidogenesis and interference with metabolic breakdown of oestrogens and detrimental effects on signalling cascades. Examination of the expression of different steroidogenic enzymes provides information on the molecular basis for alterations in hormone biosynthesis caused by exposure to BPA [46–48]. Essential male reproductive hormones are testosterone and androstenedione. Their biosynthesis is called steroidogenesis where steroidogenic enzymes step out as stable components responsible for specific cascades of reactions which transform cholesterol to endogenous male hormones. Steroidogenic processes start with the transport of cholesterol to the mitochondrial inner membrane where the first steroidogenic enzyme cytochrome P450 cholesterol side chain cleavage enzyme (CYP11A1) uses it as a substrate to produce pregnenolone. Pregnenolone subsequently diffuses to the smooth endoplasmic reticulum, where it is converted to testosterone by the enzymes such as 3β-hydroxysteroid dehydrogenase, cytochrome P450 17α-hydroxylase/17,20-lyase (P450c17) and 17β-hydroxysteroid dehydrogenase (17β-HSD). The first reaction in the smooth endoplasmic reticulum is catalyzed by 3β-HSD to progesterone. P450c17 catalyses two reactions that convert progesterone to 17α-hydroxyprogesterone and then to androstenedione. 17β-hydroxysteroid dehydrogenase catalyses the last step from androstenedione to testosterone.
Recent experimental studies have demonstrated that the production of both androstenedione and testosterone was inhibited by BPA in a concentration-dependent manner over the course of 24 h incubation. Lower concentrations of androstenedione and its direct downstream product, testosterone, after the exposure to BPA are consistent with a direct inhibition of enzymatic activities, such as 3β-HSD, cytochrome P450c17 and 17β-HSD. A decrease in the activity of 17α-hydroxylase resulted in a lower production of its direct product 17α-hydroxyprogesterone. Moreover, the decreased activity of 17,20-lyase inhibited the rate of 17α-hydroxyprogesterone conversion to androstenedione, which led to in a 7.7-fold reduction in the androstenedione synthesis and a 2.4-fold reduced testosterone level [49]. It has been reported that prenatal exposure of BPA in rodents causes a reduction in the testosterone production. It is possibly caused by the downregulation of the steroidogenic enzymes in the Leydig cells and an inhibition of LH secretion [50]. Ye et al. [51] confirmed a dose-dependent inhibition of human 3β-HSD and P450c17 by BPA. At 10 μM, BPA also weakly but significantly inhibited human and rat 17β-HSD activities. In general, human steroidogenic enzymes are more sensitive to BPA than rat enzymes. The results also demonstrate that BPA partially competes with cofactor NAD+ (for 3β-HSD) in the cofactor binding site of this enzyme. The second essential enzyme 17β-HSD, which is responsible for testosterone synthesis from androstenedione, was observed to decrease the activity of this enzyme. 17β-HSD accounts for most of the circulatory testosterones in males and in the case of genetic mutation induced by BPA may cause the autosomal recessive genetic disorder male pseudohermaphroditism in which males often are born with female external genitalia and without a prostate [52, 53]. The aromatase enzyme, which is encoded by the CYP19 gene and catalyses the conversion of androgens to oestrogens, is expressed more in the male reproductive tract than in other tissues in rodents. Some experimental data show that BPA caused a direct inhibition of aromatase gene expression and oestrogen biosynthesis. Disruption of CYP19 gene expression of aromatase in Leydig cells was ERα mediated as oestrogenic agents act via ERα to upregulate the promoter region of the aromatase gene [54, 55]. Some experimental studies indicate that a decreased androgen production by Leydig cells does not correlate with level of testosterone in serum after chronic BPA exposure which can be due to compensatory mechanisms initiated
2.3. Effects of BPA exposure during gestation through puberty
We recognize that the development is epigenetic, which refers to changes in gene activity during developments that are mediated by chemical signals. Autocrine, paracrine (growth factors) and endocrine (steroids) signals coordinate the direction of tissue differentiation during critical periods in development. Androgens, mediated by the AR, do play an indispensable role in induction of male sex differentiation and development of the male phenotype. It has been demonstrated that the developing embryo may be much more susceptible to harmful effects of environmental contaminants than adult animals. A high
3. The potential impact of BPA on the spermatogenesis
Spermatogenesis is under the control of the hypothalamic-pituitary-testicular axis and the thyroid gland. Dysfunction of this axis, initiated by endocrine disruptors such as BPA, may result in a discontinuance or alteration of spermatogenesis [80]. BPA acts through sex steroid-mediated hormone cascade pathway to influence functions of reproductive system, and it is likely that BPA is also able to modulate specific characteristics of sexually dimorphic systems, in particular gender differences in the mental functions and behaviours of the sexes [81]. The harmful impact of BPA on male reproductive function may occur over embryonic, pubertal and/or adult life [80]. Many current studies have demonstrated that low doses of this widespread oestrogenic chemical substance can induce strong, membrane-initiated oestrogenic effects [82], indicating that low levels of BPA exposure might interfere with normal oestrogenic signalling pathway [4]. It is known that oestrogen receptors are expressed in the Leydig cells (ERα), whereas ERβ have been described in Sertoli cells, pachytene spermatocytes and round spermatidis of the adult rat and male testis. ER has been also shown to be expressed in other tissues of the male reproductive tract [83]. Recent
3.1. Spermatogenesis and sperm function affected by BPA
A lot of experiments with BPA have confirmed that this chemical substance, even at levels under doses that are considered as safe for human population, is able to impair sexual functions and behaviour in rodents [89], and for male reproduction, it is proved that the exposure of adult rats to environmental doses of BPA can reduce activity of spermatogenesis and sperm count [8, 83].
BPA experiments on different animals exhibit that impact is usually more damaging throughout in utero stage, which is the most sensitive developmental phase for the foetus. It has been observed that this chemical substance is able to generate different injuries in the foetus, including male embryos feminization, reduced function of the testes and epididymides with breakdown of tissues, enlarged prostate, shortening of anogenital distance and alteration of adult sperm parameters, such as sperm count, motility and density. BPA is also able to affect embryo thyroid development [80]. Recent findings support another additional BPA activity mechanism, by a non-genomic pathway, initiated at membrane receptors, including standard ERs and/or G-protein-coupled receptor 30 [109]. By disrupting levels of hormone or receptor activity, the negative effect of this chemical substance may be to modulate male reproductive organ development throughout foetal life. In addition, harmful BPA impact can be more noticeable and nonreversible throughout this phase of development, in contrast to adults, who reached a functional sex maturity and physiology, in which the harmful impact is eventually not persistent since the first exposure [110]. In utero exposure to BPA was found to cause negative effects on reproductive organs in rodents. In utero exposure of pregnant CD-1 mice to BPA in amount 50 μg BPA/kg body weight/day during 16–18 days of gestation showed increasing the anogenital distance in male young [111]. This conflicts with study of Chahoud et al. [112], who presented shortening of the anogenital distance, following prenatal BPA exposure. However, these studies exhibited that BPA has the ability to alternate anogenital distance during prenatal life. Alteration in the development and tissue organization, changes in prostate gland weight, reduced sperm efficiency and daily sperm production were also observed [58, 62]. Oral administration of 2–20 ng BPA/g body weight to female mice on 11–17 gestational days exhibited significant decline of relative testis weight of male young [61]. Vom Saal et al. [63] researched BPA exposure on male mice during pregnancy and observed raising size for preputial glands and reduced size of epididymides, as well as reduced capacity of daily sperm production. When female mice were co-administered with BPA in combination with di(2-ethylhexyl) phthalate, another chemical plastic substance, the expression level of anti-Müllerian hormone was decreased in the testicular tissue of treated young males and also reduced the size of testes. And more significantly, the negative impact was sustained in the sexually mature young at postnatal day 42, associated with decrease counts of epididymal sperm cells [64]. A decline in fertility, daily sperm production and count and motility of sperm in BPA-exposed male offspring over maturity was also reported in Salian et al. study [113].
