Skip to main content

Advertisement

SpringerLink
Log in

Environmental endocrine disruptors: Effects on the human male reproductive system

  • Published:
Reviews in Endocrine and Metabolic Disorders Aims and scope Submit manuscript

Abstract

Incidences of altered development and neoplasia of male reproductive organs have increased during the last 50 years, as shown by epidemiological data. These data are associated with the increased presence of environmental chemicals, specifically “endocrine disruptors,” that interfere with normal hormonal action. Much research has gone into testing the effects of specific endocrine disrupting chemicals (EDCs) on the development of male reproductive organs and endocrine-related cancers in both in vitro and in vivo models. Efforts have been made to bridge the accruing laboratory findings with the epidemiological data to draw conclusions regarding the relationship between EDCs, altered development and carcinogenesis. The ability of EDCs to predispose target fetal and adult tissues to neoplastic transformation is best explained under the framework of the tissue organization field theory of carcinogenesis (TOFT), which posits that carcinogenesis is development gone awry. Here, we focus on the available evidence, from both empirical and epidemiological studies, regarding the effects of EDCs on male reproductive development and carcinogenesis of endocrine target tissues. We also critique current research methodology utilized in the investigation of EDCs effects and outline what could possibly be done to address these obstacles moving forward.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

AGD:

Anogenital distance

AR:

Androgen receptor

BPA:

Bisphenol A

BPH:

Benign prostatic hyperplasia

CIS:

Carcinoma in situ

DBP:

Dibutyl phthalate

DCE:

T-1,2-dichloroethylene

DDT:

Dichlorodiphenyltrichloroethane

DEHP:

Diethylhexyl phthalate

DES:

Diethylstilbestrol

EDC:

Endocrine disrupting chemical

ER:

Estrogen receptor

INSL3:

Insulin-like growth factor 3

MBC:

Male breast cancer

MEHP:

Mono(2-ethylhexyl) phthalate

MG:

Mammary gland

miR:

Micro-RNA

NMDR:

Non-monotonic dose response

PC:

Prostate cancer

PCB:

Polychlorinated biphenyls

PCE:

Tetrachloroethylene

PGC:

Primordial germ cells

SMT:

Somatic mutation theory of carcinogenesis

TC:

Testicular cancer

TCDD:

2,3,7,8-tetrachlorodibenzo-p-dioxin

TCE:

Trichloroethylene

TDS:

Testicular dysgenesis syndrome

TGCT:

Testicular germ cell tumors

TOFT:

Tissue organization field theory of carcinogenesis

References

  1. Global cancer facts & figures 3rd edn. Am. Cancer Soc Atlanta. 2015.

  2. Paulozzi LJ. International trends in rates of hypospadias and cryptorchidism. Environ Health Perspect. 1999;107(4):297–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Swan SH, Elkin EP, Fenster L. The question of declining sperm density revisited: An analysis of 101 studies published 1934–1996. Environ Health Perspect. 2000;108(10):961–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sharpe RM, Skakkebaek NE. Are Oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet. 1993;341(8857):1392–5.

    Article  CAS  PubMed  Google Scholar 

  5. Colborn T, Clement C. Chemically-induced alterations in sexual and functional development: the wildlife/human connection. Princeton: Princeton Scientific Publishing; 1992. p. 1–8.

    Google Scholar 

  6. Colborn T, Vom Saal FS, Soto AM. Developmental effects of endocrine-disrupting chemicals in wildlife and humans. Environ Health Perspect. 1993;101(5):378–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zoeller RT, Brown TR, Doan LL, Gore AC, Skakkebaek NE, Soto AM, et al. Endocrine-disrupting chemicals and public health protection: A statement of principles from the endocrine society. Endocrinology. 2012;153(9):4097–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Aranda A, Pascual A. Nuclear hormone receptors and gene expression. Physiol Rev. 2001;81(3):1269–304.

    CAS  PubMed  Google Scholar 

  9. Rouiller-Fabre V, Guerquin MJ, N’Tumba-Byn T, Muczynski V, Moison D, Tourpin S, et al. Nuclear receptors and endocrine disruptors in fetal and neonatal testes: A gapped landscape. Front Endocrinol (Lausanne). 2015;6:58.

    Google Scholar 

  10. Rouiller-Fabre V, Habert R, Livera G. Effects of endocrine disruptors on the human fetal testis. Ann Endocrinol (Paris). 2014;75(2):54–7.

    Article  Google Scholar 

  11. Latini G, Scoditti E, Verrotti A, De Felice C, Massaro M. Peroxisome proliferator-activated receptors as mediators of phthalate-induced effects in the male and female reproductive tract: Epidemiological and experimental evidence. PPAR Res. 2008;2008:359267.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Kelce WR, Stone CR, Laws SC, Gray LE, Kemppainen JA, Wilson EM. Persistent DDT metabolite p, p’-DDE is a potent androgen receptor antagonist. Nature. 1995;375(6532):581–5.

    Article  CAS  PubMed  Google Scholar 

  13. Moriyama K, Tagami T, Akamizu T, Usui T, Saijo M, Kanamoto N, et al. Thyroid hormone action is disrupted by bisphenol a as an antagonist. J Clin Endocrinol Metab. 2002;87(11):5185–90.

    Article  CAS  PubMed  Google Scholar 

  14. Wetherill YB, Fisher NL, Staubach A, Danielsen M, de Vere White RW, Knudsen KE. Xenoestrogen action in prostate cancer: Pleiotropic effects dependent on androgen receptor status. Cancer Res. 2005;65(1):54–65.

    CAS  PubMed  Google Scholar 

  15. Silva E, Rajapakse N, Kortenkamp A. Something from “nothing”--eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. Environ Sci Technol. 2002;36(8):1751–6.

    Article  CAS  PubMed  Google Scholar 

  16. 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. Environ Health Perspect. 1997;105(1):70–6.

  17. Soto AM, Brisken C, Schaeberle C, Sonnenschein C. Does cancer start in the womb? Altered mammary gland development and predisposition to breast cancer due to in utero exposure to endocrine disruptors. J Mammary Gland Biol Neoplasia. 2013;18(2):199–208.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Blair RM, Fang H, Branham WS, Hass BS, Dial SL, Moland CL, et al. The estrogen receptor relative binding affinities of 188 natural and xenochemicals: Structural diversity of ligands. Toxicol Sci. 2000;54(1):138–53.

    Article  CAS  PubMed  Google Scholar 

  19. Usmani KA, Rose RL, Hodgson E. Inhibition and activation of the human liver microsomal and human cytochrome P450 3A4 metabolism of testosterone by deployment-related chemicals. Drug Metab Dispos. 2003;31(4):384–91.

