Bisphenol A and Male Reproductive System

  • Fatma F. Mohamed Amraje
  • Ayşe Köylü
  • Saadet Özen Akarca Dizakar
  • İsmail Türkoğlu
  • Suna Ömeroğlu
Keywords: Bisphenol A, leydig cell, sertoli cell, sperm, sperm quality, testosterone


Bisphenol A (BPA) is an alkylphenol endocrine disruptor chemical (EDC). It is a building block for polycarbonate (PC) plastics and epoxy resins and it is used in food packaging, canned foods, baby bottles, baby food jars and medical devices. Recently, researchers have shown an increased interest in BPA and its effect on reproduction, neurodevelopment and metabolism. The experimental data are rather controversial, and there is no general consensus about BPA’s effects. In this review, potential impacts of the BPA on male reproductive system in prenatal and postnatal period are summarized.


Huo X, Chen D, He Y, Zhu W, Zhou W, Zhang J. Bisphenol-A and female infertility: a possible role of gene-environment interactions. International journal of environmental research and public health 2015;12:11101-16.

Rochester JR, Bolden AL. Bisphenol S and F: a systematic review and comparison of the hormonal activity of bisphenol A substitutes. Environmental health perspectives 2015;123:643.

Yin L, Dai Y, Cui Z, Jiang X, Liu W, Han F, et al. The regulation of cellular apoptosis by the ROS-triggered PERK/EIF2α/chop pathway plays a vital role in bisphenol A-induced male reproductive toxicity. Toxicology and applied pharmacology 2017;314:98-108.

Ahbab MA, Barlas N, Karabulut G. The toxicological effects of bisphenol A and octylphenol on the reproductive system of prepubertal male rats. Toxicology and industrial health 2017;33:133-46.

Shi M, Sekulovski N, MacLean JA, Hayashi K. Prenatal exposure to bisphenol A analogues on male reproductive functions in mice. Toxicological Sciences 2018:kfy061.

Li L, Wang Q, Zhang Y, Niu Y, Yao X, Liu H. The molecular mechanism of bisphenol A (BPA) as an endocrine disruptor by interacting with nuclear receptors: insights from molecular dynamics (MD) simulations. PloS one 2015;10:e0120330.

Cooper-Roth T. The Effects of Bisphenol A on Embryonic Development. Embryo Project Encyclopedia 2012.

YOKOTA H, IWANO H, Mari E, KOBAYASHI T, INOUE H, IKUSHIRO S-i, et al. Glucuronidation of the environmental oestrogen bisphenol A by an isoform of UDP-glucuronosyltransferase, UGT2B1, in the rat liver. Biochemical Journal 1999;340:405-9.

Stahlhut RW, Welshons WV, Swan SH. Bisphenol A data in NHANES suggest longer than expected half-life, substantial nonfood exposure, or both. Environmental health perspectives 2009;117:784.

Xu J, Huang G, Guo TL. Developmental Bisphenol A Exposure Modulates Immune-Related Diseases. Toxics 2016;4:23.

Szychowski KA, Wójtowicz AK. Components of plastic disrupt the function of the nervous system. Postepy higieny i medycyny doswiadczalnej (Online) 2013;67:499-506.

Le HH, Carlson EM, Chua JP, Belcher SM. Bisphenol A is released from polycarbonate drinking bottles and mimics the neurotoxic actions of estrogen in developing cerebellar neurons. Toxicology letters 2008;176:149-56.

Buyer Beware Toxic BPA and regrettable substitutes found in the linings of canned food (cited 2018 May 28) Available from: URL: http:

Summary of Bisphenol A (BPA) Regulation (2nd Edition) (cited 2018 May 28). Available from: URL: http:

Turkey, Minister of Agrriculture and Rural Affairs (2011). Türk gıda kodeksi gıda maddeleri ile temasta bulunan (in Turkish) (cited 2018 May 28) Available from: URL: http:

Xing L, Xu Y, Xiao Y, Shang L, Liu R, Wei X, et al. Embryotoxic and teratogenic effects of the combination of bisphenol A and genistein on in vitro cultured postimplantation rat embryos. Toxicological Sciences 2010;115:577-88.

