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Toxicant-Induced Hypospadias in the Male Rat

  • L. Earl GrayJr.
  • Joseph Ostby
  • Johnathan Furr
  • Carmen Wolf
  • Christy Lambright
  • Vickie Wilson
  • Nigel Noriega
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 545)

Abstract

Prenatal exposure to endocrine disrupting chemicals that interfere with the androgen or insulin like factor 3 signaling pathways during sexual differentiation can induce malformations of the reproductive tract of the male rodent offspring. The pattern of malformations in the male depends upon the specific mechanism of action of the toxicant, the dosage level administered and the timing of administration during pregnancy. Hypospadias occurs in male rats or mice after maternal treatment with 1). potent estrogens or estrogenic drugs, 2). drugs that inhibit 5 alpha reductase, 3). drugs, herbicides and dicarboximide and conazole fungicides that act as androgen receptor (AR) antagonists, and 4). drugs, herbicides and conazole fungicides that inhibit cytochrome P450 enzymes involved in steroid hormone synthesis. In addition, 5). several phthalate diesters including di-n-butyl phthalate (DBP), di-n-ethylhexyl phthalate (DEHP), and benzylbutyl phthalate(BBP) also induce hypospadias and by altering fetal testis Leydig cell differentiation, resulting in reduced steroid and peptide hormone production.

Keywords

Sexual Differentiation Male Offspring Phthalate Ester Ventral Prostate Male Reproductive Tract 
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. Andersen, H. R., Vinggaard, A. M., Rasmussen, T. H., Gjermandsen, I. M. and Bonefeld-Jorgensen,E. C., 2002. Effects of currently used pesticides in assays for estrogenicity, androgenicity, and aromatase activity in vitroToxicol Appl Pharmaco1.179:1–12.CrossRefGoogle Scholar
  2. Biegel, L.B., Flaws, J.A., Hirshfield, A.N.,O’Connor, J.C., Elliott, G.S., Ladics,G.S., Silbergeld, E.K., Van Pelt, C.S., Hum, M.E., Cook, J.C., Frame, S.R., 1998. 90-day feeding and one-generation reproduction study in Crl:CD BR rats with 17 beta-estradiolToxicol Sci.44(2):116–42.PubMedGoogle Scholar
  3. Birnbaum, L. S., 1994. Endocrine effects of prenatal exposure to PCBs, Dioxins, and other Xenobiotics: Implications for Policy and ResearchEnviron. Health Perspectives.102: 676–679.CrossRefGoogle Scholar
  4. Bjerke, D.L, Brown, T.J., MacLusky, N.J, Hochberg, R.B., and Peterson, R. E.,1994a. Partial demasculinization and feminization of sex behavior in male rats by in utero and lactational exposure of male rats to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) is not associated with alterations in estrogen receptor binding or volumes of sexually dimorphic brain nucleiToxicol Appl Pharm.127: 258–267.CrossRefGoogle Scholar
  5. Bjerke, D.L., Sommer, R.J., Moore, R.W., and Peterson, R.E,1994b. Effects of in utero and lactational exposure on responsiveness of the male rat reproductive system to testosterone stimulation in adulthoodToxicol Appl Pharm.127: 250–257.CrossRefGoogle Scholar
  6. Bjerke, D.L. and Peterson, R. E., 1994c. Reproductive toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in mal erats: Different effects of in utero versus lactational exposureToxicol Appl Pharm.127: 241–249.CrossRefGoogle Scholar