    Article  CAS  PubMed  Google Scholar 

  20. Usmani KA, Cho TM, Rose RL, Hodgson E. Inhibition of the human liver microsomal and human cytochrome P450 1A2 and 3A4 metabolism of estradiol by deployment-related and other chemicals. Drug Metab Dispos. 2006;34(9):1606–14.

    Article  CAS  PubMed  Google Scholar 

  21. Skinner MK, Manikkam M, Guerrero-Bosagna C. Epigenetic transgenerational actions of endocrine disruptors. Reprod Toxicol. 2011;31(3):337–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Martinez-Arguelles DB, Culty M, Zirkin BR, Papadopoulos V. In utero exposure to di-(2-ethylhexyl) phthalate decreases mineralocorticoid receptor expression in the adult testis. Endocrinology. 2009;150(12):5575–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Prins GS, Tang WY, Belmonte J, Ho SM. Perinatal exposure to oestradiol and bisphenol a alters the prostate epigenome and increases susceptibility to carcinogenesis. Basic Clin Pharmacol Toxicol. 2008;102(2):134–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pelch KE, Tokar EJ, Merrick BA, Waalkes MP. Differential DNA methylation profile of key genes in malignant prostate epithelial cells transformed by inorganic arsenic or cadmium. Toxicol Appl Pharmacol. 2015;286(3):159–67.

    Article  CAS  PubMed  Google Scholar 

  25. Guerrero-Bosagna C, Settles M, Lucker B, Skinner MK. Epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome. PLoS One. 2010;5(9):e13100.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Wu S, Zhu J, Li Y, Lin T, Gan L, Yuan X, et al. Dynamic epigenetic changes involved in testicular toxicity induced by di-2-(ethylhexyl) phthalate in mice. Basic Clin Pharmacol Toxicol. 2010;106(2):118–23.

    Article  CAS  PubMed  Google Scholar 

  27. Anderson AM, Carter KW, Anderson D, Wise MJ. Coexpression of nuclear receptors and histone methylation modifying genes in the testis: Implications for endocrine disruptor modes of action. PLoS One. 2012;7(4):e34158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Clement TM, Savenkova MI, Settles M, Anway MD, Skinner MK. Alterations in the developing testis transcriptome following embryonic vinclozolin exposure. Reprod Toxicol. 2010;30(3):353–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lopez-Casas PP, Mizrak SC, Lopez-Fernandez LA, Paz M, de Rooij DG, del Mazo J. The effects of different endocrine disruptors defining compound-specific alterations of gene expression profiles in the developing testis. Reprod Toxicol. 2012;33(1):106–15.

    Article  CAS  PubMed  Google Scholar 

  30. Stouder C, Paoloni-Giacobino A. Transgenerational effects of the endocrine disruptor vinclozolin on the methylation pattern of imprinted genes in the mouse sperm. Reproduction. 2010;139(2):373–9.

    Article  CAS  PubMed  Google Scholar 

  31. Stouder C, Paoloni-Giacobino A. Specific transgenerational imprinting effects of the endocrine disruptor methoxychlor on male gametes. Reproduction. 2011;141(2):207–16.

    Article  CAS  PubMed  Google Scholar 

  32. Del-Mazo J, Brieno-Enriquez MA, Garcia-Lopez J, Lopez-Fernandez LA, De-Felici M. Endocrine disruptors, gene deregulation and male germ cell tumors. Int J Dev Biol. 2013;57(2–4):225–39.

    Article  CAS  PubMed  Google Scholar 

  33. Choi JS, Oh JH, Park HJ, Choi MS, Park SM, Kang SJ, et al. MiRNA regulation of cytotoxic effects in mouse Sertoli cells exposed to nonylphenol. Reprod Biol Endocrinol. 2011;9:126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Watson CJ, Khaled WT. Mammary development in the embryo and adult: A journey of morphogenesis and commitment. Development. 2008;135(6):995–1003.

    Article  CAS  PubMed  Google Scholar 

  35. Singh M, Jha R, Melamed J, Shapiro E, Hayward SW, Lee P. Stromal androgen receptor in prostate development and cancer. Am J Pathol. 2014;184(10):2598–607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bissell MJ, Radisky D. Putting tumours in context. Nat Rev Cancer. 2001;1(1):46–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Maffini MV, Soto AM, Calabro JM, Ucci AA, Sonnenschein C. The stroma as a crucial target in rat mammary gland carcinogenesis. J Cell Sci. 2004;117(Pt 8):1495–502.

    Article  CAS  PubMed  Google Scholar 

  38. Grossfeld GD, Hayward SW, TLsty TD, Cunha GR. The role of stroma in prostatic carcinogenesis. Endocr Relat Cancer. 1998;5:253–70.

    Article  Google Scholar 

  39. Ramos JG, Varayoud J, Sonnenschein C, Soto AM, De Toro Munoz M, Luque EH. Prenatal exposure to low doses of bisphenol A alters the periductal stroma and glandular cell function in the rat ventral prostate. Biol Reprod. 2001;65(4):1271–7.

    Article  CAS  PubMed  Google Scholar 

  40. Vandenberg LN, Maffini MV, Wadia PR, Sonnenschein C, Rubin BS, Soto AM. Exposure to environmentally relevant doses of the xenoestrogen bisphenol-a alters development of the fetal mouse mammary gland. Endocrinology. 2007;148(1):116–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wadia PR, Cabaton NJ, Borrero MD, Rubin BS, Sonnenschein C, Shioda T, et al. Low-dose BPA exposure alters the mesenchymal and epithelial transcriptomes of the mouse fetal mammary gland. PLoS One. 2013;8(5):e63902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Markey CM, Luque EH, De Toro Munoz M, Sonnenschein C, Soto AM. In utero exposure to bisphenol A alters the development and tissue organization of the mouse mammary gland. Biol Reprod. 2001;65(4):1215–23.

    CAS  PubMed  Google Scholar 

  43. Ko K, Moore RW, Peterson RE. Aryl hydrocarbon receptors in urogenital sinus mesenchyme mediate the inhibition of prostatic epithelial bud formation by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol. 2004;196(1):149–55.

    Article  CAS  PubMed  Google Scholar 

  44. Lew BJ, Manickam R, Lawrence BP. Activation of the aryl hydrocarbon receptor during pregnancy in the mouse alters mammary development through direct effects on stromal and epithelial tissues. Biol Reprod. 2011;84(6):1094–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hendry 3rd WJ, Weaver BP, Naccarato TR, Khan SA. Differential progression of neonatal diethylstilbestrol-induced disruption of the hamster testis and seminal vesicle. Reprod Toxicol. 2006;21(3):225–40.