García-Córcoles M, Cipa M, Rodríguez-Gómez R, Rivas A, Olea-Serrano F, Vílchez J, et al. Determination of bisphenols with estrogenic activity in plastic packaged baby food samples using solid-liquid extraction and clean-up with dispersive sorbents followed by gas chromatography tandem mass spectrometry analysis. Talanta 2018;178:441-8.

Snijder CA, Heederik D, Pierik FH, Hofman A, Jaddoe VW, Koch HM, et al. Fetal growth and prenatal exposure to bisphenol A: the generation R study. Environmental health perspectives 2013;121:393.

Sadler TW. Langman's medical embryology: Lippincott Williams & Wilkins 2011.

Palanza P, Nagel SC, Parmigiani S, vom Saal FS. Perinatal exposure to endocrine disruptors: sex, timing and behavioral endpoints. Current opinion in behavioral sciences 2016;7:69-75.

Walker DM, Gore AC. Transgenerational neuroendocrine disruption of reproduction. Nature Reviews Endocrinology 2011;7:197.

Preciados M, Yoo C, Roy D. Estrogenic endocrine disrupting chemicals influencing NRF1 regulated gene networks in the development of complex human brain diseases. International journal of molecular sciences 2016;17:2086.

Stein TP, Schluter MD, Steer RA, Guo L, Ming X. Bisphenol A exposure in children with autism spectrum disorders. Autism Research 2015;8:272-83.

Sarrouilhe D, Dejean C. Les relations entre le bisphénol A et les troubles du spectre autistique se précisent: la sérotonine est-elle le lien manquant? L'Encéphale 2017;43:402-4.

Keil KP, Lein PJ. DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? Environmental epigenetics 2016;2.

Rich AL, Phipps LM, Tiwari S, Rudraraju H, Dokpesi PO. The increasing prevalence in intersex variation from toxicological dysregulation in fetal reproductive tissue differentiation and development by endocrine-disrupting chemicals. Environmental health insights 2016;10:EHI. S39825.

Svechnikov K, Stukenborg J-B, Savchuck I, Söder O. Similar causes of various reproductive disorders in early life. Asian journal of andrology 2014;16:50.

Braun JM, Kalkbrenner AE, Calafat AM, Yolton K, Ye X, Dietrich KN, et al. Impact of early-life bisphenol A exposure on behavior and executive function in children. Pediatrics 2011;128:873-82.

Konieczna A, Rutkowska A, Rachon D. Health risk of exposure to Bisphenol A (BPA). Roczniki Państwowego Zakładu Higieny 2015;66.

Evans SF, Kobrosly RW, Barrett ES, Thurston SW, Calafat AM, Weiss B, et al. Prenatal bisphenol A exposure and maternally reported behavior in boys and girls. Neurotoxicology 2014;45:91-9.

França LR, Ogawa T, Avarbock MR, Brinster RL, Russell LD. Germ cell genotype controls cell cycle during spermatogenesis in the rat. Biology of reproduction 1998;59:1371-7.

Chen H, Mruk DD, Lee WM, Cheng CY. Regulation of spermatogenesis by a local functional axis in the testis: role of the basement membrane–derived noncollagenous 1 domain peptide. The FASEB Journal 2017;31:3587-607.

Gurmeet K, Rosnah I, Normadiah M, Das S, Mustafa A. Detrimental effects of bisphenol A on development and functions of the male reproductive system in experimental rats. EXCLI journal 2014;13:151.

PeknicovÁ J, KyselovÁ V, BuckiovÁ D, BoubelÍk M. Effect of an endocrine disruptor on mammalian fertility. Application of monoclonal antibodies against sperm proteins as markers for testing sperm damage. American Journal of Reproductive Immunology 2002;47:311-8.

Sakaue M, Ohsako S, Ishimura R, KUROSAWA S, KUROHMARU M, HAYASHI Y, et al. Bisphenol-A affects spermatogenesis in the adult rat even at a low dose. Journal of occupational health 2001;43:185-90.

Ashby J, Tinwell H, Lefevre P, Joiner R, Haseman J. The effect on sperm production in adult Sprague-Dawley rats exposed by gavage to bisphenol A between postnatal days 91–97. Toxicological Sciences 2003;74:129-38.

Jin P, Wang X, Chang F, Bai Y, Li Y, Zhou R, et al. 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.

Xie M, Bu P, Li F, Lan S, Wu H, Yuan L, et al. Neonatal bisphenol A exposure induces meiotic arrest and apoptosis of spermatogenic cells. Oncotarget 2016;7:10606.

