Environmental Endocrine Disrupters and Disorders of Sexual Differentiation

ABSTRACT

Endocrine disrupters are exogenous substances that cause adverse effects in the endocrine system. Sexual differentiation is regulated by reproductive hormones. Male differentiation is critically dependent on normal androgen action, which in turn depends on normal production of luteinizing hormone. Other essential hormones include follicle-stimulating hormone, anti-Müllerian hormone, and insulin-like hormone 3 (insl-3). Estrogens influence transcription of insl-3 and affect sexual differentiation both directly and indirectly. Diethylstilbestrol is the best known endocrine disrupter and has caused abnormalities of sexual differentiation in both exposed male and female human fetuses. There is a growing group of chemicals that have weak estrogenic properties, but, in addition, there are several antiandrogenic compounds that have been shown to disturb sexual differentiation in experimental animals. It is a challenge for endocrinologists to find out whether or not these chemicals or mixtures of them are involved in any of the abnormalities of human sexual differentiation.

KEYWORDS

Antiandrogen - estrogen - endocrine disrupter - sexual differentiation - environment - cryptorchidism - hypospadias

REFERENCES

• 1 Skakkebaek N E, Rajpert-De Meyts E, Main K M. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects.  Hum Reprod . 2001;  16 972-978
• 2 Paulozzi L J. International trends in rates of hypospadias and cryptorchidism.  Environ Health Perspect . 1999;  107 297-302
• 3 Toppari J. Trends in the incidence of cryptorchidism and hypospadias, and methodological limitations of registry-based data.  Hum Reprod Update . 2001;  7 282-286
• 4 Gray L E, Ostby J, Furr J. Effects of environmental antiandrogens on reproductive development in experimental animals.  Hum Reprod Update . 2001;  7 248-264
• 5 Cooke B, Hegstrom C D, Villeneuve L S, Breedlove S M. Sexual differentiation of the vertebrate brain: principles and mechanisms.  Front Neuroendocrinol . 1998;  19 323-362
• 6 Ostby J, Kelce W R, Lambright C. The fungicide procymidone alters sexual differentiation in the male rat by acting as an androgen-receptor antagonist in vivo and in vitro.  Toxicol Ind Health . 1999;  15 80-93
• 7 Lambright C, Ostby J, Bobseine K. Cellular and molecular mechanisms of action of linuron: an antiandrogenic herbicide that produces reproductive malformations in male rats.  Toxicol Sci . 2000;  56 389-399
• 8 Hershberger L, Shipley E, Meyer R. Myotrophic activity of 19-nortestosterone and other steroids determined by modified levator ani muscle method.  Proc Soc Exp Biol Med . 1953;  83 175-180
• 9 Gray Jr E L, Wolf C, Lambright C. Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p'-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat.  Toxicol Ind Health . 1999;  15 94-118
• 10 McIntyre B S, Barlow N J, Wallace D G. Effects of in utero exposure to linuron on androgen-dependent reproductive development in the male Crl:CD(SD)BR rat.  Toxicol Appl Pharmacol . 2000;  167 87-99
• 11 Hodge H C, Downs W L, Smith D W. Oral toxicity of linuron (3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea) in rats and dogs.  Food Cosmet Toxicol . 1968;  6 171-183
• 12 Szeto S Y, Burlinson N E, Rahe J E, Oloffs P C. Kinetics of hydrolysis of the dicarboximide vinclozolin.  J Agric Food Chem . 1989;  37 523-529
• 13 Kelce W R, Monosson E, Gamcsik M P, Laws S C, Gray Jr E L. Environmental hormone disruptors: evidence that vinclozolin developmental toxicity is mediated by antiandrogenic metabolites.  Toxicol Appl Pharmacol . 1994;  126 276-285