    Article  CAS  PubMed  Google Scholar 

  46. Mao Y, Baum B. Tug of war--the influence of opposing physical forces on epithelial cell morphology. Dev Biol. 2015;401(1):92–102.

    Article  CAS  PubMed  Google Scholar 

  47. Kim HY, Varner VD, Nelson CM. Apical constriction initiates new bud formation during monopodial branching of the embryonic chicken lung. Development. 2013;140(15):3146–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gjorevski N, Nelson CM. Branch formation during organ development. Wiley Interdiscip Rev Syst Biol Med. 2010;2(6):734–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Latacha KS, Remond MC, Ramasubramanian A, Chen AY, Elson EL, Taber LA. Role of actin polymerization in bending of the early heart tube. Dev Dyn. 2005;233(4):1272–86.

    Article  CAS  PubMed  Google Scholar 

  50. Barnes C, Speroni L, Quinn KP, Montevil M, Saetzler K, Bode-Animashaun G, et al. From single cells to tissues: Interactions between the matrix and human breast cells in real time. PLoS One. 2014;9(4):e93325.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Spoerl E, Zubaty V, Raiskup-Wolf F, Pillunat LE. Oestrogen-induced changes in biomechanics in the cornea as a possible reason for keratectasia. Br J Ophthalmol. 2007;91(11):1547–50.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Hillebrand U, Hausberg M, Lang D, Stock C, Riethmuller C, Callies C, et al. How steroid hormones act on the endothelium--insights by atomic force microscopy. Pflugers Arch. 2008;456(1):51–60.

    Article  CAS  PubMed  Google Scholar 

  53. Lee CY, Liu X, Smith CL, Zhang X, Hsu HC, Wang DY, et al. The combined regulation of estrogen and cyclic tension on fibroblast biosynthesis derived from anterior cruciate ligament. Matrix Biol. 2004;23(5):323–9.

    Article  CAS  PubMed  Google Scholar 

  54. Speroni L, Whitt GS, Xylas J, Quinn KP, Jondeau-Cabaton A, Barnes C, et al. Hormonal regulation of epithelial organization in a three-dimensional breast tissue culture model. Tissue Eng C Methods. 2014;20(1):42–51.

    Article  CAS  Google Scholar 

  55. Barcus CE, Keely PJ, Eliceiri KW, Schuler LA. Stiff collagen matrices increase tumorigenic prolactin signaling in breast cancer cells. J Biol Chem. 2013;288(18):12722–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, et al. Tensional homeostasis and the malignant phenotype. Cancer Cell. 2005;8(3):241–54.

    Article  CAS  PubMed  Google Scholar 

  57. Martin LJ, Boyd NF. Mammographic density. Potential mechanisms of breast cancer risk associated with mammographic density: Hypotheses based on epidemiological evidence. Breast Cancer Res. 2008;10(1):201.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Miroshnikova YA, Jorgens DM, Spirio L, Auer M, Sarang-Sieminski AL, Weaver VM. Engineering strategies to recapitulate epithelial morphogenesis within synthetic three-dimensional extracellular matrix with tunable mechanical properties. Phys Biol. 2011;8(2):026013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hoyt K, Castaneda B, Zhang M, Nigwekar P, di Sant’agnese PA, Joseph JV, et al. Tissue elasticity properties as biomarkers for prostate cancer. Cancer Biomark. 2008;4(4–5):213–25.

    PubMed  PubMed Central  Google Scholar 

  60. Wang X, Wang J, Liu Y, Zong H, Che X, Zheng W, et al. Alterations in mechanical properties are associated with prostate cancer progression. Med Oncol. 2014;31(3):876.

    Article  PubMed  Google Scholar 

  61. Thompson PA, Khatami M, Baglole CJ, Sun J, Harris SA, Moon EY, et al. Environmental immune disruptors, inflammation and cancer risk. Carcinogenesis. 2015;36 Suppl 1:S232–53.

    Article  PubMed  Google Scholar 

  62. Gilbert SF. Ecological developmental biology: Developmental biology meets the real world. Dev Biol. 2001;233(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  63. Weinberg RA. One renegade cell: How cancer begins. New York, NY: Basic Books; 1998.

    Google Scholar 

  64. Soto AM, Sonnenschein C. Environmental causes of cancer: Endocrine disruptors as carcinogens. Nat Rev Endocrinol. 2010;6(7):363–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Soto AM, Sonnenschein C. The tissue organization field theory of cancer: A testable replacement for the somatic mutation theory. Bioessays. 2011;33(5):332–40.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Herbst AL, Anderson D. Clear cell adenocarcinoma of the vagina and cervix secondary to intrauterine exposure to diethylstilbestrol. Semin Surg Oncol. 1990;6(6):343–6.

    Article  CAS  PubMed  Google Scholar 

  67. Palmer JR, Boggs DA, Hatch EE, Troisi R, Titus-Ernstoff L, Strohsnitter WC, et al. Prenatal DES exposure in relation to breast size. Cancer Causes Control. 2013;24(9):1757–61.

    Article  PubMed  Google Scholar 

  68. Sonnenschein C, Davis B, Soto AM. A novel pathogenic classification of cancers. Cancer Cell Int. 2014;14(1):113.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Soto AM, Sonnenschein C. Regulation of cell proliferation: The negative control perspective. Ann N Y Acad Sci. 1991;628:412–8.

    Article  CAS  PubMed  Google Scholar 

  70. Soto AM, Murai JT, Siiteri PK, Sonnenschein C. Control of cell proliferation: Evidence for negative control on estrogen-sensitive T47D human breast cancer cells. Cancer Res. 1986;46(5):2271–5.

    CAS  PubMed  Google Scholar 

  71. Sonnenschein C, Olea N, Pasanen ME, Soto AM. Negative controls of cell proliferation: Human prostate cancer cells and androgens. Cancer Res. 1989;49(13):3474–81.

    CAS  PubMed  Google Scholar 

  72. Geck P, Maffini MV, Szelei J, Sonnenschein C, Soto AM. Androgen-induced proliferative quiescence in prostate cancer cells: The role of AS3 as its mediator. Proc Natl Acad Sci U S A. 2000;97(18):10185–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Bruchovsky N, Lesser B, Van Doorn E, Craven S. Hormonal effects on cell proliferation in rat prostate. Vitam Horm. 1975;33:61–102.