Wang C, Zhang J, Li Q, Zhang T, Deng Z, Lian J, et al. Low concentration of BPA induces mice spermatocytes apoptosis via GPR30. Oncotarget 2017;8:49005.

Toyama Y, Suzuki-Toyota F, Maekawa M, Ito C, Toshimori K. Adverse effects of bisphenol A to spermiogenesis in mice and rats. Archives of Histology and Cytology 2004;67:373-81.

Karnam S, Ghosh R, Mondal S, Mondal M. Evaluation of subacute bisphenol–A toxicity on male reproductive system. Veterinary world 2015;8:738.

Li Y-J, Song T-B, Cai Y-Y, Zhou J-S, Song X, Zhao X, et al. Bisphenol A exposure induces apoptosis and upregulation of Fas/FasL and caspase-3 expression in the testes of mice. Toxicol Sci 2009;108:427-36.

Zhang G-L, Zhang X-F, Feng Y-M, Li L, Huynh E, Sun X-F, et al. Exposure to bisphenol A results in a decline in mouse spermatogenesis. Reproduction, Fertility and Development 2013;25:847-59.

Park B, Kwon JE, Cho SM, Kim CW, Koo YT, Lee SH, et al. Protective effect of Lespedeza cuneata ethanol extract on Bisphenol A-induced testicular dysfunction in vivo and in vitro. Biomedicine & Pharmacotherapy 2018;102:76-85.

Rahman MS, Kwon W-S, Ryu D-Y, Khatun A, Karmakar PC, Ryu B-Y, et al. Functional and Proteomic Alterations of F1 Capacitated Spermatozoa of Adult Mice Following Gestational Exposure to Bisphenol A. Journal of proteome research 2017;17:524-35.

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 Volume 228: Springer 2014:57-82.

Xiao G, Wang R, Cai Y, He G, Zhou Z. Effect of bisphenol A on semen quality of exposed workers: a pilot study. Zhonghua lao dong wei sheng zhi ye bing za zhi= Zhonghua laodong weisheng zhiyebing zazhi= Chinese journal of industrial hygiene and occupational diseases 2009;27:741-3.

Li DK, Zhou Z, Miao M, He Y, Qing D, Wu T, et al. Relationship Between Urine Bisphenol‐A Level and Declining Male Sexual Function. Journal of andrology 2010;31:500-6.

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;30:532-9.

Adoamnei E, Mendiola J, Vela-Soria F, Fernández MF, Olea N, Jørgensen N, et al. urinary bisphenol A concentrations are associated with reproductive parameters in young men. Environmental research 2018;161:122-8.

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;122:478.

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.

Alves MG, Rato L, Carvalho RA, Moreira PI, Socorro S, Oliveira PF. Hormonal control of Sertoli cell metabolism regulates spermatogenesis. Cellular and Molecular Life Sciences 2013;70:777-93.

Jambor T, Jana B, Hana G, Eva T, Norbert L. Male Reproduction: One of the Primary Targets of Bisphenol. Male Reproduction: One of the Primary Targets of Bisphenol 2017.

Wisniewski P, Romano RM, Kizys MM, Oliveira KC, Kasamatsu T, Giannocco G, et al. Adult exposure to bisphenol A (BPA) in Wistar rats reduces sperm quality with disruption of the hypothalamic–pituitary–testicular axis. Toxicology 2015;329:1-9.

Tarapore P, Hennessy M, Song D, et al.High butter-fat diet and bisphenol A additively impair male rat spermatogenesis. Reprod Toxicol. 2017; 68: 191–199.

N’Tumba-Byn T, Moison D, Lacroix M, Lecureuil C, Lesage L, Prud’homme SM, et al. Differential Effects of Bisphenol A and Diethylstilbestrol on Human, Rat and Mouse Fetal Leydig Cell Function. PLoS ONE 2012;7.

Hong J, Chen F, Wang X, Bai Y, Zhou R, Li Y, et al. Exposure of preimplantation embryos to low-dose bisphenol A impairs testes development and suppresses histone acetylation of StAR promoter to reduce production of testosterone in mice. Molecular and cellular endocrinology 2016;427:101-11.

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;145:592-603.