  7. Chapin, R.E., Harris, M.W., Davis, B.J., Ward, S.M., Wilson, R.E., Mauney, M.A., Lockhart, A.C., Smialowicz, R.J., Moser, V.C., Burka, L.T., Collins, B.J., 1997. The effects of perinatal/juvenilemethoxychlor exposure on adult rat nervous, immune, and reproductive system functionFundam Appl Toxicol.40(1): 138–57.PubMedCrossRefGoogle Scholar
  8. Chapin, R.E., Delaney, J., Wang, Y., Lanning, L., Davis, B., Collins, B., Mintz, N., Wolfe, G,. 1999.The effects of 4-nonylphenol in rats: a multigeneration reproduction studyToxicol Sci.52(1):80–91.PubMedCrossRefGoogle Scholar
  9. Clark, R.L., C.A. Anderson, S. Prahalada, Y. M. Leonard, J. L. Stevens and A.M. Hoberman., 1990. 5-alpha reductase inhibitor-inducedcongenital abnormalities inmale rat external genitaliaTeratology.41,5, A 544.Google Scholar
  10. Clark, R.L., Anderson, C.A., Prahalada, S., Robertson, R.T., Lochry, E.A., Leonard, Y.M., Stevens, J.L., Hoberman, A.M., 1993. Critical developmental periods for effects on male rat genitalia induced by finasteride, a 5 alpha-reductase inhibitorToxicol Appl Pharmacol.119(1): 34–40.PubMedCrossRefGoogle Scholar
  11. Cook, J.C., Mullin, L.S., Frame, S.R., Biegel, L.B., 1993. Investigation of a mechanism for Leydig cell tumorigenesis by linuron in ratsToxicol Appl Pharmacol.119: 195–204.PubMedCrossRefGoogle Scholar
  12. Delclos, K.B., Bucci, T.J., Lomax, L.G., Latendresse, J.R., Warbritton, A., Weis, C.C., Newbold, R.R., 2001. Effects of dietary genistein exposure during development on male and female CD (Sprague-Dawley) ratsReprod Toxicol.15(6): 647–63.PubMedCrossRefGoogle Scholar
  13. de Jager, C., Bornman, M.S., Oosthuizen, J.M., 1999. The effect of p-nonylphenol on the fertility potential of male rats after gestational, lactational and direct exposureAndrologia.31(2): 107–13.PubMedCrossRefGoogle Scholar
  14. Ema, M., Fujii, S., Furukawa, M., Kiguchi, M., Ikka, T.,Harazono, A., 2001. Rat two-generation reproductive toxicity study of bisphenol AReprod Toxicol.15(5): 505–23.PubMedCrossRefGoogle Scholar
  15. Goldman, A.S., Eavey, R.D., Baker, M.K., 1976. Production of male pseudohermaphroditism in rats by two new inhibitors of steroid 17alpha-hydroxylase and C 17–20 lyaseEndocrinol.71(3), 289–97.CrossRefGoogle Scholar
  16. Gray, L.E., Jr., 1982. Neonatal chlordecone exposure alters behavioral sex differentiation in female hamstersNeurotoxicology.3(2): 67–80.PubMedGoogle Scholar
  17. Gray, L.E.Jr., Ferrell, J.M., and Ostby, J.S., 1985. Alteration of behavioral sex differentiation by exposure to estrogenic compounds during a critical neonatal period: Effects of Zearalenone, Methoxychlor, and Estradiol in hamstersToxicology and Applied Pharmacology.80 (1): 127–136.PubMedCrossRefGoogle Scholar
  18. Gray, L.E. Jr., Ostby, J., Ferrell, J., Rehnberg, G., Linder, R., Cooper, R., Goldman, J., Slott, V., Laskey, J, 1989. A dose-response analysis of methoxychlor-induced alterations of reproductive development and function in the ratFundam Appl Toxicol.12(1): 92–108.PubMedCrossRefGoogle Scholar
  19. Gray, L.E., Kelce, W.R., Monosson, E., Ostby, J.S., and Birnbaum, L.S.,1995. Exposure to TCDD during development permanently alters reproductive function in male LE rats and Hamsters: Reduced ejaculated and epididymal sperm numbers and sex accessory gland weights in offspring with normal androgenic statusToxicol and Appl Pharmacol.131: 108–118.CrossRefGoogle Scholar