3.2. Impact of BPA on Sertoli cell function
Normal function of Sertoli cells that are part of a seminiferous tubule is crucial in the spermatogenesis. Process of differentiation and production of mature sperm cells is under the control of the FSH because Sertoli cells are equipped with FSH receptors on their membranes and are activated by secretion of this adenohypophysis hormone. Inhibition of the Sertoli cell function by BPA, directly or indirectly through reduction of hormone synthesis, may impair reproductive function in exposed males [80]. Sertoli cell function is to provide support, in other words, provide the adequate metabolic and structural background for developing spermatozoa because a lot of factors important for gamete maturation are associated with functions of somatic Sertoli cells. Consequently, any agent that impairs the viability and the function of Sertoli cells may have profound effects on spermatogenesis [114]. Experimental study dealing with impact of BPA on Sertoli cells demonstrates that exposure of cultured Sertoli cells to BPA decreased cell viability. Treated cells showed alterations in morphology, including blebs on membrane, breakdown of cytoskeletal structures, cell rounding and condensation and fragmentation of DNA that conform to the morphological changes of apoptosis. Results strongly suggest that death of BPA-exposed Sertoli cells is not due to necrosis, but to activation of the apoptotic signal pathways in the cells [115]. In cultured Sertoli cells, BPA also has been shown to induce apoptosis. Moreover, BPA-induced damage of Sertoli cells has been reported by blocking endoplasmic reticulum Ca2+ homeostasis [116] and the ectoplasmic specialization between Sertoli cells and spermatids [117]. Previous findings suggested this chemical inhibits endoplasmic reticulum Ca2+-ATPase activity and mobilizes intracellular Ca2+ concentration in mouse Sertoli cell lines, TM4 [45]. Fiorini et al. [118] also studied mechanism of BPA action on Sertoli cells. Sertoli cells establish intercellular junctions that are essential for spermatogenesis. Currently, it is known that SerW3 Sertoli cells form characteristic protein elements of cell junctions such as gap junctions with connexin 43, tight junctions with occludin and zonula occludens-1 and anchoring junctions with N-cadherin. This xenobiotic substance impairs junctions between adjacent cells in the tissue by decreasing their number or by inducing abnormal position of these membrane proteins within cells. In addition, BPA is also able to induce downregulation of several genes associated with Sertoli cell function (Msi1h, Ncoa1, Nid1, Hspb2 and Gata6) in 6-week-old-male mice after prenatal exposure [119], thereby disrupting the blood-testis barrier and impairing spermatogenesis [120].
3.3. Induction of oxidative stress by BPA in the male reproductive system
Exposure to environmental toxicants such as BPA induces the overproduction of reactive oxygen species, leading to testicular oxidative stress. It is known that BPA decreases the activity of the male-specific cytochrome P450 isoforms, and cytochrome P450 has been shown to induce reactive oxygen species that impairs sperm functions and spermatogenesis [121]. Reactive oxygen species can modify the sperm cytoskeletal and axoneme structures, causing a decrease of sperm motility parameters and low probability of sperm-oocyte fusion and therefore leading to low fertility potential [122]. Free radicals are also able to impair the genetic information within the nucleus of the sperm cell, and this damage to the genome may be translated into infertility [102]. In El-Beshbishy et al. [123] experiment, body weight of BPA orally applied for 14 days to male rats was 10 mg/kg, and considerable decline of enzymes with antioxidant activity in testicular tissue such as catalase, glutathione reductase, superoxide dismutase and glutathione peroxidase has been found. Also, hydrogen peroxide quantity and lipid peroxidation were increased in testes and spermatozoa of BPA-treated animals. Kabuto et al. [86] investigated the modifications in endogenous antioxidant capacity and oxidative damage in the mice testis exposed to BPA, whilst animals were treated with BPA during embryonic and foetal phase of life and during lactation phase by oral administration of drinking water with BPA (5 or 10 μg/L) to their pregnant/lactating mothers and male mice were killed in the fourth week of life. BPA increased levels of thiobarbituric acid-reactive substances in the testis, and results suggested that exposure to this chemical substance induces tissue oxidative stress and peroxidation, ultimately leading to testicular underdevelopment. In another
3.4. Epigenetic effect of BPA on male reproduction
Some chemicals with oestrogenic properties pass through CYP-mediated redox cycle to quinones. Quinones represent biologically active molecules that can bind by covalent bonds to DNA and proteins occurring in the nucleus, such as DNA and RNA polymerases.