    Article  CAS  PubMed  Google Scholar 

  74. Sonnenschein C, Soto AM. Pituitary uterotrophic effect in the estrogen-dependent growth of the rat uterus. J Steroid Biochem. 1978;9(6):533–7.

    Article  CAS  PubMed  Google Scholar 

  75. Vandenberg LN, Wadia PR, Schaeberle CM, Rubin BS, Sonnenschein C, Soto AM. The mammary gland response to estradiol: Monotonic at the cellular level, non-monotonic at the tissue-level of organization? J Steroid Biochem Mol Biol. 2006;101(4–5):263–74.

    Article  CAS  PubMed  Google Scholar 

  76. Schweizer MT, Antonarakis ES, Wang H, Ajiboye AS, Spitz A, Cao H, et al. Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: Results from a pilot clinical study. Sci Transl Med. 2015;7(269):269ra2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Denmeade SR, Isaacs JT. Bipolar androgen therapy: The rationale for rapid cycling of supraphysiologic androgen/ablation in men with castration resistant prostate cancer. Prostate. 2010;70(14):1600–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Gleave M, Goldenberg SL, Bruchovsky N, Rennie P. Intermittent androgen suppression for prostate cancer: Rationale and clinical experience. Prostate Cancer Prostatic Dis. 1998;1(6):289–96.

    Article  CAS  PubMed  Google Scholar 

  79. Vom Saal FS, Timms BG, Montano MM, Palanza P, Thayer KA, Nagel SC, et al. Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proc Natl Acad Sci U S A. 1997;94(5):2056–61.

    Article  CAS  PubMed  Google Scholar 

  80. Alworth LC, Howdeshell KL, Ruhlen RL, Day JK, Lubahn DB, Huang TH, et al. Uterine responsiveness to estradiol and DNA methylation are altered by fetal exposure to diethylstilbestrol and methoxychlor in CD-1 mice: Effects of low versus high doses. Toxicol Appl Pharmacol. 2002;183(1):10–22.

    Article  CAS  PubMed  Google Scholar 

  81. Welshons WV, Nagel SC, Thayer KA, Judy BM, Vom Saal FS. Low-dose bioactivity of xenoestrogens in animals: Fetal exposure to low doses of methoxychlor and other xenoestrogens increases adult prostate size in mice. Toxicol Ind Health. 1999;15(1–2):12–25.

    Article  CAS  PubMed  Google Scholar 

  82. Vandenberg LN. Low-dose effects of hormones and endocrine disruptors. Vitam Horm. 2014;94:129–65.

    Article  PubMed  CAS  Google Scholar 

  83. Lagarde F, Beausoleil C, Belcher SM, Belzunces LP, Emond C, Guerbet M, et al. Non-monotonic dose–response relationships and endocrine disruptors: A qualitative method of assessment. Environ Health. 2015;14:13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Vandenberg LN. Non-monotonic dose responses in studies of endocrine disrupting chemicals: Bisphenol a as a case study. Dose Response. 2014;12(2):259–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Bay K, Asklund C, Skakkebaek NE, Andersson A-M. Testicular dysgenesis syndrome: Possible role of endocrine disrupters. Best Pract Res Clin Endocrinol Metab. 2006;20(1):77–90.

    Article  CAS  PubMed  Google Scholar 

  86. Prins GS. Neonatal estrogen exposure induces lobe-specific alterations in adult rat prostate androgen receptor expression. Endocrinology. 1992;130(6):3703–14.

    CAS  PubMed  Google Scholar 

  87. Saffarini CM, McDonnell-Clark EV, Amin A, Huse SM, Boekelheide K. Developmental exposure to estrogen alters differentiation and epigenetic programming in a human fetal prostate xenograft model. PLoS One. 2015;10(3):e0122290.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Wu CP, Gu FL. The prostate in eunuchs. Prog Clin Biol Res. 1991;370:249–55.

    CAS  PubMed  Google Scholar 

  89. Cunha GR, Donjacour AA, Cooke PS, Mee S, Bigsby RM, Higgins SJ, et al. The endocrinology and developmental biology of the prostate. Endocr Rev. 1987;8(3):338–62.

    Article  CAS  PubMed  Google Scholar 

  90. He WW, Kumar MV, Tindall DJ. A frame-shift mutation in the androgen receptor gene causes complete androgen insensitivity in the testicular-feminized mouse. Nucleic Acids Res. 1991;19(9):2373–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Brown TR, Lubahn DB, Wilson EM, Joseph DR, French FS, Migeon CJ. Deletion of the steroid-binding domain of the human androgen receptor gene in one family with complete androgen insensitivity syndrome: Evidence for further genetic heterogeneity in this syndrome. Proc Natl Acad Sci U S A. 1988;85(21):8151–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Takeda H, Lasnitzki I, Mizuno T. Analysis of prostatic bud induction by brief androgen treatment in the fetal rat urogenital sinus. J Endocrinol. 1986;110(3):467–70.

    Article  CAS  PubMed  Google Scholar 

  93. George FW, Wilson JD. Sex determination and differentiation. In: Neill EKAJD, editor. The physiology of reproduction. New York: Raven; 1994. p. 3–29.

    Google Scholar 

  94. Swyer GIM. Post-natal growth changes in the human prostate. J Anat. 1944;78(Pt 4):130–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Cowin PA, Foster PMD, Risbridger GP. Endocrine disruption in the male. In: Gore AC, editor. Endrocrine-disrupting chemicals: From basic research to clinical practice. Totowa, NJ: Humana Press Inc; 2007. p. 33–62.

    Chapter  Google Scholar 

  96. Jarred RA, Cancilla B, Prins GS, Thayer KA, Cunha GR, Risbridger GP. Evidence that estrogens directly alter androgen-regulated prostate development. Endocrinology. 2000;141(9):3471–7.

    CAS  PubMed  Google Scholar 

  97. Price D. Normal development of the prostate and seminal vesicles of the rat with a study of experimental postnatal modifications. Am J Anat. 1936;60(1):79–127.

    Article  Google Scholar 

  98. Weihua Z, Makela S, Andersson LC, Salmi S, Saji S, Webster JI, et al. A role for estrogen receptor beta in the regulation of growth of the ventral prostate. Proc Natl Acad Sci U S A. 2001;98(11):6330–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Santti R, Newbold RR, Makela S, Pylkkanen L, McLachlan JA. Developmental estrogenization and prostatic neoplasia. Prostate. 1994;24(2):67–78.