Zhou Q, Nie R, Prins GS, Saunders PT, Katzenellenbogen BS, Hess RA. Localization of androgen and estrogen receptors in adult male mouse reproductive tract. Journal of andrology 2002;23:870-81.

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;86:12.

Nie R, Zhou Q, Jassim E, Saunders PTK, Hess RA. Differential Expression of Estrogen Receptors α and β in the Reproductive Tractsof Adult Male Dogs and Cats1. Biology of Reproduction 2002;66:1161-8.

Saunders PT, Sharpe RM, Williams K, Macpherson S, Urquart H, Irvine DS, et al. Differential expression of oestrogen receptor α and β proteins in the testes and male reproductive system of human and non-human primates. Molecular Human Reproduction 2001;7:227-36.

Danzo BJ. Environmental xenobiotics may disrupt normal endocrine function by interfering with the binding of physiological ligands to steroid receptors and binding proteins. Environmental Health Perspectives 1997;105:294-301.

Bolger R, Wiese TE, Ervin K, Nestich S, Checovich W. Rapid screening of environmental chemicals for estrogen receptor binding capacity. Environmental Health Perspectives 1998;106:551-7.

Gaido KW, Maness SC, McDonnell DP, Dehal SS, Kupfer D, Safe S. Interaction of Methoxychlor and Related Compounds with Estrogen Receptor α and β, and Androgen Receptor: Structure-Activity Studies. Molecular Pharmacology 2000;58:852-8.

Matthews JB, Twomey K, Zacharewski TR. In vitro and in vivo interactions of bisphenol A and its metabolite, bisphenol A glucuronide, with estrogen receptors alpha and beta. Chemical research in toxicology 2001;14:149-57.

Wetherill YB, Akingbemi BT, Kanno J, McLachlan JA, Nadal A, Sonnenschein C, et al. In vitro molecular mechanisms of bisphenol A action. Reproductive toxicology (Elmsford, NY) 2007;24:178-98.

Lassen T, Frederiksen H, Jensen T, Petersen J, Joensen UN, Main KM, et al. Urinary bisphenol A levels in young men: association with reproductive hormones and semen quality. Environmental health perspectives 2014;122:478.

Goncalves GD, Semprebon SC, Biazi BI, Mantovani MS, Fernandes GSA. Bisphenol A reduces testosterone production in TM3 Leydig cells independently of its effects on cell death and mitochondrial membrane potential. Reproductive toxicology (Elmsford, NY) 2018;76:26-34.

Song K-HH, Lee K, Choi H-SS. Endocrine disrupter bisphenol a induces orphan nuclear receptor Nur77 gene expression and steroidogenesis in mouse testicular Leydig cells. Endocrinology 2002;143:2208-15.

Sriraman V, Rao VS, Sairam MR, Rao AJ. Effect of deprival of LH on Leydig cell proliferation: involvement of PCNA, cyclin D3 and IGF-1. Molecular and cellular endocrinology 2000;162:113-20.

Wetherill YB, Petre CE, Monk KR, Puga A, Knudsen KE. The xenoestrogen bisphenol A induces inappropriate androgen receptor activation and mitogenesis in prostatic adenocarcinoma cells. Molecular cancer therapeutics 2002;1:515-24.

Lee HJ, Chattopadhyay S, Gong E-YY, Ahn RS, Lee K. Antiandrogenic effects of bisphenol A and nonylphenol on the function of androgen receptor. Toxicological sciences : an official journal of the Society of Toxicology 2003;75:40-6.

Cannon JM, Kostoryz E, Russo KA, Smith RE, Yourtee DM. Bisphenol A and its biomaterial monomer derivatives alteration of in vitro cytochrome P450 metabolism in rat, minipig, and human. Biomacromolecules 2000;1:656-64.

Rouiller-Fabre V, Carmona S, Merhi RA, Cate R, Habert R, Vigier B. Effect of anti-Mullerian hormone on Sertoli and Leydig cell functions in fetal and immature rats. Endocrinology 1998;139:1213-20.

Lee MM, Seah CC, Masiakos PT, et al. Mullerian-inhibiting substance type II receptor expression and function in purified rat Leydig cells. Endocrinology. 1999;140:2819-27.

Salva A, Hardy MP, Wu X-fF, Sottas CM, MacLaughlin DT, Donahoe PK, et al. Müllerian-inhibiting substance inhibits rat Leydig cell regeneration after ethylene dimethanesulphonate ablation. Biology of reproduction 2004;70:600-7.