Experiments on toxicity of reproductive system exhibited that pregnant female exposed to BPA in prenatal period involved significant fertility disorders of not explicitly F1 male descendants but also subsequent F2 and F3 generations. It also causes increased occurrence of damage during implantation phase in all the three generations. This increase was significant in F3 generation suggesting that this xenobiotic is able to perform its impacts through male germline [130]. Current studies have also begun to suggest the possibility of translation of early exposures to physiological modifications later in life and across generations by epigenetic mechanisms such as methylation-meditated promoter silencing [4]. Epigenetics deals with molecular processes that are associated with hereditary and permanent changes in gene expression. However, these changes do not involve modifications in sequences of DNA. DNA sequences stay constant, but the expression or silencing of genes and regions of gene is mediated by different epigenetic processes, such as methylation, and in reaction to different exposures of environment. DNA methylation is a process by which methyl groups are linked to the DNA molecule, specifically to the cytosine in cytosine-phosphate-guanine segment of DNA. Methylation is able to modify the activity of a DNA sequence without modifying the sequence, and it may cause silencing of gene expression in the segment of DNA [131]. Experiments with rats have demonstrated that BPA exposure and its impact on sexual hormones may cause persistent alterations in the whole male hypothalamic-pituitary-gonadal axis, including development of transgenerational alterations in the levels of steroid hormone receptors in testes, motility of spermatozoa as well as sperm count [113]. Adverse effect of BPA on male germ cells is not matter only prenatal exposure; Tiwari and Vanage [130] experiment demonstrated that adult male rats exposed to 5 mg/kg body weight of BPA during a time of 6 days will generate fatal mutations in spermatozoa. It leads to low sperm motility parameters and sperm production. Due to these facts, it is key to research the epigenetic alterations in male fertility caused by BPA also in later life, not only in critical stages of development. BPA exposure has also been connected to sexually dimorphic alterations in anxiety-like behaviour and general motor activity [132]. This suggests that dose-dependent effects of BPA on emotional aspects and sexually dimorphic manner are associated with demasculinization of characteristic male behaviour [133]. There were also observed alterations in sexual behaviour, especially in a decreased performance in latency and frequency of intromission among BPA-exposed rodents [10, 11]. An impairment in the timing of copulatory sequence was found in Sprague-Dawley male rats, perinatally exposed to BPA via oral administration during pregnancy or lactation [11] or exposed throughout early stages of development [134]. In animals that were postnatally treated by oral administration of BPA, a decrease activity in terms of latence and intromission frequency was noticed [11]. Moreover, same effect in this direction was observed with animals treated in phase of early puberty [134]. Results obtained from study with workers of manufacturers of BPA in China also showed relevant proof that BPA exposure at work significantly increases the possibility of sexual dysfunction in male. The results were the same for all tested parameters that were measured regarding to male sexual dysfunction, all indicating increased risks associated with exposure of BPA. The noticed findings remained after monitoring of wide physiological and psychological aspects that may be related to reproductive disorders between workers exposed to BPA and unexposed workers. Moreover, the relationship between dose and response for found associations also supports the discovery. These findings strengthen probably essential association between exposure to high doses of BPA and raising possibility of reproductive dysfunction in males [93]. Apoptosis of spermatogenic cells was also affected intergenerationally with differential DNA methylation of sperm promoter regions in the F3 generation which was observed in all exposed male lines [135]. Considering the imprinted-like nature of the modified epigenetic DNA methylation sites, sperm cells transfer this epigenome and adult onset disease phenotype to next generations, which is termed epigenetic transgenerational inheritance [136].
Acknowledgments
This study was supported by the Slovak Research and Development Agency Grant nos. APVV-15-0543 and APVV-15-0544.
References
- 1.
Junk GA, Svec HJ, Vick RD, Avery MJ. Contamination of water by synthetic polymer tubes. Environmental Science and Technology. 1974; 8 :1100-1106. DOI: 10.1021/es60098a009 - 2.
Vitku J, Sosvorova L, Chlupacova T, Hampl R, Hill M, Sobotka V, Heracek J, Bicikova M, Starka L. Differences in bisphenol A and estrogen levels in the plasma and seminal plasma of men with different degrees of infertility. Physiological Research. 2015; 64 :303–311 - 3.
Pavlovich CP, King P, Goldstein M, Schlegel PN. Evidence of a treatable endocrinopathy in infertile men. The Journal of Urology. 2001; 165 :837–841. DOI: 10.1016/s0022-5347(05)66540-8 - 4.
Wetherill YB, Akingbemi BT, Kanno J, McLachlan JA, Nadaf A, Sonnenschein C, Watson CS, Zoeller RT, Belcher SM. In vitro molecular mechanisms of bisphenol A action. Reproductive Toxicology. 2007;24 :178–198. DOI: 10.1016/j.reprotox.2007.05.010 - 5.
Nakamura D, Yanagiba Y, Duan Z, Ito Y, Okamura A, Asaeda N, Tagawa Y, Li C, Taya K, Zhang SY, Naito H, Ramdhan DH, Kamijima M, Nakajima T. Bisphenol A may cause testosterone reduction by adversely affecting both testis and pituitary systems similar to estradiol. Toxicology Letters. 2010; 194 :16–25. DOI: 10.1016/j.toxlet.2010.02.002 - 6.
Xu LC, Sun H, Chen JF, Bian Q, Qian J, Song L, Wang XR. Evaluation of androgen receptor transcriptional activities of bisphenol A, octylphenol and nonylphenol in vitro. Toxicology. 2005;216 :197–203. DOI: 10.1016/j.tox.2005.08.006 - 7.
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 :163–172. DOI: 10.1385/endo:25:2:163 - 8.
Chitra KC, Latchoumycandane C, Mathur PP. Induction of oxidative stress by bisphenol A in the epididymal sperm of rats. Toxicology. 2003; 185 :119–127. DOI: 10.1016/s0300-483x(02)00597-8 - 9.
Welshons WV, Nagel SC, Vom Saal FS. Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure. Endocrinology. 2006; 147 :56–69. DOI: 10.1210/en.2005-1159 - 10.
Richter CA, Birnbaum LS, Farabollini F, Newbold RR, Rubin BS, Talsness CE, Vandenbergh JG, Walser-Kuntz DR, Vom Saal FS. In vivo effects of bisphenol A in laboratory rodent studies. Reproductive Toxicology. 2007;24 :199–224. DOI: 10.1016/j.reprotox.2007.06.004 - 11.
Farabollini F, Porrini S, Della Seta D, Bianchi F, Dessi-Fulgheri F. Effects of perinatal exposure to bisphenol A on sociosexual behavior of female and male rats. Environmental Health Perspectives. 2002; 110 :409–414. DOI: 10.1289/ehp.02110s3409 - 12.
Li D, Zhou Z, Qing D, He Y, Wu T, Miao M, Wang J, Weng X, Ferber JR, Herrinton LJ, Zhu Q, Gao E, Checkoway H, Yuan W. Occupational exposure to bisphenol-A (BPA) and the risk of self-reported male sexual dysfunction. Human Reproduction. 2009; 25 :19–27. DOI: 10.1093/humrep/dep381 - 13.
Kundakovic M, Champagne FA. Epigenetic perspective on the developmental effects of bisphenol A. Brain, Behavior, and Immunity. 2011; 25 :1084–1093. DOI: 10.1016/j.bbi.2011.02.005 - 14.
Singh S, Li SS. Epigenetic effects of environmental chemicals bisphenol A and phthalates. International Journal of Molecular Sciences. 2012; 13 :10143–10153. DOI: 10.3390/ijms130810143 - 15.
Shin BS, Kim CH, Jun YS, Kim DH, Lee BM, Yoon CH, Park EH, Lee KC, Han SY, Park KL, Kim HS, Yoo SD. Physiologically based pharmacokinetics of BPA. Journal of Toxicology and Environmental Health A. 2004; 67 :1971–1985. DOI: 10.1080/15287390490514615 - 16.
Vandenberg LN, Maffini MV, Sonnenschein C, Rubin BS, Soto AM. Bisphenol-A and the great divide: A review of controversies in the field of endocrine disruption. Endocrine Reviews. 2009; 30 :75–95. DOI: 10.1210/er.2008-0021 - 17.
Huleihel M, Lunenfeld E. Regulation of spermatogenesis by paracrine/autocrine testicular factors. Asian Journal of Andrology. 2004; 6 :259–268 - 18.
Diemer T, Allen JA, Hales KH, Hales DB. Reactive oxygen disrupts mitochondria in MA-10 tumor Leydig cells and inhibits steroidogenic acute regulatory (StAR) protein and steroidogenesis. Endocrinology. 2003; 144 :2882–2891. DOI: 10.1210/en.2002-0090 - 19.
