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Developmental Effects and Molecular Mechanisms of Environmental Antiandrogens

  • William R. Kelce
  • Elizabeth M. Wilson
Part of the Serono Symposia USA Norwell, Massachusetts book series (SERONOSYMP)

Abstract

Industrial chemicals and environmental pollutants can disrupt reproductive development in wildlife and humans by altering the synthesis, transport, action, or elimination of gonadal steroid hormones. Steroid hormones control fundamental events in embryonic development and sex differentiation by binding to their cognate nuclear receptors, which act as steroid-inducible transcription factors to activate or repress transcription of target genes. The consequences of disrupting these events can be especially profound during embryonic development because the role of steroid hormones is crucial in controlling transient and irreversible developmental processes. Recent studies suggest that certain industrial pollutants and environmental pesticides have the potential to alter male sex development and reproductive processes in wildlife and human populations by acting as environmental antiandrogens (1–3). In some cases, laboratory studies have confirmed abnormalities of reproductive development observed in the field and have provided mechanisms to explain the disruptive effects of these environmental chemicals.

Keywords

Androgen Receptor Endocrine Disruptor Androgen Receptor Gene Reproductive Toxicity Human Androgen Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Kelce WR, Stone CS, Laws SC, Gray LE, Kemppainen JA, Wilson EM. Persistent DDT metabolite, p,p’-DDE, is a potent androgen receptor antagonist. Nature (Lond) 1995;375:581–5.CrossRefGoogle Scholar
  2. 2.
    Kelce WR, Monosson E, Gamcsik MP, Laws SC, Gray LE Jr. Environmental hormone disruptors: evidence that vinclozolin developmental toxicity is mediated by anti-androgenic metabolites. Toxicol Appl Pharmacol 1994;126:276–85.PubMedCrossRefGoogle Scholar
  3. 3.
    Gray LE Jr, Ostby JS, Kelce WR. Developmental effects of an environmental antiandrogen: the fungicide vinclozolin alters sex differentiation of the male rat. Toxicol Appl Pharmacol 1994;129:46–52.PubMedCrossRefGoogle Scholar
  4. 4.
    Kelce WR. Sex steroid hormone receptor agonists and antagonists. In: Drug toxicity and embryonic development, Handbook of experimental pharmacology, Vol. 124. 1997:435–74.Google Scholar
  5. 5.
    Peterson R, Cooke P, Gray LE Jr, Kelce WR. Endocrine disruptors. In: Boekelheide K, Chapin R, eds. Reproductive and endocrine toxicology: male reproductive toxicology, Vol. 10. Sipes G, McQueen C, Gandolfi J, eds. Comprehensive toxicology. New York: Pergamon, 1997:181–91.Google Scholar
  6. 6.
    Gray LE Jr, Monosson E, and Kelce WR. Emerging issues: the effects of endocrine disruptors on reproductive development. In: Di Giulio R, Monosson E, eds. Interconnections between human and ecosystem health. New York: Chapman & Hall, 1996: 48–84.Google Scholar
  7. 7.
    Guillette LJ, Crain DA. Endocrine-disrupting contaminants and reproductive abnormalities in reptiles. Comments Toxicol 1996;5:381–99.Google Scholar
  8. 8.
    Guillette LJ, Arnold SF, McLachlan JA Ecoestrogens and embryos—is there a scientific basis for concern. Animal Reprod Sci 1996;42:13–24.CrossRefGoogle Scholar
  9. 9.
    Toppari J, Larsen JC, Christiansen P, Giwercman A, Grandjean P, Guillette LJ, et al. Male reproductive health and environmental chemicals with estrogenic effects. Mil-joprojekt 1995;290:1–166.Google Scholar
  10. 10.
    Kelce WR, Wilson EM. Clinical, functional and molecular implications of environmental antiandrogens. J Mol Med 1997;75:198–207.PubMedCrossRefGoogle Scholar
  11. 11.
    Kavlock RJ, Daston GP, DeRosa C, Fenner-Crisp P, et al. Research needs for the risk assessment of health and environmental effects of endocrine disruptors: a report of the US EPA-sponsored workshop. Environ Health Perspect 1996;104:715–40.PubMedGoogle Scholar
  12. 12.
    Zhou Z-X, Lane MV, Kemppainen JA, French FS, Wilson EM. Specificity of ligand-dependent androgen receptor stabilization: receptor domain interactions influence ligand dissociation and receptor stability. Mol Endocrinol 1995;9:208–18.PubMedCrossRefGoogle Scholar