• 14 Wolf C J, LeBlanc G A, Ostby J S, Gray Jr E L. Characterization of the period of sensitivity of fetal male sexual development to vinclozolin.  Toxicol Sci . 2000;  55 152-161
• 15 Gray Jr L E. Chemical-induced alterations of sexual differentiation: a review of effects in humans and rodents. In: Colborn T, Clement C, eds. Advances in Modern Environmental Toxicology. Vol XXI. Chemical-Induced Alterations in Sexual and Functional Development: The Wildlife/Human Connection Princeton, NJ: Princeton Scientific Publishing 1992: 203-230
• 16 Wong C, Kelce W R, Sar M, Wilson E M. Androgen receptor antagonist versus agonist activities of the fungicide vinclozolin relative to hydroxyflutamide.  J Biol Chem . 1995;  270 19998-20003
• 17 Laws S C, Carey S A, Kelce W R, Cooper R L, Gray Jr E L. Vinclozolin does not alter progesterone receptor (PR) function in vivo despite inhibition of PR binding by its metabolites in vitro.  Toxicology . 1996;  112 173-182
• 18 Moreno Frias M, Garrido Frenich A, Martinez Vidal L J. Analyses of lindane, vinclozolin, aldrin, p,p'-DDE, o,p'-DDT and p,p'-DDT in human serum using gas chromatography with electron capture detection and tandem mass spectrometry.  J Chromatogr B Biomed Sci Appl. . 2001;  760 1-15
• 19 Zober A, Hoffmann G, Ott M G. Study of morbidity of personnel with potential exposure to vinclozolin.  Occup Environ Med . 1995;  52 233-241
• 20 Kelce W R, Stone C R, Laws S C. Persistent DDT metabolite p,p'-DDE is a potent androgen receptor antagonist.  Nature . 1995;  375 581-585
• 21 Guillette Jr J L, Woodward A R, Crain D A. Plasma steroid concentrations and male phallus size in juvenile alligators from seven Florida lakes.  Gen Comp Endocrinol . 1999;  116 356-372
• 22 Guillette Jr J L, Gross T S, Gross D A, Rooney A A, Percival H F. Gonadal steroidogenesis in vitro from juvenile alligators obtained from contaminated or control lakes.  Environ Health Perspect . 1995;  31-36
• 23 You L, Casanova M, Archibeque-Engle S. Impaired male sexual development in perinatal Sprague-Dawley and Long-Evans hooded rats exposed in utero and lactationally to p,p'-DDE.  Toxicol Sci . 1998;  45 162-173
• 24 Veeramachaneni D NR, Tesari J, Nett T. Male reproductive toxicity following perinatal exposures to the antiandrogen p,p'-DDT.  Toxicologist . 1996;  30 143
• 25 Curley A, Copeland M F, Kimbrough R D. Chlorinated hydrocarbon insecticides in organs of stillborn and blood of newborn babies.  Arch Environ Health . 1969;  19 628-632
• 26 Mably T A, Moore R W, Peterson R E. In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin: I. Effects on androgenic status.  Toxicol Appl Pharmacol . 1992;  114 97-107
• 27 Mably T A, Moore R W, Goy R W, Peterson R E. In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin: II. Effects on sexual behavior and the regulation of luteinizing hormone secretion in adulthood.  Toxicol Appl Pharmacol . 1992;  114 108-117
• 28 Mably T A, Bjerke D L, Moore R W, Gendron-Fitzpatrick A, Peterson R E. In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin: III. Effects on spermatogenesis and reproductive capability.  Toxicol Appl Pharmacol . 1992;  114 118-126
• 29 Theobald H M, Peterson R E. In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-rho-dioxin: effects on development of the male and female reproductive system of the mouse.  Toxicol Appl Pharmacol . 1997;  145 124-135
• 30 Gray L E, Ostby J S, Kelce W R. A dose-response analysis of the reproductive effects of a single gestational dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin in male Long Evans hooded rat offspring.  Toxicol Appl Pharmacol . 1997;  146 11-20
• 31 Gray L E, Wolf C, Mann P, Ostby J S. In utero exposure to low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin alters reproductive development of female Long Evans hooded rat offspring.  Toxicol Appl Pharmacol . 1997;  146 237-244