Labohá P, Jambor T, Yawer A, Lukáč N, Sovadinová I. Molecular mechanisms of alkylphenol-mediated endocrine disruption in Leydig cells. Toxicology Letters. 2016; 258 :245–246. DOI: 10.1016/j.toxlet.2016.06.1872 - 20.
Tsai M, O'Malley BW. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annual Review of Biochemistry. 1994; 63 :451–486. DOI: 10.1146/annurev.biochem.63.1.451 - 21.
Danzo BJ. Environmental xenobiotics may disrupt normal endocrine function by interfering with the binding of physiological ligand to steroid receptors and binding proteins. Environmental Health Perspectives. 1997; 105 :294–301. DOI: 10.2307/3433266 - 22.
Bolger R, Wiese TE, Ervin K, Nestich S, Checovich W. Rapid screening of environmental chemicals for estrogen receptor binding capacity. Environmental Health Perspectives. 1998; 106 :551–557. DOI: 10.2307/3434229 - 23.
Gould JC, Leonar LS, Maness SC, Wagner BL, Conner K, Zacharewski T, Safe S, McDonnell DP, Gaido KW. Bisphenol A interacts with the estrogen receptor alpha in a distinct manner from estradiol. Molecular and Cellular Endocrinology. 1998; 142 :203–214. DOI: 10.1016/s0303-7207(98)00084-7 - 24.
Tora L, White J, Brou Ch, Tasset D, Webster N, Scheer E, Chambon P. The human estrogen receptor has two independent nonacidic transcriptional activation functions. Cell. 1989; 59 :477–487. DOI: 10.1016/0092-8674(89)90031-7 - 25.
Pennie WD, Aldridge TC, Brooks AN. Differential activation by xenoestrogens of ERα and ERβ when linked to different response elements. Journal of Endocrinology. 1998; 158 :11–14. DOI: 10.1677/joe.0.158r011 - 26.
Routledge EJ, White R, Parker MG, Sumpter JP. Differential effects of xenoestrogens on coactivator recruitment by estrogen receptor (ER) alpha and ER beta. The Journal of Biological Chemistry. 2000; 275 :35986–35993. DOI: 10.1074/jbc.m006777200 - 27.
Song KH, Lee K, Choi HS. Endocrine disrupter bisphenol A induces orphan nuclear receptor Nur77 gene expression and steroidogenesis in mouse testicular Leydig cells. Endocrinology. 2002; 143 :2208–2215. DOI: 10.1210/endo.143.6.8847 - 28.
An BS, Kang SK, Shin JH, Jeung EB. Stimulation of calbindin-D(9k) mRNA expression in the rat uterus by octylphenol, nonylphenol and bisphenol. Molecular and Cellular Endocrinology. 2002; 191 :177–186. DOI: 10.1016/s0303-7207(02)00042-4 - 29.
Vivacqua A, Recchia AG, Fasanella G, Gabriele S, Carpino A, Rago V, Di Gioia ML, Leggio A, Bonofiglio D, Liguori A, Maggiolini M. The food contaminants bisphenol A and 4-nonylphenol act as agonists for estrogen receptor alpha in MCF7 breast cancer cells. Endocrine. 2003; 22 :275–284. DOI: 10.1385/endo:22:3:275 - 30.
Rankouhi R, Sanderson JT, Van Holstejin I, Van Kooten P, Bosveld AT, Van den Berg M. Effects of environmental and natural estrogens on vitellogenin production in hepatocytes of the brown frog ( Rana temporaria ). Aquatic Toxicology. 2005;71 :97–101. DOI: 10.1016/j.aquatox.2004.09.009 - 31.
Wersinger SR, Haisenleder DJ, Lubahn DB, Rissman EF. Steroid feedback on gonadotropin release and pituitary gonadotropin subunit mRNA in mice lacking a functional estrogen receptor alpha. Endocrine. 1999; 11 :137–143. DOI: 10.1385/endo:11:2:137 - 32.
Sohoni P, Sumpter JP. Several environmental oestrogens are also anti-androgens. Journal of Endocrinology. 1998; 158 :327–339. DOI: 10.1677/joe.0.1580327 - 33.
Gaido KW, Maness SC, McDnnell DP, Dehal SS, Kupfer D, Safe S. Interaction of methoxychlor and related compounds with estrogen receptor alpha and beta, and androgen receptor: Structure-activity studies. Molecular Pharmacology. 2000; 58 :852–858. DOI: 10.1124/mol.58.4.852 - 34.
Wong CH, Zhou ZX, Sar M, Wilson EM. Steroid requirement for androgen receptor dimerization and DNA binding. The Journal of Biological Chemistry. 1993; 268 :19004–19012 - 35.
McKenna NJ, Lanz RB, O'Malley BW. Nuclear receptor coregulators: Cellular and molecular biology. Endocrine Reviews. 1999; 20 :321–344. DOI: 10.1210/er.20.3.321 - 36.
Yeh S, Chang C. Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells. Proceedings of the National Academy of Sciences. 1996; 93 :5517–5521. DOI: 10.1073/pnas.93.11.5517 - 37.
Quigley CA, De Bellis A, Marschke KB, el-Awady MK, Wilson EM, French FS. Androgen receptor defects: Historical, clinical, and molecular perspectives. Endocrine Reviews. 1995; 16 :271–321. DOI: 10.1210/er.16.3.271 - 38.
Lee HJ, Chattopadhyay S, Gong EY, Ahn RS, Lee K. Antiandrogenic effects of bisphenol A and nonylphenol on the function of androgen receptor. Toxicological Sciences. 2003; 75 :40–46. DOI: 10.1093/toxsci/kfg150 - 39.
Sun H, Xu LC, Chen JF, Song L, Wang XR. Effect of bisphenol A, tetrachlorobisphenol A and pentachlorophenol on the transcriptional activities of androgen receptor-mediated reporter gene. Food and Chemical Toxicology. 2006; 44 :1916–1921. DOI: 10.1016/j.fct.2006.06.013 - 40.
Kitamura S, Suzuki T, Sanoh S, Kohta R, Jinno N, Suigihara K, Yoshihara S, Fujimota N, Watanabe H, Ohta S. Comparative study of the endocrine-disrupting activity of bisphenol A and 19 related compounds. Toxicological Sciences. 2005; 84 :249–259. DOI: 10.1093/toxsci/kfi074 - 41.
Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinänen R, Palmgerg Ch, Palotie A, Tammela T, Isola J, Kallioniemi OP. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nature Genetics. 1995;9 :401–406. DOI: 10.1038/ng0495-401 - 42.
Ramos JG, Varayoud J, Sonnenschein C, Soto AM, Toro MM, Luque EH. Prenatal exposure to low doses of bisphenol A alters the periductal stroma and glandular cell function in the rat ventral prostate. Biology of Reproduction. 2001; 65 :1271–1277. DOI: 10.1095/biolreprod65.4.1271 - 43.