  13. 13.
    Wong CI, Zhou ZX, Sar M, Wilson EM. Steroid requirement for androgen receptor dimerization and DNA binding: modulation by intramolecular interactions between the NH2-terminal and steroid binding domains. J Biol Chem 1993;268:19004–12.PubMedGoogle Scholar
  14. 14.
    Ho KC, Marschke KB, Tan JA, Power SGA, Wilson EM, French FS. A complex response element in intron 1 of the androgen regulated 20 kDa protein gene displays cell-type dependent androgen receptor specificity. J Biol Chem 1993;268:27226–35.PubMedGoogle Scholar
  15. 15.
    Tan JA, Marschke KB, Ho KC, Perry ST, Wilson EM, French FS. Response elements of the androgen regulated C3 gene. J Biol Chem 1992;267:4456–66.PubMedGoogle Scholar
  16. 16.
    Eckert RL, Katzenellenbogen BS. Physical properties of estrogen receptor complexes in MCF-7 human breast cancer cells. J Biol Chem 1982;257:8840–6.PubMedGoogle Scholar
  17. 17.
    Hansen JC, Gorski J. Conformational transitions of the estrogen receptor monomer. J Biol Chem 1986;261:13990–6.PubMedGoogle Scholar
  18. 18.
    Martin PM, Berthois Y, Jensen EV. Binding of antiestrogens exposes an occult antigenic determinant in the human estrogen receptor. Proc Natl Acad Sci USA 1988; 85:2533–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Truss M, Bartsch J, Beato M. Antiprogestins prevent progesterone recptor binding to hormone responsive elements in vivo. Proc Natl Acad Sci USA 1994;91:11333–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Wong, CI, Kelce WR, Sar M, Wilson EM. Androgen receptor antagonist versus agonist activities of the fungicide vinclozolin relative to hydroxyflutamide. J Biol Chem 1995;270:19998–20003.PubMedCrossRefGoogle Scholar
  21. 21.
    Kemppainen JA, Lane MV, Sar M, Wilson EM. Androgen receptor phosphorylation, turnover, nuclear transport, and transcriptional activation. J Biol Chem 1992;267:968–74.Google Scholar
  22. 22.
    Langley E, Zhou Z-X, Wilson EM. Evidence for an anti-parallel orientation of the ligand-activated human androgen receptor dimer. J Biol Chem 1995;270:29983–90.Google Scholar
  23. 23.
    Kuil CW, Mulder E. Mechanism of antiandrogen action: conformational changes of the receptor. Mol Cell Endocrinol 1994; 102:R 1–5.CrossRefGoogle Scholar
  24. 24.
    Kuil CW, Berrevoets CA, Mulder E. Ligand-induced conformational alterations of the androgen receptor analyzed by limited trypsinization. J Biol Chem 1995;270:27569–76.PubMedCrossRefGoogle Scholar
  25. 25.
    Wilson JD. Sexual differentiation. Annu Rev Physiol 1978;40:279–306.PubMedCrossRefGoogle Scholar
  26. 26.
    George FW, Wilson JD. Sex determination and differentiation. In: Knobil E, Neill J, eds. The physiology of reproduction. New York: Raven Press, 1988:3–26.Google Scholar
  27. 27.
    George FW. Androgen metabolism in the prostate of the finasteride-treated, adult rat: a possible explanation for the differential action of testosterone and 5a-dihydro-testosterone during development of the male urogenital tract. Endocrinology 1997; 138:871–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Wilson EM, French FS. Binding properties of androgen receptors. Evidence for identical receptors in rat testis, epididymis and prostate. J Biol Chem 1976;25:5620–9.Google Scholar
  29. 29.
    Mizokami A, Chang C. Induction of translation by the 5’-untranslated region of human androgen receptor mRNA. J Biol Chem 1994;269:25655–9.PubMedGoogle Scholar
  30. 30.
    Lubahn DB, Joseph DR, Sullivan PM, Willard HF, French FS, Wilson EM. Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science 1988;240:327–30.PubMedCrossRefGoogle Scholar
  31. 31.
    Brown CJ, Goss SJ, Lubahn DB, Joseph DR, Wilson EM, French FS, et al. Androgen receptor locus on the human X chromosome: regional localization to Xq 11–12 and description of a genetic polymorphism. Am J Hum Genet 1989;44:264–9.PubMedGoogle Scholar
  32. 32.
    Mahtani MM, Lafrenier RG, Kruse TA, Willard HF. An 18-locus linkage map of the pericentromeric region of the human X-chromosome: genetic framework for mapping X- linked disorders. Genomics 1991;10:849–57.PubMedCrossRefGoogle Scholar
  33. 33.