    Article  CAS  PubMed  Google Scholar 

  100. Rohrmann S, Nelson WG, Rifai N, Brown TR, Dobs A, Kanarek N, et al. Serum estrogen, but not testosterone, levels differ between black and white men in a nationally representative sample of Americans. J Clin Endocrinol Metab. 2007;92(7):2519–25.

    Article  CAS  PubMed  Google Scholar 

  101. Henderson BE, Bernstein L, Ross RK, Depue RH, Judd HL. The early in utero oestrogen and testosterone environment of blacks and whites: Potential effects on male offspring. Br J Cancer. 1988;57(2):216–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hayes JH, Barry MJ. Screening for prostate cancer with the prostate-specific antigen test: A review of current evidence. JAMA. 2014;311(11):1143–9.

    Article  CAS  PubMed  Google Scholar 

  103. Dalgaard JB, Giertsen JC. Primary carcinoma of the seminal vesicle. Acta Pathol Microbiol. 1956;39(4):255–67.

    Article  CAS  Google Scholar 

  104. Katzenwadel A, Wolf P. Androgen deprivation of prostate cancer: Leading to a therapeutic dead end. Cancer Lett. 2015;367(1):12–7.

    Article  CAS  PubMed  Google Scholar 

  105. Ahmed A, Ali S, Sarkar FH. Advances in androgen receptor targeted therapy for prostate cancer. J Cell Physiol. 2014;229(3):271–6.

    Article  CAS  PubMed  Google Scholar 

  106. Finkelstein JS, Lee H, Burnett-Bowie S-AM, Pallais CJ, Yu EW, Borges LF, et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013;369(11):1011–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Driscoll SG, Taylor SH. Effects of prenatal maternal estrogen on the male urogenital system. Obstet Gynecol. 1980;56(5):537–42.

    CAS  PubMed  Google Scholar 

  108. Tarapore P, Ying J, Ouyang B, Burke B, Bracken B, Ho SM. Exposure to bisphenol a correlates with early-onset prostate cancer and promotes centrosome amplification and anchorage-independent growth in vitro. PLoS One. 2014;9(3):e90332.

  109. Lakshman M, Xu L, Ananthanarayanan V, Cooper J, Takimoto CH, Helenowski I, et al. Dietary genistein inhibits metastasis of human prostate cancer in mice. Cancer Res. 2008;68(6):2024–32.

    Article  CAS  PubMed  Google Scholar 

  110. Prins GS, Hu WY, Shi GB, Hu DP, Majumdar S, Li G, et al. Bisphenol a promotes human prostate stem-progenitor cell self-renewal and increases in vivo carcinogenesis in human prostate epithelium. Endocrinology. 2014;155(3):805–17.

  111. Toppari J, Larsen JC, Christiansen P, Giwercman A, Grandjean P, Guillette LJ, et al. Male reproductive health and environmental xenoestrogens. Environ Health Perspect. 1996;104 Suppl 4:741–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Zeegers MP, Friesema IH, Goldbohm RA, van den Brandt PA. A prospective study of occupation and prostate cancer risk. J Occup Environ Med. 2004;46(3):271–9.

    Article  PubMed  Google Scholar 

  113. Prince MM, Ruder AM, Hein MJ, Waters MA, Whelan EA, Nilsen N, et al. Mortality and exposure response among 14,458 electrical capacitor manufacturing workers exposed to polychlorinated biphenyls (PCBs). Environ Health Perspect. 2006;114(10):1508–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Grandjean P, Gronlund C, Kjaer IM, Jensen TK, Sorensen N, Andersson AM, et al. Reproductive hormone profile and pubertal development in 14-year-old boys prenatally exposed to polychlorinated biphenyls. Reprod Toxicol. 2012;34(4):498–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM, et al. Endocrine-disrupting chemicals: An endocrine society scientific statement. Endocr Rev. 2009;30(4):293–342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Koutros S, Beane Freeman LE, Lubin JH, Heltshe SL, Andreotti G, Barry KH, et al. Risk of total and aggressive prostate cancer and pesticide use in the agricultural health study. Am J Epidemiol. 2013;177(1):59–74.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Leav I, Ho SM, Ofner P, Merk FB, Kwan PW, Damassa D. Biochemical alterations in sex hormone-induced hyperplasia and dysplasia of the dorsolateral prostates of noble rats. J Natl Cancer Inst. 1988;80(13):1045–53.

    Article  CAS  PubMed  Google Scholar 

  118. Ho SM, Tang WY, De Frausto Belmonte J, Prins GS. Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4. Cancer Res. 2006;66(11):5624–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Brandt JZ, Silveira LT, Grassi TF, Anselmo-Franci JA, Favaro WJ, Felisbino SL, et al. Indole-3-carbinol attenuates the deleterious gestational effects of bisphenol a exposure on the prostate gland of male F1 rats. Reprod Toxicol. 2014;43:56–66.

    Article  CAS  PubMed  Google Scholar 

  120. Boberg J, Johansson HK, Hadrup N, Dreisig K, Berthelsen L, Almstrup K, et al. Perinatal exposure to mixtures of anti-androgenic chemicals causes proliferative lesions in rat prostate. Prostate. 2015;75(2):126–40.

    Article  CAS  PubMed  Google Scholar 

  121. Gray Jr LE, Ostby J, Monosson E, Kelce WR. Environmental antiandrogens: low doses of the fungicide vinclozolin alter sexual differentiation of the male rat. Toxicol Ind Health. 1999;15(1–2):48–64.

    Article  PubMed  Google Scholar 

  122. Ito N, Nagasaki H, Arai M, Makiura S, Sugihara S, Hirao K. Histopathologic studies on liver tumorigenesis induced in mice by technical polychlorinated biphenyls and its promoting effect on liver tumors induced by benzene hexachloride. J Natl Cancer Inst. 1973;51(5):1637–46.

    CAS  PubMed  Google Scholar 

  123. Ahlborg, U.G., Hanberg, A. and Kenne, K. Risk assessment of polychlorinated biphenyls (PCBs). In Nord. Institute Environmental Medicine Karolinska Institutet, 1992.

  124. Brevini TA, Lonergan P, Cillo F, Francisci C, Favetta LA, Fair T, et al. Evolution of mRNA polyadenylation between oocyte maturation and first embryonic cleavage in cattle and its relation with developmental competence. Mol Reprod Dev. 2002;63(4):510–7.

    Article  CAS  PubMed  Google Scholar 

  125. Cillo F, de Eguileor M, Gandolfi F, Brevini TA. Aroclor-1254 affects mRNA polyadenylation, translational activation, cell morphology, and DNA integrity of rat primary prostate cells. Endocr Relat Cancer. 2007;14(2):257–66.