Su L, Mruk DD, Cheng YC. Drug transporters, the bloodtestis barrier, and spermatogenesis. Journal of Endocrinology 2011;208:207-23.

Rato L, Alves MG, Socorro S,et al Metabolic regulation is important for spermatogenesis. Nature Reviews Urology 2012; 9: 330–8

Franca LR, Hess RA, Dufour JM, Hofmann MC, Griswold. The Sertoli cell: one hundred fifty years of beauty and plasticity. Andrology 2016;4:189-212.

Manfo FP, 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.

Chen G, Shinka T, Kinoshita K, Yan H-TT, Iwamoto T, Nakahori Y. Roles of estrogen receptor alpha (ER alpha) in the regulation of the human Müllerian inhibitory substance (MIS) promoter. The journal of medical investigation : JMI 2003;50:192-8.

Iida H, Maehara K, Doiguchi M, Mōri T, Yamada F. Bisphenol A-induced apoptosis of cultured rat Sertoli cells. Reproductive Toxicology 2003;17:457-64.

Rytting E, Mathiesen L, Paulesu L, Reproductive K-LE. Placental transport and in vitro effects of Bisphenol A. Reprod Toxicol. 2010;30:131-7.

Wang C, Fu W, Quan C, Yan M, Liu C, Qi S, et al. The role of Pten/Akt signaling pathway involved in BPA‐induced apoptosis of rat sertoli cells. Environmental toxicology 2014.

Qian W, Zhu J, Mao C, Liu J, Wang Y, Wang Q, et al. Involvement of CaM-CaMKII-ERK in bisphenol A-induced Sertoli cell apoptosis. Toxicology 2014.

Hughes PJ, McLellan H, Lowes DA, Kahn SZ, Bilmen JG, Tovey SC, et al. Estrogenic Alkylphenols Induce Cell Death by Inhibiting Testis Endoplasmic Reticulum Ca2+ Pumps. Biochemical and Biophysical Research Communications 2000;277:568-74.

Griswold MD. Interactions Between Germ Cells and Sertoli Cells in the Testis. Biology of Reproduction 1995;52:211-6.

Fiorini C, Tilloy-Ellul A, Chevalier S, Charuel C, Pointis G. Sertoli cell junctional proteins as early targets for different classes of reproductive toxicants. Reproductive Toxicology 2004;18:413-21.

Cheng YC, Wong EWP, Lie PPY, Li MWM, Su L, Siu ER, et al. Environmental toxicants and male reproductive function. Spermatogenesis 2011;1:2-13.

Wang Q, Zhao X-F, Ji Y-L, Wang H, Liu P, Zhang C, et al. Mitochondrial signaling pathway is also involved in bisphenol A induced germ cell apoptosis in testes. Toxicology letters 2010;199:129-35.

Tainaka H, Takahashi H, Umezawa M, Tanaka H, Nishimune Y, Oshio S, et al. 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;37:539-48.

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 2011;19:163-72.

Kokk K, Veräjänkorva E, Wu X-KK, Tapfer H, Põldoja E, Simovart H-EE, et al. Expression of insulin signaling transmitters and glucose transporters at the protein level in the rat testis. Annals of the New York Academy of Sciences 2007;1095:262-73.

Huang D, Wu J, Su X, Yan H, Sun Z. Effects of low dose of bisphenol A on the proliferation and mechanism of primary cultured prostate epithelial cells in rodents. Oncology letters 2017;14:2635-42.

Takahashi O, Oishi S. Testicular toxicity of dietary 2, 2-bis (4-hydroxyphenyl) propane (bisphenol A) in F344 rats. Archives of toxicology 2001;75:42-51.

Ho S-M, Tang W-Y, De Frausto JB, Prins GS. Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4. Cancer research 2006;66:5624-32.

Derouiche S, Warnier M, Mariot P, Gosset P, Mauroy B, Bonnal J-L, et al. Bisphenol A stimulates human prostate cancer cell migration via remodelling of calcium signalling. Springerplus 2013;2:54.

Cheong A, Zhang X, Cheung Y-Y, Tang W-y, Chen J, Ye S-H, et al. DNA methylome changes by estradiol benzoate and bisphenol A links early-life environmental exposures to prostate cancer risk. Epigenetics 2016;11:674-89.

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