  20. Gray, L.E. Jr., and Ostby, J.S.,1995. In utero 2,3,7,8 Tetrachlorodibenzo-p-dioxin(TCDD) Alters Reproductive Morphology and Function in Female Rat OffspringToxicol Appl Pharm.133: 285–294.CrossRefGoogle Scholar
  21. Gray, L.E. Jr, Ostby, J.S., Kelce, W.R., 1997a. A dose-response analysis of the reproductive effects of a single gestational dose of 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) in male Long Evans hooded rat offspringToxicol Appl Pharmacol.146: 11–20.CrossRefGoogle Scholar
  22. Gray, L.E., Wolf, C., Mann, P., Ostby, J.S., 1997b. In utero exposure to low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin alters reproductive development of female Long Evans hooded rat offspringToxicol Appl Pharmacol.146(2): 237–244.CrossRefGoogle Scholar
  23. Gray, L.E. Jr and Ostby, J., 1998. Effects of pesticides and toxic substances on behavioral and morphological reproductive development: Endocrine versus nonendocrinemechanismsToxicollndustrialHealth.14:159184.Google Scholar
  24. Gray, L.E. Jr, Ostby, J., Monosson, E., Kelce, W.R., 1999a. Environmental antiandrogens: low doses of the fungicide vinclozolin alter sexual differentiation of the male ratToxicol Ind Health15 (1–2): 48–64.CrossRefGoogle Scholar
  25. Gray, L.E. Jr., Wolf, C., Lambright, C., Mann, P., Price, M., Cooper, R.L., Ostby, J.,1999b. 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 ratJ Toxicol Ind Health.15(1–2): 94–118.CrossRefGoogle Scholar
  26. Gray, L.E. Jr, Ostby, J., Furr, J., Price, M., Veeramachaneni, D.N.R., Parks, L., 2000. Perinatal exposure to the phthalates DEHP, BBP and DINP but not DEP, DMP or DOTP alters sexual differentiation of the male ratToxicol Sci.58: 350–365.PubMedCrossRefGoogle Scholar
  27. Gray, L.E. Jr, Ostby, J., Furr, J., Wolf, C.J., Lambright, C., Parks, L., Veeramachaneni, D.N.R., Wilson, V., Price, M., Hotchkiss, A., Orlando, E., Guillette, L., 2001. Effects of environmental antiandrogens on reproductive development in experimental animalsHuman Reproduction Update.7(3): 248–64.PubMedCrossRefGoogle Scholar
  28. Gray, L.E. Jr., Ostby, J., Fun, J., Wolf, C., Hotchkiss, A., Parks, L., Price, M., Lambright, C. and Wilson, V., 2003. Cumulative Developmental Effects of Endocrine Disrupters: Synergy or Additivity?Biology of Reproduction Suppl. Google Scholar
  29. Guillette, L., Brock, J., Rooney, A., Woodward, A., 1999. Serum concentrations of various environmental contaminants and their relationship to sex steroid concentrations and phallus size in juvenile male alligatorsArch Environ Contam Toxicol.36: 447–455.PubMedCrossRefGoogle Scholar
  30. Henderson, B.E., Benton, B., Cosgrove, M., Baptista, J., Aldrich, J., Townsend, D., Hart, W., Mack, T.M., 1976. Urogenital tract abnormalities in sons of women treated with diethylstilbestrolPediatrics.58(4): 505–7.PubMedGoogle Scholar
  31. Hirsch, K.S., mAdams, E.R., Hoffman, D.G., Markham, J.K., and Owen, N.V., 1987. Studies to elucidate the mechanism of fenarimol-induced infertility in the male ratToxicology and Applied Pharmacology.86: 391–399.CrossRefGoogle Scholar