    Wilson CM, Griffin JE, Wilson JD, Marcelli M, Zoppi S, McPhaul MJ. Immunoreac-tive androgen receptor expression in subjects with androgen resistance. J Clin Endocrinol Metab 1992;75:1474–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Quarmby VE, Kemppainen JA, Sar M, Lubahn DB, French FS, Wilson EM. Expression of recombinant androgen receptor in cultured mammalian cells. Mol Endocrinol 1990;4:1399–407.PubMedCrossRefGoogle Scholar
  35. 35.
    Jenster G, van der Korput HAGM, van Vroonhoven C, van der Kwast TH, Trapman J, Brinkmann AO. Domains of the human androgen receptor involved in steroid binding, transcriptional activation and subcellular localization. Mol Endocrinol 1991;5:1396–404.PubMedCrossRefGoogle Scholar
  36. 36.
    Lubahn DB, Joseph DR, Sar M, Tan J-A, Higgs HN, Larson RE, et al. The human androgen receptor: complementary deoxyribonucleic acid cloning, sequence analysis and gene expression in prostate. Mol Endocrinol 1988;2:1265–75.PubMedCrossRefGoogle Scholar
  37. 37.
    Chang C, Kokontis J, Liao S. Structural analysis of complementary DNA and amino acid sequences of human and rat androgen receptors. Proc Natl Acad Sci USA 1988;85:7211–5.PubMedCrossRefGoogle Scholar
  38. 38.
    Trapman J, Klaassen P, Kuiper GGJM, van der Korput JAGM, Faber PW, van Rooij HCJ, Geurts van Kessel A, Voorhorst MM, Mulder E, Brinkmann AO. Cloning, structure, and expression of a cDNA encoding the human androgen receptor. Biochem Biophys Res Commun 1988;153:241–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Tilley WD, Marcelli M, Wilson JD, McPhaul MJ. Characterization and expression of a cDNA encoding the human androgen receptor. Proc Natl Acad Sci USA 1989;86:327–31.PubMedCrossRefGoogle Scholar
  40. 40.
    Lubahn DB, Brown TR, Simental JA, Higgs HN, Migeon CJ, Wilson EM, et al. Sequence of the intron/exon junctions of the coding region of the human androgen receptor gene and identification of a point mutation in a family with complete androgen insensitivity. Proc Natl Acad Sci USA 1989;86:9534–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Bentvelsen FM, McPhaul MJ, Wilson JD, George FW. The androgen receptor of the urogenital tract of the fetal rat is regulated by androgen. Mol Cell Endocrinol 1994; 105:21–6.PubMedCrossRefGoogle Scholar
  42. 42.
    Fail PA, Pearce SW, Anderson SA, Tyl RW, Gray LE. Endocrine and reproductive toxicity of vinclozolin (vin) in male Long-Evans hooded rats. Fundam Appl Toxicol 1995;15:293.Google Scholar
  43. 43.
    Szokolay A, Rosival L, Uhnak J, Madaric A. Dynamics of benzene hexachloride (BHC) isomers and other chlorinated pesticides in the food chain and in human fat. Ecotoxicol Environ Saf 1977;1:349–59.PubMedCrossRefGoogle Scholar
  44. 44.
    Spindler M. DDT: health aspects in relation to man and risk/benefit assessment based thereupon. Residue Rev 1983;90:1–34.PubMedGoogle Scholar
  45. 45.
    Wyllie J, Gabica J, Benson WW. Comparative organochlorine pesticide residues in serum and biopsied lipoid tissue: a survey of 200 persons in southern Idaho—1970. Pestic Monit J 1972;6:84–8.PubMedGoogle Scholar
  46. 46.
    Barquet A, Morgade C, Pfaffenberger CD. Determination of organochlorine pesticides and metabolites in drinking water, human blood serum, and adipose tissue. J Toxicol Environ Health 1981;7:469–79.PubMedCrossRefGoogle Scholar
  47. 47.
    Adamovic VM, Sokic B, Smiljanski M-J. Some observations concerning the ratio of the intake of organochlorine insecticides through the food and amounts excreted in the milk of breast-feeding mothers. Bull Environ Contam Toxicol 1978;20:280–5.PubMedCrossRefGoogle Scholar
  48. 48.
    O’Leary JA, Davies JE, Edmundson WF, Reich GA. Transplacental passage of pesticides. Am J Obstet Gynecol 1970;107:65–8.PubMedGoogle Scholar
  49. 49.
    Rogan WJ, Gladen BC, McKinney JD, Carreras N, Hardy P, Thullen J, et al. Polychlorinated biphenyls (PCB’s) and dichlorodiphenyl dichloroethane (DDE) in human milk: effects of maternal factors and previous lactation. Am J Public Health 1986; 76:172–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Robison AK, Schmidt WA, Stancel GM. Estrogenic activity of DDT: estrogen-receptor profiles and the responses of individual uterine cell types following o.p’-DDT administration. J Toxicol Environ Health 1985;16:493–508.PubMedCrossRefGoogle Scholar