Cagen SZ, Waechter JM, Dimond SS, Breslin WJ, Butala JH, Jekat FW, Joiner RL, Shiotsuka RN, Veenstra GE, Harris LR. Normal reproductive organ development in CF-1 mice following prenatal exposure to bisphenol A. Toxicological Sciences. 1999; 50 :36–44. DOI: 10.1093/toxsci/50.1.36 - 44.
Takahashi O, Oishi S. Disposition of orally administered 2,2-bis (4-hydroxyphenyl) propane (BPA) in pregnant rats and the placental transfer to fetuses. Environmental Health Perspectives. 2000; 108 :931–935. DOI: 10.2307/3435050 - 45.
Hughes PJ, McLellan H, Lowes DA, Kahn SZ, Bilmen JG, Tovey SC, Godfrey RE, Michell RH, Kirk CJ, Michelangeli F. Estrogenic alkylphenols induce cell death by inhibiting testis endoplasmic reticulum CA(2+) pumps. Biochemical and Biophysical Research Communications. 2000; 277 :568–574. DOI: 10.1006/bbrc.2000.3710 - 46.
Sanderson JT, Seinen W, Giesy JP, van den Berg M. 2-chloro-s-triazine herbicides induce aromatase (CYP19) activity in H295R human adrenocortical carcinoma cells: A novel mechanism for estrogenicity. Toxicological Sciences. 2000; 54 :121–127. DOI: 10.1093/toxsci/54.1.121 - 47.
Hilscherova K, Jones PD, Gracia T, Newsted JL, Zhang XW, Sanderson JT, Yu RMK, Wu RSS, Giesy JP. Assessment of the effects of chemicals on the expression of ten steroidogenic genes in the H295R cell line using real-time PCR. Toxicological Sciences. 2004; 81 :78–89. DOI: 10.1093/toxsci/kfh191 - 48.
Zhang X, Yu RM, Jones PD, Lam GK, Newsted JL, Gracia T, Hecker M, Hilscherova K, Sanderson T, Wu RS, Giesy JP. Quantitative RT-PCR methods for evaluating toxicant-induced effects on steroidogenesis using the H295R cell line. Environmental Science and Technology. 2005; 39 :2777–2785. DOI: 10.1021/es048679k - 49.
Zhang X, Chang H, Wiseman S, He Y, Higley E, Jones P, Wong CK, Al-Khedhairy A, Giesy JP, Hecker M. Bisphenol A disrupts steroidogenesis in human H295R cells. Toxicological Sciences. 2011; 121 :320–327. DOI: 10.1093/toxsci/kfr061 - 50.
Akingbemi BT, Sottas CHM, 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 :592–603. DOI: 10.1210/en.2003-1174 - 51.
Ye X, Wong LY, Bishop AM, Calafat AM. Variability of urinary concentrations of bisphenol A in spot samples, first-morning voids, and 24-hour collections. Environmental Health Perspectives. 2011; 119 :983–988. DOI: 10.1289/ehp.1002701 - 52.
Geissler WM, Davis DL, Wu L, Bradshaw KD, Patel S, Mendonca BB, Elliston KO, Wilson JD, Russell DW, Andersson S. Male pseudohermaphroditism caused by mutations of testicular 17 beta-hydroxysteroid dehydrogenase 3. Nature Genetics. 1994; 7 :34–39. DOI: 10.1038/ng0594-34 - 53.
Andersson S, Moghrabi N. Physiology and molecular genetics of 17 beta-hydroxysteroid dehydrogenases. Steroids. 1997; 62 :143–147. DOI: 10.1016/s0039-128x(96)00173-0 - 54.
Hess RA. Oestrogen in fluid transport in efferent ducts of the male reproductive tract. Reviews of Reproduction. 2000; 5 :84–92. DOI: 10.1530/revreprod/5.2.84 - 55.
Kinoshita Y, Chen S. Induction of aromatase (CYO19) expression in breast cancer cells through a nongenomic action of estrogen receptor α. Cancer Research. 2003; 63 :3546–3555 - 56.
Nikula H, Talonpoika T, Kaleva M, Toppari J. Inhibition of hCG-stimulated steroidogenesis in cultured mouse Leydig tumor cells by BPA and octylphenols. Toxicology and Applied Pharmacology. 1999; 157 :166–173. DOI: 10.1006/taap.1999.8674 - 57.
Gaskell TL, Robinson LL, Groome, NP, Anderson RA, Saunders PT. Differential expression of two estrogen receptor-β isoforms in the human fetal testis during the second trimester of pregnancy. The Journal of Clinical Endocrinology and Metabolism. 2003; 88 :424–432. DOI: 10.1210/jc.2002-020811 - 58.
Schönfelder G, Wittfoht W, Hopp H, Talsness CHE, Paul M, Chahoud I. Parental bisphenol A accumulation in the human maternal-fetal-placental unit. Environmental Health Perspectives. 2002; 110 :703–707. DOI: 10.1289/ehp.021100703 - 59.
Ikezuki Y, Tsutsumi O, Takai Y, Kamei Y, Taketani Y. Determination of bisphenol A concentrations in human biological fluids reveals significant early prenatal exposure. Human Reproduction. 2002; 17 :2839–2841. DOI: 10.1093/humrep/17.11.2839 - 60.
Uchida K, Suzuki A, Kobayashi Y, Buchanan DL, Sato T, Watanabe H, Katsu Y, Suzuki J, Asaoka K, Mori Ch, Arizono K, Iguchi T. Bisphenol A administration during pregnancy results in fetal exposure in mice and monkeys. Journal of Health Science. 2002; 48 :579–582. DOI: 10.1248/jhs.48.579 - 61.
Kawai K, Nozaki T, Nishikata H, Aou S, Takii M, Kubo Ch. Aggressive behavior and serum testosterone concentration during the maturation process of male mice: The effects of fetal exposure to bisphenol A. Environmental Health Perspectives. 2003; 111 :175–178. DOI: 10.1289/ehp.5440 - 62.
Nagel SC, Vom Saal FS, Thayer KA, Dhar MG, Boechler M, Welshons WV. Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol. Environmental Health Perspectives. 1997;105 :70–76. DOI: 10.2307/3433065 - 63.
Vom Saal FS, Cooke PS, Buchanan DL, Palanza P, Thayer KA, Nagel SC, Parmigiani S, Welshons WV. 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 :239–260. DOI: 10.1177/074823379801400115 - 64.
Xi W, Wan HT, Zhao YG, Wong MH, Giesy JP, Wong CK. Effects of perinatal exposure to bisphenol A and di(2-ethylhexyl)-phthalate on gonadal development of male mice. Environmental Science and Pollution Research International. 2012; 19 :2515–2527. DOI: 10.1007/s11356-012-0827-y - 65.
Takeuchi T, Tsutsumi O. Serum bisphenol A concentrations showed gender differences, possibly linked to androgen levels. Biochemical and Biophysical Research Communications. 2002; 291 :76–78. DOI: 10.1006/bbrc.2002.6407 - 66.