    Article  CAS  PubMed  Google Scholar 

  126. Dieckmann KP, Pichlmeier U. Clinical epidemiology of testicular germ cell tumors. World J Urol. 2004;22(1):2–14.

    Article  PubMed  Google Scholar 

  127. Soto AM, Maffini MV, Sonnenschein C. Neoplasia as development gone awry: The role of endocrine disruptors. Int J Androl. 2008;31(2):288–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Koopman P, Münsterberg A, Capel B, Vivian N, Lovell-Badge R. Expression of a candidate sex-determining gene during mouse testis differentiation. Nature. 1990;348(6300):450–2.

    Article  CAS  PubMed  Google Scholar 

  129. Kassim NM, McDonald SW, Reid O, Bennett NK, Gilmore DP, Payne AP. The effects of pre- and postnatal exposure to the Nonsteroidal antiandrogen Flutamide on testis descent and morphology in the albino swiss rat. J Anat. 1997;190(Pt 4):577–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Klonisch T, Fowler PA, Hombach-Klonisch S. Molecular and genetic regulation of testis descent and external genitalia development. Dev Biol. 2004;270(1):1–18.

    Article  CAS  PubMed  Google Scholar 

  131. Baskin LS. Hypospadias and urethral development. J Urol. 2000;163(3):951–6.

    Article  CAS  PubMed  Google Scholar 

  132. Skakkebaek NE, Meyts R-DE, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod. 2001;16(5):972–78.

    Article  CAS  PubMed  Google Scholar 

  133. McLachlan JA, Newbold RR, Bullock B. Reproductive tract lesions in male mice exposed prenatally to diethylstilbestrol. Science. 1975;190(4218):991–2.

    Article  CAS  PubMed  Google Scholar 

  134. Mahawong P, Sinclair A, Li Y, Schlomer B, Rodriguez Jr E, Ferretti MM, et al. Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains. Differentiation. 2014;88(2–3):51–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Baroni, C., Magrini, U., Martinazzi, M. and Bertoli, G., Testicular Leydig cell tumourigenesis by diethylstilbestrol in the BALB/c mouse: Histologic and histochemical study. Eur J Cancer. 1966.

  136. Giannandrea F, Paoli D, Figa-Talamanca I, Lombardo F, Lenzi A, Gandini L. Effect of endogenous and exogenous hormones on testicular cancer: The epidemiological evidence. Int J Dev Biol. 2013;57(2–4):255–63.

    Article  CAS  PubMed  Google Scholar 

  137. Bray F, Richiardi L, Ekbom A, Pukkala E, Cuninkova M, Moller H. Trends in testicular cancer incidence and mortality in 22 European countries: Continuing increases in incidence and declines in mortality. Int J Cancer. 2006;118(12):3099–111.

    Article  CAS  PubMed  Google Scholar 

  138. Stevens LC. Spontaneous and experimentally induced testicular teratomas in mice. Cell Differ. 1984;15(2–4):69–74.

    Article  CAS  PubMed  Google Scholar 

  139. Almstrup K, Sonne SB, Hoei-Hansen CE, Ottesen AM, Nielsen JE, Skakkebaek NE, et al. From embryonic stem cells to testicular germ cell cancer-- should we be concerned? Int J Androl. 2006;29(1):211–8.

    Article  CAS  PubMed  Google Scholar 

  140. Peng X, Zeng X, Peng S, Deng D, Zhang J. The association risk of male subfertility and testicular cancer: A systematic review. PLoS One. 2009;4(5):e5591.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Martin OV, Shialis T, Lester JN, Scrimshaw MD, Boobis AR, Voulvoulis N. Testicular dysgenesis syndrome and the estrogen hypothesis: A quantitative meta-analysis. Environ Health Perspect. 2008;116(2):149–57.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Strohsnitter WC, Noller KL, Hoover RN, Robboy SJ, Palmer JR, Titus-Ernstoff L, et al. Cancer risk in men exposed in utero to diethylstilbestrol. J Natl Cancer Inst. 2001;93(7):545–51.

    Article  CAS  PubMed  Google Scholar 

  143. Choi H, Kim J, Im Y, Lee S, Kim Y. The association between some endocrine disruptors and hypospadias in biological samples. J Environ Sci Health A Tox Hazard Subst Environ Eng. 2012;47(13):2173–9.

    Article  CAS  PubMed  Google Scholar 

  144. Chevalier N, Brucker-Davis F, Lahlou N, Coquillard P, Pugeat M, Pacini P, et al. A negative correlation between insulin-like peptide 3 and bisphenol a in human cord blood suggests an effect of endocrine disruptors on testicular descent during fetal development. Hum Reprod. 2015;30(2):447–53.

    Article  PubMed  Google Scholar 

  145. Hardell L, Van Bavel B, Lindstrom G, Carlberg M, Eriksson M, Dreifaldt AC, et al. Concentrations of polychlorinated biphenyls in blood and the risk for testicular cancer. Int J Androl. 2004;27(5):282–90.

    Article  CAS  PubMed  Google Scholar 

  146. McGlynn KA, Quraishi SM, Graubard BI, Weber JP, Rubertone MV, Erickson RL. Persistent organochlorine pesticides and risk of testicular germ cell tumors. J Natl Cancer Inst. 2008;100(9):663–71.

    Article  CAS  PubMed  Google Scholar 

  147. Le Cornet C, Fervers B, Oksbjerg Dalton S, Feychting M, Pukkala E, Tynes T, et al. Testicular germ cell tumours and parental occupational exposure to pesticides: A register-based case–control study in the Nordic countries (NORD-TEST study). Occup Environ Med. 2015;72(11):805–11.

    Article  PubMed  Google Scholar 

  148. Paoli D, Giannandrea F, Gallo M, Turci R, Cattaruzza MS, Lombardo F, et al. Exposure to polychlorinated biphenyls and hexachlorobenzene, semen quality and testicular cancer risk. J Endocrinol Investig. 2015;38(7):745–52.

    Article  CAS  Google Scholar 

  149. Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, Calafat AM, et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect. 2005;113(8):1056–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Miao M, Yuan W, He Y, Zhou Z, Wang J, Gao E, et al. In utero exposure to bisphenol-a and anogenital distance of male offspring. Birth Defects Res A Clin Mol Teratol. 2011;91(10):867–72.

    Article  CAS  PubMed  Google Scholar 

  151. Dean A, Sharpe RM. Clinical review: Anogenital distance or digit length ratio as measures of fetal androgen exposure: Relationship to male reproductive development and its disorders. J Clin Endocrinol Metab. 2013;98(6):2230–8.