• 32 Guo Y L, Hsu P C, Hsu C C, Lambert G H. Semen quality after prenatal exposure to polychlorinated biphenyls and dibenzofurans.  Lancet . 2000;  356 1240-1241
• 33 Nikula H, Talonpoika T, Kaleva M, Toppari J. Inhibition of hCG-stimulated steroidogenesis in cultured mouse Leydig tumor cells by bisphenol A and octylphenols.  Toxicol Appl Pharmacol . 1999;  157 166-173
• 34 Parks L G, Ostby J S, Lambright C R. The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male rat.  Toxicol Sci . 2000;  58 339-349
• 35 Arcadi F A, Costa C, Imperatore C. Oral toxicity of bis(2-ethylhexyl) phthalate during pregnancy and suckling in the Long-Evans rat.  Food Chem Toxicol . 1998;  36 963-970
• 36 Moore R W, Rudy T A, Lin T M, Ko K, Peterson R E. Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer di(2-ethylhexyl) phthalate.  Environ Health Perspect . 2001;  109 229-237
• 37 Foster P M, Mylchreest E, Gaido K W, Sar M. Effects of phthalate esters on the developing reproductive tract of male rats.  Hum Reprod Update . 2001;  7 231-235
• 38 Gray Jr E L, Ostby J, Furr J. Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat.  Toxicol Sci . 2000;  58 350-365
• 39 Blount B C, Silva M J, Caudill S P. Levels of seven urinary phthalate metabolites in a human reference population.  Environ Health Perspect . 2000;  108 979-982
• 40 Williams K, McKinnell C, Saunders P T. Neonatal exposure to potent and environmental oestrogens and abnormalities of the male reproductive system in the rat: evidence for importance of the androgen-oestrogen balance and assessment of the relevance to man.  Hum Reprod Update . 2001;  7 236-247
• 41 McLachlan J A. Environmental signaling: what embryos and evolution teach us about endocrine disrupting chemicals.  Endocr Rev . 2001;  22 319-341
• 42 McLachlan J A, Newbold R R, Burow M E, Li S F. From malformations to molecular mechanisms in the male: three decades of research on endocrine disrupters.  APMIS . 2001;  109 263-272
• 43 Gill W B, Schumacher G F, Bibbo M. Pathological semen and anatomical abnormalities of the genital tract in human male subjects exposed to diethylstilbestrol in utero.  J Urol . 1977;  117 477-480
• 44 Gill W B, Schumacher G F, Bibbo M, Straus II H F, Schoenberg H W. Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities.  J Urol . 1979;  122 36-39
• 45 Toppari J, Larsen J C, Christiansen P. Male reproductive health and environmental xenoestrogens.  Environ Health Perspect . 1996;  741-803
• 46 Wilcox A J, Baird D D, Weinberg C R, Hornsby P P, Herbst A L. Fertility in men exposed prenatally to diethylstilbestrol.  N Engl J Med . 1995;  332 1411-1416
• 47 Strohsnitter W C, Noller K L, Hoover R N. Cancer risk in men exposed in utero to diethylstilbestrol.  J Natl Cancer Inst . 2001;  93 545-551
• 48 Herbst A L, Ulfelder H, Poskanzer D C. Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women.  N Engl J Med . 1971;  284 878-881
• 49 Kaufman R H, Adam E, Binder G L, Gerthoffer E. Upper genital tract changes and pregnancy outcome in offspring exposed in utero to diethylstilbestrol.  Am J Obstet Gynecol . 1980;  137 299-308
• 50 Siegler A M, Wang C F, Friberg J. Fertility of the diethylstilbestrol-exposed offspring.  Fertil Steril . 1979;  31 601-607
• 51 Pomerance W. Post-stilbestrol secondary syndrome.  Obstet Gynecol . 1973;  42 12-18
• 52 Newbold R R. Effects of developmental exposure to diethylstilbestrol (DES) in rodents: clues for other environmental estrogens.  APMIS . 2001;  S261-S271
• 53 Arai Y, Mori T, Suzuki Y, Bern H A. Long-term effects of perinatal exposure to sex steroids and diethylstilbestrol on the reproductive system of male mammals.  Int Rev Cytol . 1983;  84 235-268