Tanaka M, Nakaya S, Katayama M, Leffers H, Nozawa S, Nakazawa R, Iwamoto T, Kobayashi S. Effect of prenatal exposure to bisphenol A on the serum testosterone concentration of rats at birth. Human and Experimental Toxicology. 2006; 25 :369–373. DOI: 10.1191/0960327106ht638oa - 67.
Nanjappa MK, Simon L, Akingbemi BT. The industrial chemical bisphenol A (BPA) interferes with proliferative activity and development of steroidogenic capacity in rat Leydig cells. Biology of Reproduction. 2012; 86 :1–12. DOI: 10.1095/biolreprod.111.095349 - 68.
Timms BG, Petersen SL, Vom Saal FS. Prostate gland growth during development is stimulated in both male and female rat fetuses by intrauterine proximity to female fetuses. The Journal of Urology. 1999; 161 :1694–1701. DOI: 10.1016/s0022-5347(05)69007-6 - 69.
Marker PC, Donjacour AA, Dahiya R, Cunha GR. Hormonal, cellular, and molecular control of prostatic development. Developmental Biology. 2003; 253 :165–174. DOI: 10.1016/s0012-1606(02)00031-3 - 70.
Adam BL, Qu Y, Davis JW, Ward MD, Clements MA, Cazares LH, Semmes OJ, Schellhammer PF, Yasui Y, Feng Z, Wright GL. Serum protein fingerprinting coupled with a pattern-matching algorithm distinguishes prostate cancer from benign prostate hyperplasia and healthy men. Cancer Research. 2002; 62 :3609–3614 - 71.
Alonso-Magdalena P, Vieira E, Soriano S, Menes L, Burks, D, Quesada I, Nadal A. Bisphenol A exposure during pregnancy disrupts glucose homeostasis in mother and adult male offspring. Environmental Health Perspectives. 2010; 118 :1243–1250. DOI: 10.1289/ehp.1001993 - 72.
Kloas W, Lutz I, Einspanier R. Amphibians as a model to study endocrine disruptors: II. Estrogenic activity of environmental chemicals in vitro andin vivo . The Science of the Total Environment. 1999;225 :59–68. DOI: 10.1016/s0048-9697(98)00332-5 - 73.
Miyata S, Koike S, Kubo T. Hormonal reversal and the genetic control of sex differentiation in Xenopus. Zoological Science. 1999;16 :335–340. DOI: 10.2108/zsj.16.335 - 74.
Bögi C, Levy G, Luts I, Kloas W. Functional genomics and sexual differentiation in amphibians. Comparative biochemistry and Physiology. Part B, Biochemistry & Molecular Biology. 2002; 133 :559–570. DOI: 10.1016/s1096-4959(02)00162-8 - 75.
Yokota H, Tsuruda Y, Maeda M, Oshima Y, Tadokoro H, Nakazono A, Honjo T, Kobayashi K. Effect of bisphenol A on the early life stage in Japanese medaka ( Oryzias latipes ). Environmental Toxicology and Chemistry. 2000;19 :1925–1930. DOI: 10.1002/etc.5620190730 - 76.
Ashfield LA, Pottinger TG, Sumpter JP. Exposure of female juvenile rainbow trout to alkylphenolic compounds results in modifications to growth and ovosomatic index. Environmental Toxicology. 1998; 17 :679–686. DOI: 10.1897/1551-5028(1998)017<0679:eofjrt>2.3.co;2 - 77.
Pryor JL, Hughes C, Foster W, Hales BF, Rodaire B. Critical windows of exposure for children´s health: The reproductive system in animals and humans. Environmental Health Perspectives. 2000; 108 :491–503. DOI: 10.2307/3454541 - 78.
Aoki T, Takada T. Bisphenol A modulates germ cell differentiation and retinoic acid signaling in mouse ES cells. Reproductive Toxicology. 2012; 34 :463–470. DOI: 10.1016/j.reprotox.2012.06.001 - 79.
Morrissey RE, Lamb JC, Schwetz BA, Teague JL, Morris RW. Association of sperm, vaginal cytology, and reproductive organ weight data with results of continuous breeding reproduction studies in Swiss (CD-1) mice. Fundamental and Applied Toxicology. 1988; 11 :359–371. DOI: 10.1016/0272-0590(88)90160-1 - 80.
Manfo FPT, Jubendradass R, Nantia EA, Moundipa PF, Mathur PP. Adverse effects of bisphenol A on male reproductive function. Reviews of Environmental Contamination and Toxicology. 2014; 228 :57–82. DOI: 10.1007/978-3-319-01619-1_3 - 81.
Kato H, Furuhashi T, Tanaka M, Katsu Y, Watanabe H, Ohta Y, Iguchi T. Effects of BPA given neonatally on reproductive functions of male rats. Reproductive Toxicology. 2006; 22 :20–29. DOI: 10.1016/j.reprotox.2005.10.003 - 82.
Wozniak AL, Bulayeva NN, Watson CS. Xenoestrogens at picomolar to nanomolar concentrations trigger membrane estrogen receptor-α-mediated Ca2+ fluxes and prolactin release in GH3/B6 pituitary tumor cells. Environmental Health Perspectives. 2005; 113 :431–439. DOI: 10.1289/ehp.7505 - 83.
Sakaue M, Ohsako S, Ishimura R, Kurosawa S, Kurohmaru M, Hayashi Y, Aoki Y, Yonemoto J, Tohyama C. Bisphenol-A affects spermatogenesis in the adult rat even at low dose. Journal of Occupational Health. 2001; 43 :185–190. DOI: 10.1539/joh.43.185 - 84.
Mínquez-Alarcón L, Hauser R, Gaskins AJ. Effects of bisphenol A on male and couple reproductive health: A review. Fertility and Sterility. 2016; 106 :864–870. DOI: 10.1016/j.fertnstert.2016.07.1118 - 85.
Mathur PP, D’Cruz SC. The effect of environmental contaminants on testicular function. Asian Journal of Andrology. 2011; 13 :585–591. DOI: 10.1038/aja.2011.40 - 86.
Kabuto H, Amakawa M, Shishibori T. Exposure to bisphenol A during embryonic/fetal life and infancy increases oxidative injury and causes underdevelopment of the brain and testis in mice. Life Sciences. 2004; 74 :2931–2940. DOI: 10.1016/j.lfs.2003.07.060 - 87.
Hulak M, Gazo I, Shaliutina A, Linhartova P. In vitro effects of BPA on the quality parameters, oxidative stress, DNA integrity and adenosine triphosphate content in sterlet (Acipenser ruthenus ) spermatozoa. Comparative Biochemistry and Physiology. 2013;158 :64–71. DOI: 10.1016/j.cbpc.2013.05.002 - 88.
D’Cruz SC, Jubendradass R, Mathur PP. Bisphenol A induces oxidative stress and decreases levels of insulin receptor substrate 2 and glucose transporter 8 in rat testis. Reproductive Sciences. 2012; 19 :163–172. DOI: 10.1177/1933719111415547 - 89.
Rubin BS, Murray MK, Damassa DA, King JC, Soto AM. Perinatal exposure to low doses of bisphenol A affects body weight, patterns of estrous cyclicity, and plasma LH levels. Environmental Health Perspectives. 2001; 109 :675–680. DOI: 10.2307/3454783 - 90.