    Article  CAS  PubMed  Google Scholar 

  152. Ge RS, Chen GR, Tanrikut C, Hardy MP. Phthalate ester toxicity in Leydig cells: Developmental timing and dosage considerations. Reprod Toxicol. 2007;23(3):366–73.

    Article  CAS  PubMed  Google Scholar 

  153. Mylchreest E, Wallace DG, Cattley RC, Foster PM. Dose-dependent alterations in androgen-regulated male reproductive development in rats exposed to Di(n-butyl) phthalate during late gestation. Toxicol Sci. 2000;55(1):143–51.

    Article  CAS  PubMed  Google Scholar 

  154. Perez-Martinez C, Garcia-Iglesias MJ, Ferreras-Estrada MC, Bravo-Moral AM, Espinosa-Alvarez J, Escudero-Diez A. Effects of in-utero exposure to zeranol or diethylstilboestrol on morphological development of the fetal testis in mice. J Comp Pathol. 1996;114(4):407–18.

    Article  CAS  PubMed  Google Scholar 

  155. Brouwer A, Ahlborg UG, van Leeuwen FX, Feeley MM. Report of the WHO working group on the assessment of health risks for human infants from exposure to PCDDs, PCDFs and PCBs. Chemosphere. 1998;37(9–12):1627–43.

    Article  CAS  PubMed  Google Scholar 

  156. National Toxicology Program. Carcinogenesis bioassay of bisphenol a (CAS No. 80-05-7) in F344 rats and B6C3F1 mice (feed study). Natl Toxicol Program Tech Rep Ser. 1982;215:1–116.

    Google Scholar 

  157. Seachrist DD, Bonk KW, Ho SM, Prins GS, Soto AM, Keri RA. A review of the carcinogenic potential of bisphenol A. Reprod Toxicol. 2015;S0890-6238(15):30024–1.

    Google Scholar 

  158. 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. Biol Reprod. 2012;86(5):135. 1–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. LaRocca J, Boyajian A, Brown C, Smith SD, Hixon M. Effects of in utero exposure to bisphenol a or diethylstilbestrol on the adult male reproductive system. Birth Defects Res B Dev Reprod Toxicol. 2011;92(6):526–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Vrooman LA, Oatley JM, Griswold JE, Hassold TJ, Hunt PA. Estrogenic exposure alters the spermatogonial stem cells in the developing testis, permanently reducing crossover levels in the adult. PLoS Genet. 2015;11(1):e1004949.

    Article  PubMed  PubMed Central  Google Scholar 

  161. Tanaka M, Nakaya S, Katayama M, Leffers H, Nozawa S, Nakazawa R, et al. Effect of prenatal exposure to bisphenol a on the serum testosterone concentration of rats at birth. Hum Exp Toxicol. 2006;25(7):369–73.

    Article  CAS  PubMed  Google Scholar 

  162. Kobayashi K, Miyagawa M, Wang RS, Sekiguchi S, Suda M, Honma T. Effects of in utero and lactational exposure to bisphenol a on somatic growth and anogenital distance in F1 rat offspring. Ind Health. 2002;40(4):375–81.

    Article  CAS  PubMed  Google Scholar 

  163. Murray TJ, Maffini MV, Ucci AA, Sonnenschein C, Soto AM. Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol a exposure. Reprod Toxicol. 2007;23(3):383–90.

  164. Iuanow E, Kettler M, Slanetz PJ. Spectrum of disease in the male breast. AJR Am J Roentgenol. 2011;196(3):W247–59.

    Article  PubMed  Google Scholar 

  165. Vandenberg LN, Schaeberle CM, Rubin BS, Sonnenschein C, Soto AM. The male mammary gland: A target for the xenoestrogen bisphenol a. Reprod Toxicol. 2013;37:15–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Cardy RH. Sexual dimorphism of the normal rat mammary gland. Vet Pathol. 1991;28(2):139–45.

    Article  CAS  PubMed  Google Scholar 

  167. Khan MH, Allerton R, Pettit L. Hormone therapy for breast cancer in men. Clin Breast Cancer. 2015;15(4):245–50.

    Article  CAS  PubMed  Google Scholar 

  168. What are the key statistics about breast cancer in men? 2015 02/26/2015 [cited 2015; Available from: http://www.cancer.org/cancer/breastcancerinmen/detailedguide/breast-cancer-in-men-key-statistics.

  169. Fentiman I. Male breast cancer: A review. Ecancermedicalscience. 2009;3:140.

    PubMed  PubMed Central  Google Scholar 

  170. Maidment SL. Question 2. Which medications effectively reduce pubertal gynaecomastia? Arch Dis Child. 2010;95(3):237–9.

    Article  PubMed  Google Scholar 

  171. Brinton LA, Cook MB, McCormack V, Johnson KC, Olsson H, Casagrande JT, et al. Anthropometric and hormonal risk factors for male breast cancer: Male breast cancer pooling project results. J Natl Cancer Inst. 2014;106(3):djt465.

    Article  PubMed  PubMed Central  Google Scholar 

  172. Soto AM, Sonnenschein C. Endocrine disruptors: DDT, endocrine disruption and breast cancer. Nat Rev Endocrinol. 2015;11(9):507–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  173. McClure J, Higgins CC. Bilateral carcinoma of male breast after estrogen therapy. J Am Med Assoc. 1951;146(1):7–9.

    Article  CAS  PubMed  Google Scholar 

  174. Ruckart PZ, Bove FJ, Shanley 3rd E, Maslia M. Evaluation of contaminated drinking water and male breast cancer at marine corps base camp Lejeune north Carolina: A case control study. Environ Health. 2015;14:74.

    Article  PubMed  PubMed Central  Google Scholar 

  175. Braunstein GD. Environmental gynecomastia. Endocr Pract. 2008;14(4):409–11.

    Article  PubMed  Google Scholar 

  176. Harrington JM, Stein GF, Rivera RO, de Morales AV. The occupational hazards of formulating oral contraceptives--a survey of plant employees. Arch Environ Health. 1978;33(1):12–5.

    Article  CAS  PubMed  Google Scholar 

  177. Brody SA, Loriaux DL. Epidemic of gynecomastia among Haitian refugees: Exposure to an environmental antiandrogen. Endocr Pract. 2003;9(5):370–5.

    Article  PubMed  Google Scholar 

  178. Clemons J, Glode LM, Gao D, Flaig TW. Low-dose diethylstilbestrol for the treatment of advanced prostate cancer. Urol Oncol. 2013;31(2):198–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Nebesio TD, Eugster EA. Current concepts in normal and abnormal puberty. Curr Probl Pediatr Adolesc Health Care. 2007;37(2):50–72.