  51. 51.
    Imperato-McGinley J, Sanchez RS, Spencer JR, Yee B, Vaugan ED. Comparision of the effects of the 5-alpha-reductase inhibitor finasteride and the antiandrogen fluta-mide on prostate and genital differentiation: dose response studies. Endocrinology 1992;131:1149–56.PubMedCrossRefGoogle Scholar
  52. 52.
    Simonich SL, Hites RA. Global distribution of persistent organochlorine compounds. Science 1995;269:1851–4.PubMedCrossRefGoogle Scholar
  53. 53.
    Bouwman H, Cooppan RM, Becker PJ, Ngxongo S. Malaria control and levels of DDT in serum of two populations in Kwazulu. J Toxicol Environ Health 1991;33:141–55.PubMedCrossRefGoogle Scholar
  54. 54.
    Bouwman H, Reinecke AJ, Cooppan RM, Becker PJ. Factors affecting levels of DDT and metabolites in human breast milk from Kwazulu. J Toxicol Environ Health 1990;31:93–115.PubMedCrossRefGoogle Scholar
  55. 55.
    Curley A, Copeland MF, Kimbrough RD. Chlorinated hydrocarbon insecticides in organs of stillborn and blood of newborn babies. Arch Environ Health 1969; 19:628—32.Google Scholar
  56. 56.
    Sweet RA, Schrott HG, Kurland R, Culp OS. Study of the incidence of hypospadias in Rochester, Minn, 1940—1970, and a case-control comparision of possible etiologic factors. Mayo Clin Proc 1974;49:52–8.PubMedGoogle Scholar
  57. 57.
    Allera A, Herbst MA, Griffin JE, Wilson JD, Schweikert H-U, McPhaul MJ. Mutations of the androgen receptor coding sequence are infrequent in patients with isolated hypospadias. J Clin Endocrinol Metab 1995;80:2697–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Hiort O, Klauber G, Cendron M, Sinnecker GGH, Keim L, Schwinger E, et al. Molecular characterization of the androgen receptor gene in boys with hypospadias. Eur J Pediatr 1994;153:317–21.PubMedCrossRefGoogle Scholar
  59. 59.
    Wilson JD, Griffin JE, Russell DW. Steroid 5α-reductase 2 deficiency. Endocr Rev 1993;14:577–93.PubMedGoogle Scholar
  60. 60.
    Bentvelsen FM, Brinkmann AO, van der Linden JETM, Schroder FH, Nijman JM. Decreased immunoreactive androgen receptor levels are not the cause of isolated hypospadias. Br J Urol 1995;76:384–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Henderson BE, Benton B, Cogsgrove M, Baptista J, Aldrich J, Townsend D, et al. Urogenital tract abnormalities in sons of women treated with diethylstilbestrol. Pediatrics 1976;58:505–7.PubMedGoogle Scholar
  62. 62.
    Kalloo NB, Gearhart JP, Barrack ER. Sexually dimorphic expression of estrogen receptors, but not of androgen receptors in human fetal external genitalia. J Clin Endocrinol Metab 1993;77:692–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Schardein J. Hormones and hormone antagonists. In: Chemically induced birth defects, 2nd Ed. New York: Dekker, 1993:271–339.Google Scholar
  64. 64.
    Palmer T. Regulatory requirements for reproductive toxicology: theory and practice. In: Kimmel C, Buelke-Sam J, eds. Developmental toxicology. New York: Raven Press, 1981;259–88.Google Scholar
  65. 65.
    Makris S. Proposed revisions to the testing guidelines for developmental toxicity and two-generation reproductive toxicity studies conducted under FIFRA and TSCA—a progress update. Toxicologist 1995; 15:287.Google Scholar
  66. 66.
    Gray LE Jr, Ostby J, Sigmonn R, Ferrell J, Rehnberg G, Linder R, et al. The development of a protocol to assess reproductive effects of toxicants in the rat. Reprod Toxicol 1988;2:281–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Zenick H, Clegg ED, Perreault SD, Klinefelter GR, Gray LE. Assessment of male reproductive toxicity: a risk assessment approach. In: Hayes AW, ed. Principles and methods of toxicology, 3rd Ed. New York: Raven Press, 1994:937–88.Google Scholar
  68. 68.
    Waller CL, Juma BW, Gray LE, Kelce WR. Three-dimensional quantitative structure activity relationships for androgen receptor ligands. Toxicol Appl Pharmacol 1996; 137:219–27.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag New York, Inc. 1998

Authors and Affiliations

  • William R. Kelce
  • Elizabeth M. Wilson

There are no affiliations available

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