• 54 Thayer K A, Ruhlen R L, Howdeshell K L. Altered prostate growth and daily sperm production in male mice exposed prenatally to subclinical doses of 17alpha-ethinyl oestradiol.  Hum Reprod . 2001;  16 988-996
• 55 Raman-Wilms L, Tseng A L, Wighardt S, Einarson T R, Koren G. Fetal genital effects of first-trimester sex hormone exposure: a meta-analysis.  Obstet Gynecol . 1995;  85 141-149
• 56 Damgaard I, Main K M, Toppari J, Skakkebæk N E. Impact of exposure to endocrine disrupters in utero and in childhood and adult reproduction.  Best Pract Res Clin Endocrinol Metab . 2002;  16 289-309
• 57 Ashby J. Getting the problem of endocrine disruption into focus: the need for a pause for thought.  APMIS . 2000;  108 805-813
• 58 Spearow J L, Doemeny P, Sera R, Leffler R, Barkley M. Genetic variation in susceptibility to endocrine disruption by estrogen in mice.  Science . 1999;  285 1259-1261
• 59 Nef S, Shipman T, Parada L F. A molecular basis for estrogen-induced cryptorchidism.  Dev Biol . 2000;  224 354-361
• 60 Emmen J M, McLuskey A, Adham I M. Hormonal control of gubernaculum development during testis descent: gubernaculum outgrowth in vitro requires both insulin-like factor and androgen.  Endocrinology . 2000;  141 4720-4727
• 61 Nef S, Parada L F. Cryptorchidism in mice mutant for Insl3.  Nat Genet . 1999;  22 295-299
• 62 Zimmermann S, Steding G, Emmen J M. Targeted disruption of the Insl3 gene causes bilateral cryptorchidism.  Mol Endocrinol . 1999;  13 681-691
• 63 Tomboc M, Lee P A, Mitwally M F. Insulin-like 3/ relaxin-like factor gene mutations are associated with cryptorchidism.  J Clin Endocrinol Metab . 2000;  85 4013-4018
• 64 Koskimies P, Virtanen H, Lindstrom M. A common polymorphism in the human relaxin-like factor (RLF) gene: no relationship with cryptorchidism.  Pediatr Res . 2000;  47 538-541
• 65 Krausz C, Quintana-Murci L, Fellous M, Siffroi J P, McElreavey K. Absence of mutations involving the INSL3 gene in human idiopathic cryptorchidism.  Mol Hum Reprod . 2000;  6 298-302
• 66 Lim H N, Raipert-de Meyts E, Skakkebaek N E, Hawkins J R, Hughes I A. Genetic analysis of the INSL3 gene in patients with maldescent of the testis.  Eur J Endocrinol . 2001;  144 129-137
• 67 Wilkins L, Jones H W, Holman G H. Masculinization of the female fetus associated with administration of oral and intramuscular progestins during gestation: non-adrenal female pseudohermaphroditism.  J Clin Endocrinol Metab . 1958;  18 559-586
• 68 Schardein J L. Hormones and hormone antagonists. In: Schardein L, ed. Chemically Induced Birth Defects New York: Marcel Dekker 1993: 271-339
• 69 Balaguer P, Francois F, Comunale F. Reporter cell lines to study the estrogenic effects of xenoestrogens.  Sci Total Environ . 1999;  233 47-56
• 70 Terouanne B, Tahiri B, Georget V. A stable prostatic bioluminescent cell line to investigate androgen and antiandrogen effects.  Mol Cell Endocrinol . 2000;  160 39-49
• 71 Vinggaard A M, Joergensen E C, Larsen J C. Rapid and sensitive reporter gene assays for detection of antiandrogenic and estrogenic effects of environmental chemicals.  Toxicol Appl Pharmacol . 1999;  155 150-160
• 72 Sultan C, Balaguer P, Terouanne B. Environmental xenoestrogens, antiandrogens and disorders of male sexual differentiation.  Mol Cell Endocrinol . 2001;  178 99-105
• 73 Sultan C, Paris F, Terouanne B. Disorders linked to insufficient androgen action in male children.  Hum Reprod Update . 2001;  7 314-322
• 74 Waller C L, Juma B W, Gray Jr E L, Kelce W R. Three-dimensional quantitative structure-activity relationships for androgen receptor ligands.  Toxicol Appl Pharmacol . 1996;  137 219-227