    Article  PubMed  Google Scholar 

  180. Durmaz E, Ozmert EN, Erkekoglu P, Giray B, Derman O, Hincal F, et al. Plasma phthalate levels in pubertal gynecomastia. Pediatrics. 2010;125(1):e122–9.

    Article  PubMed  Google Scholar 

  181. Delclos KB, Bucci TJ, Lomax LG, Latendresse JR, Warbritton A, Weis CC, et al. Effects of dietary genistein exposure during development on male and female CD (Sprague–Dawley) rats. Reprod Toxicol. 2001;15(6):647–63.

    Article  CAS  PubMed  Google Scholar 

  182. Latendresse JR, Bucci TJ, Olson G, Mellick P, Weis CC, Thorn B, et al. Genistein and Ethinyl estradiol dietary exposure in multigenerational and chronic studies induce similar proliferative lesions in mammary gland of male Sprague–Dawley rats. Reprod Toxicol. 2009;28(3):342–53.

    Article  CAS  PubMed  Google Scholar 

  183. Tate-Ostroff BA, Bridges RS. Nipple development and pup-induced prolactin release in male rats treated prenatally with the antiandrogen Flutamide. Psychoneuroendocrinology. 1988;13(4):309–16.

    Article  CAS  PubMed  Google Scholar 

  184. You L, Sar M, Bartolucci EJ, McIntyre BS, Sriperumbudur R. Modulation of mammary gland development in prepubertal male rats exposed to genistein and methoxychlor. Toxicol Sci. 2002;66(2):216–25.

    Article  CAS  PubMed  Google Scholar 

  185. Wang XJ, Bartolucci-Page E, Fenton SE, You L. Altered mammary gland development in male rats exposed to genistein and methoxychlor. Toxicol Sci. 2006;91(1):93–103.

    Article  CAS  PubMed  Google Scholar 

  186. Diamanti-Kandarakis E, B. J., H. R. Giudice L. C., Prins G. S., Soto A. M., and a. G. A. C. Zoeller R. T. Endocrine disrupting chemicals: an endocrine society scientific statement. Endocrine reviews 2015; Available from: https://www.endocrine.org/~/media/endosociety/files/publications/scientific-statements/edc_scientific_statement.pdf?la=en.

  187. Soto AM, Sonnenschein C. In: Naz RK, editor. Estrogens, xenoestrogens, and the development of neoplasms in endocrine disruptors: Effects in male and female reproductive systems. Boca Raton: CRC Press; 1999. p. 125–63.

    Google Scholar 

  188. Waddell WJ. Dose–response curves in chemical carcinogenesis. Nonlinearity Biol Toxicol Med. 2004;2(1):11–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Soto, A. M., Michaelson, C. L., Prechtl, N. L., and Sonnenschein, C., In vitro endocrine disruptor screening. Environmental toxicology and risk assessment. Vol. 8, West Conshohocken, PA: American Society for Testing and Materials; 1999.

  190. Villalobos M, Olea N, Brotons JA, Olea-Serrano MF, De Almodovar Ruiz JM, Pedraza V. The E-screen assay: a comparison of different MCF7 cell stocks. Environ Health Perspect. 1995;103(9):844–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, Jacobs Jr DR, Lee DH, et al. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr Rev. 2012;33(3):378–455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Zoeller RT, Bergman A, Becher G, Bjerregaard P, Bornman R, Brandt I, et al. A path forward in the debate over health impacts of endocrine disrupting chemicals. Environ Health. 2015;14:118.

    Article  CAS  Google Scholar 

  193. Vom Saal FS, Akingbemi BT, Belcher SM, Crain DA, Crews D, Guidice LC, et al. Flawed experimental design reveals the need for guidelines requiring appropriate positive controls in endocrine disruption research. Toxicol Sci. 2010;115(2):612–3. author reply 614–20.

    Article  CAS  PubMed  Google Scholar 

  194. Myers JP, Vom Saal FS, Akingbemi BT, Arizono K, Belcher S, Colborn T, et al. Why public health agencies cannot depend on good laboratory practices as a criterion for selecting data: the case of bisphenol A. Environ Health Perspect. 2009;117(3):309–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. 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(12):e51579.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  196. Desdoits-Lethimonier C, Albert O, Le Bizec B, Perdu E, Zalko D, Courant F, et al. Human testis steroidogenesis is inhibited by phthalates. Hum Reprod. 2012;27(5):1451–9.

    Article  CAS  PubMed  Google Scholar 

  197. Delclos KB, Camacho L, Lewis SM, Vanlandingham MM, Latendresse JR, Olson GR, et al. Toxicity evaluation of bisphenol a administered by gavage to Sprague Dawley rats from gestation day 6 through postnatal day 90. Toxicol Sci. 2014;139(1):174–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Vom Saal FS, Welshons WV. Evidence that bisphenol A (BPA) can be accurately measured without contamination in human serum and urine, and that BPA causes numerous hazards from multiple routes of exposure. Mol Cell Endocrinol. 2014;398(1–2):101–13.

    Article  CAS  PubMed  Google Scholar 

  199. Acevedo N, Davis B, Schaeberle CM, Sonnenschein C, Soto AM. Perinatally administered bisphenol a as a potential mammary gland carcinogen in rats. Environ Health Perspect. 2013;121(9):1040–6.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by Award Number R01ES08314 from the National Institute of Environmental Health Sciences. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. We are grateful to Lucia Speroni and Cheryl Schaeberle for their critical reading of the manuscript.

Author information

Author notes

    Authors and Affiliations

    1. Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, 02111, USA

      M. F. Sweeney, A. M. Soto & C. Sonnenschein

    2. Program in Cell, Molecular & Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, 02111, USA

      N. Hasan, A. M. Soto & C. Sonnenschein

    3. Department of Integrative Physiology & Pathobiology, Tufts University, 136 Harrison Ave, Boston, MA, 02111, USA

      A. M. Soto & C. Sonnenschein

    Authors
    1. M. F. Sweeney
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. N. Hasan
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. A. M. Soto
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. C. Sonnenschein
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to C. Sonnenschein.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Additional information

    M. F. Sweeney and N. Hasan contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Sweeney, M.F., Hasan, N., Soto, A.M. et al. Environmental endocrine disruptors: Effects on the human male reproductive system. Rev Endocr Metab Disord 16, 341–357 (2015). https://doi.org/10.1007/s11154-016-9337-4

    Download citation

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s11154-016-9337-4

    Keywords

    Search

    Navigation