Jin P, Wang X, Chang F, Bai Y, Li Y, Zhou R, Chen L. Low dose bisphenol A impairs spermatogenesis by suppressing reproductive hormone production and promoting germ cell apoptosis in adult rats. Journal of Biomedical Research. 2013; 27 :135–144. DOI: 10.7555/jbr.27.20120076 - 91.
Gurmeet KSS, Rosnah I, Normadiah MK, Das S, Mustafa AM. Detrimental effects of BPA on development and functions of the male reproductive system in experimental rats. Experimental and Clinical Sciences Journal 2014; 13 :151–160 - 92.
Furuya M, Adachi K, Kuwahara S, Ogawa K, Tsukamoto Y. Inhibition of male chick phenotypes and spermatogenesis by bisphenol-A. Life Sciences. 2006; 78 :1767–1776. DOI: 10.1016/j.lfs.2005.08.016 - 93.
Li D, Zhou Z, Miao M, He Y, Wang J, Ferber J, Herrinton LJ, Gao E, Yuan W. Urine bisphenol-A (BPA) level in relation to semen quality. Fertility and Sterility. 2011; 95 :625–630. DOI: 10.1016/j.fertnstert.2010.09.026 - 94.
Wang T, Lu J, Xu M, Xu Y, Li M, Liu Y, Tian X, Chen Y, Dai M, Wang W, Lai S, Bi Y, Ning G. Urinary bisphenol A concentration and thyroid function in Chinese adults. Epidemiology. 2013; 24 :295–302. DOI: 10.1097/ede.0b013e318280e02f - 95.
Bennetts LE, De Iuliis GN, Nixon B, Kime M, Zelski K, McVicar CM, Lewis SE, Aitken RJ. Impact of estrogenic compounds on DNA integrity in human spermatozoa: Evidence for cross-linking and redox cycling activities. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 2008; 641 :1–11. DOI: 10.1016/j.mrfmmm.2008.02.002 - 96.
Martinez C, Mar C, Azcarate M, Pascual P, Aritzeta JM, Lopez-Urrutia A. Sperm motility index: A quick screening parameter from sperm quality analyser-IIB to rule out oligo- and asthenozoospermia in male fertility study. Human Reproduction. 2000; 15 :1727–1733. DOI: 10.1093/humrep/15.8.1727 - 97.
Jansen RPS, Burton GJ. Mitochondrial dysfunction in reproduction. Mitochondrion. 2004; 4 :577–600. DOI: 10.1016/j.mito.2004.07.038 - 98.
Kotwicka M, Skibinska I, Jendraszak M, Jedrzejczak P. 17β-estradiol modifies human spermatozoa mitochondrial function in vitro. Reproductive Biology and Endocrinology . 2016;14 :50. DOI: 10.1186/s12958-016-0186-5 - 99.
Anjum S, Rahman A, Kaur M, Ahmad F, Rashid H, Ansari RA, Raisuddin S. Melatonin Ameliorates BPA-induced biochemical toxicity in testicular mitochondria of mouse. Food and Chemical Toxicology. 2011; 49 :2849–2854. DOI: 10.1016/j.fct.2011.07.062 - 100.
Al-Hiyasat AS, Darmani H, Elbetieha AM. Effects of bisphenol A on adult male mouse fertility. European Journal of Oral Sciences. 2002; 110 :163–167. DOI: 10.1034/j.1600-0722.2002.11201.x - 101.
Dobrzyńska MM, Radzikowska J. Genotoxicity and reproductive toxicity of bisphenol A and X-ray/bisphenol A combination in male mice. Drug and Chemical Toxicology. 2013; 36 :19–26. DOI: 10.3109/01480545.2011.644561 - 102.
Singh RP, Shafeeque CM, Sharma SK, Pandey NK, Singh R, Mohan J, Kolluri G, Saxena M, Sharma B, Sastry KV, Kataria JM, Azeez PA. Bisphenol A reduces fertilizing ability and motility by compromising mitochondrial function of sperm. Enviromental Toxicology and Chemistry. 2015; 34 :1617–1622. DOI: 10.1002/etc.2957 - 103.
Deutschmann A, Hans M, Meyer R, Häberlein H, Swandulla D. Bisphenol A inhibits voltage-activated Ca2+ channels in vitro : Mechanisms and structural requirements. Molecular Pharmacology. 2013;83 :501–511. DOI: 10.1124/mol.112.081372 - 104.
Lukacova J, Jambor T, Knazicka Z, Tvrda E, Kolesarova A, Lukac N. Dose- and time-dependent effects of BPA on bovine spermatozoa in vitro . Journal of Environmental Science and Health. 2015;50 :669–676. DOI: 10.1080/10934529.2015.1011963 - 105.
Rahman MS, Kwon WS, Lee JS, Yoon SJ, Ryu BY, Pang MG. Bisphenol-A affects male fertility via fertility-related proteins in spermatozoa. Scientific Reports. 2015; 5 :9169. DOI: 10.1038/srep09169 - 106.
Hatef A, Alavi SMH, Linhartova Z, Rodina M, Policar T, Linhart O. In vitro effects of BPA on sperm motility characteristics perca fluviatilis L. (Percidae; Teleostei). Journal of Applied Ichthyology. 2010;26 :696–701. DOI: 10.1111/j.1439-0426.2010.01543.x - 107.
Meeker JD, Ehrlich S, Toth TL, Wright DL, Calafat AM, Trisini AT, Ye X, Hauser R. Semen quality and sperm DNA damage in relation to urinary bisphenol A among men from an infertility clinic. Reproductive Toxicology. 2010; 30 :532–539. DOI: 10.1016/j.reprotox.2010.07.005 - 108.
Lassen TH, Frederiksen H, Jensen TK, Petersen JH, Joensen UN, Main KM, Skakkebaek NE, Juul A, Jorgensen N, Andersson A. Urinary bisphenol A levels in young men: Association with reproductive hormones and semen quality. Environmental Health Perspectives. 2014; 122 :478–484. DOI: 10.1289/ehp.1307309 - 109.
Iwakura T, Iwafuchi M, Muraoka D, Yokosuka M, Shiga T, Watanabe C, Ohtani-Kaneko R. In vitro effects of bisphenol A on developing hypothalamic neurons. Toxicology. 2010;272 :52–58. DOI: 10.1016/j.tox.2010.04.005 - 110.
Miao M, Yuan W, He Y, Zhou Z, Wang J, Gao E, Li G, Li D. In utero exposure to bisphenol-A and anogenital distance of male offspring. Birth Defects Research. 2011; 91 :867–872. DOI: 10.1002/bdra.22845 - 111.
Gupta CH. Reproductive malformation of the male offspring following maternal exposure to estrogenic chemicals. Proceedings of the Society for Experimental Biology and Medicine. 2000; 224 :61–68. DOI: 10.1046/j.1525-1373.2000.22402.x - 112.
Chahoud I, Fialkowski O, Gericke CH, Merker H, Talsness CE. The effects of low and high doses of bisphenol A on the reproductive system of female and male rat offspring. Reproductive Toxicology. 2000; 40 :587–599. DOI: 10.1016/S0890‐6238(01)00153-8 - 113.
Salian S, Doshi T, Vanage G. Perinatal exposure of rats to bisphenol A affects fertility of male offspring-an overview. Reproductive Toxicology. 2011; 31 :359–362. DOI: 10.1016/j.reprotox.2010.10.008 - 114.
Griswold MD. Interactions between germ cells and Sertoli cells in the testis. Biology of Reproduction. 1995; 52 :211–216. DOI: 10.1095/biolreprod52.2.211 - 115.
Iida H, Maehara K, Doiguchi M, Mori T, Yamada F. Bisphenol A-induced apoptosis of cultured rat Sertoli cells. Reproductive Toxicology. 2003; 17 :457–464. DOI: 10.1016/s0890-6238(03)00034-0 - 116.
Tabuchi Y, Konodo T. cDNA microarray analysis reveals chop-10 plays a key role in Sertoli cell injury induced by bisphenol A. Biochemical and Biophysical Research Communications. 2003; 305 :54–61. DOI: 10.1016/s0006-291x(03)00708-3 - 117.
Toyama Y, Suzuki-Toyota F, Maekawa M, Ito C, Toshimori K. Adverse effects of bisphenol A to spermatogenesis in mice and rats. Archives of Histology and Cytology. 2004; 67 :373–381. DOI: 10.1679/aohc.67.373 - 118.
Fiorini C, Tilloy-Ellul A, Chevalier S, Charusel C, Pointis G. Sertoli cell junctional proteins as early targets for different classes of reproductive toxicants. Reproductive Toxicology. 2004; 18 :413–421. DOI: 10.1016/j.reprotox.2004.01.002 - 119.
Tainaka H, Takahashi H, Umezawa M, Tanaka H, Nishimune Y, Oshio S, Takeda K. Evaluation of the testicular toxicity of prenatal exposure to bisphenol A based on microarray analysis combined with MeSH annotation. The Journal of Toxicological Sciences. 2012; 37 :539–548. DOI: 10.2131/jts.37.539 - 120.
Su L, Mruk DD, Cheng CY. Drug transporters, the blood-testis barrier, and spermatogenesis. Journal of Endocrinology. 2011; 208 :207–223. DOI: 10.5353/th_b4775281 - 121.
Griveau JF, Dumont E, Renard P, Callegari JP, Le Lannou D. Reactive oxygen species, lipid peroxidation and enzymatic defence systems in human spermatozoa. The Journal of the Society for Reproduction and Fertility. 1995; 103 :17–26. DOI: 10.1530/jrf.0.1030017 - 122.
Aitken RJ, Clarkson JS, Fishel S. Generation of reactive oxygen species, lipid peroxidation, and human sperm function. Biology of Reproduction. 1989; 41 :183–197. DOI: 10.1095/biolreprod41.1.183 - 123.
El-Beshbishy HA, Aly HAA, El-Shafey M. Lipoic acid mitigates bisphenol A-induced testicular mitochondrial toxicity in rats. Toxicology and Industrial Health. 2013; 29 :875–887. DOI: 10.1177/0748233712446728 - 124.
De Flora S, Micale RT, La Maestra S, Izzotti A, D’Agostini F, Camoirano A, Davoli SA, Troglio MG, Rizzi F, Davalli P, Bettuzzi S. Upregulation of clusterin in prostate and DNA damage in spermatozoa from bisphenol A-treated rats and formation of DNA adducts in cultured human prostatic cells. Toxicological Sciences. 2011; 122 :45–51. DOI: 10.1093/toxsci/kfr096 - 125.
Barbonetti A, Castellini C, Di Giammarco N, Santilli G, Francavilla S, Francavilla F. In vitro exposure of human spermatozoa to BPA induces pro-oxidative/apoptotic mitochondrial dysfunction. Reproductive Toxicology. 2016;66 :61–67. DOI: 10.1016/j.reprotox.2016.09.014 - 126.
Atkinson A, Roy D. In vitro conversion of environmental estrogenic chemical bisphenol A to DNA binding metabolite(s). Biochemical and Biophysical Research Communications. 1995;210 :424–433. DOI: 10.1006/bbrc.1995.1678 - 127.
Jonathan N, Steinmets R. Xenoestrogens: The emerging story of bisphenol A. Trends in Endocrinology and Metabolism. 1998; 9 :124–128. DOI: 10.1016/s1043-2760(98)00029-0 - 128.
Atkinson A, Roy D. In vivo DNA adduct formation by bisphenol A. Environmental and Molecular Mutagenesis. 1995;26 :60–66. DOI: 10.1002/em.2850260109 - 129.
Knaak JB, Sullivan LJ. Metabolism of bisphenol A in the rat. Toxicology and Applied Pharmacology. 1966; 8 :175–184. DOI: 10.1016/s0041-008x(66)80001-7 - 130.
Tiwari D, Vanage G. Mutagenic effect of bisphenol A on adult rat male germ cells and their fertility. Reproductive Toxicology. 2013; 40 :60–68. DOI: 10.1016/j.reprotox.2013.05.013 - 131.
Mileva G, Baker SL, Konkle ATM, Bielajew C. Bisphenol-A: Epigenetic reprogramming and effects on reproduction and behavior. International Journal of Environmental Research and Public Health. 2014; 11 :7537–7561. DOI: 10.3390/ijerph110707537 - 132.
Farabollini F, Porrini S, Dessi-Fulgheri F. Perinatal exposure to the estrogenic pollutant bisphenol A affects behavior in male and female rats. Pharmacology Biochemistry and Behavior. 1999; 64 :687–694. DOI: 10.1016/s0091-3057(99)00136-7 - 133.
Jones BA, Watson NV. Perinatal BPA exposure demasculinizes males in measures of affect but has no effect on water maze learning in adulthood. Hormones and Behavior. 2012; 61 :605–610. DOI: 10.1016/j.yhbeh.2012.02.011 - 134.
Della Seta D, Minder I, Belloni V, Aloisi AM, Dessi-Fulgheri F, Farabollini F. Pubertal exposure to estrogenic chemicals affects behavior in juvenile and adult male rats. Hormones and Behavior. 2006; 50 :301–307. DOI: 10.1016/j.yhbeh.2006.03.015 - 135.
Manikkam M, Guerrero-Bosagna C, Tracey R, Haque M, Skinner MK. Transgenerational actions of environmental compounds on reproductive disease and identification of epigenetic biomarkers of ancestral exposures. PLoS One. 2012; 7 :31901. DOI: 10.1371/journal.pone.0031901 - 136.
Skinner MK, Guerrero-Bosagna C, Haque M, Nilsson E, Bhandari R, McCarrey JR. Environmentally induced transgenerational epigenetic reprogramming of primordial germ cells and the subsequent germ line. PLoS One. 2013; 8 :66318. DOI: 10.1371/journal.pone.0066318