  32. Hossaini, A., Dalgaard, M., Vinggaard, A.M., Frandsen, H., Larsen, J.J., 2001. In utero reproductive study in rats exposed to nonylphenolReprod Toxicol.15(5): 537–43.PubMedCrossRefGoogle Scholar
  33. Hurst, C., DeVito, M., Abbott, B., and Birnbaum L., 1996. 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) in pregnant rats: Distribution to maternal and fetal tissuesThe Toxicologist.30: 198.Google Scholar
  34. Hurst, C., DeVito, M., Abbott, B., and Birnbaum, L., 1997. Dose-response of (TCDD) distribution in pregnant Long Evans ratsThe Toxicologist.36: 257.Google Scholar
  35. Husmann, D.A., McPhaul, M.J., 1991. Time-specific androgen blockade withflutamide inhibits testicular descent in the ratEndocrinology.129(3): 1409–16.PubMedCrossRefGoogle Scholar
  36. Imperato-McGinley, J., Sanchez, R.S., Spencer, J.R., Yee, B. and Vaughan, E.D., 1992. Comparison of the effects of the 5 alpha-reductase inhibitorfinasteride and the antiandrogen flutamide on prostate and genital differentiation: Dose-response studiesEndocrinology.131: 1149–1156.PubMedCrossRefGoogle Scholar
  37. Kelce, W.R., Monosson, E., Gamcsik, M.P., Laws, S., Gray, L.E. Jr., 1994. Environmental hormone disruptors: Evidence that vinclozolin developmental toxicity is mediated by antiandrogenic metabolitesToxicol Appl Pharmacol.126: 275–285.CrossRefGoogle Scholar
  38. Kelce, W.R., Stone, C.R., Laws, S.C., Gray, L.E., Kemppainen, J.A., Wilson, E.M., 1995. The persistent DDT metabolite p,p’ DDE is a potent androgen receptor antagonistNature.375: 581–585.PubMedCrossRefGoogle Scholar
  39. Kelce W., Lambright, C., Gray, L. and Roberts, K., 1997. Vinclozolin and p,p’ DDE alter androgen-dependent gene expression: In vivo confirmation of an androgen receptor mediated mechanismToxicol Appl Pharm.142: 192–200.CrossRefGoogle Scholar
  40. Khera, K.S. and Ruddick, J.A., 1973. Polychlorodibenzo-p-dioxins: Perinatal effects and the dominant lethal test in Wistar rats. In: Chlorodioxins-origin and fate (E.H. Blair, Ed.) pp. 70–84.American. Chem. Soc.Washington, D.C.Google Scholar
  41. Klip, H., Verloop, J., van Gool, J.D., Koster, M.E., Burger, C.W., van Leeuwen, F.E., 2002. Hypospadias in sons of women exposed to diethylstilbestrol in utero: a cohort studyLancet.2002 Mar 30;359(9312):1081–2.CrossRefGoogle Scholar
  42. Kwon, S., Stedman, D.B., Elswick, B.A., Cattley, R.C., Welsch, F., 2000. Pubertal development and reproductive functions of Crl:CD BR Sprague-Dawley rats exposed to bisphenol A during prenatal and postnatal developmentToxicol Sci.55(2): 399–406.PubMedCrossRefGoogle Scholar
  43. Laignelet, L., Narbonne, J. F., Lhuguenot, J. C. and Riviere, J. L., 1989. Induction and inhibition of rat liver cytochrome(s) P-450 by an imidazole fungicide (prochloraz)Toxicology.59: 271–84.PubMedCrossRefGoogle Scholar
  44. Lambright, C., Ostby, J., Bobseine, K., Wilson, V., Hotchkiss, A.K. and Gray, L.E. Jr., 2000. Cellular and molecular mechanisms of action of linuron: An antiandrogenic herbicide that produces reproductive malformations in male ratsToxicology Sciences.56: 389–399.CrossRefGoogle Scholar
  45. Lambright, C., Wilson, V., Furr, J., Wolf, C., Noriega, N. and Gray, L.E., 2003. Effects of endocrine disrupting chemicals on fetal testes hormone productionThe Toxicologist72: S1, A 1323 p 272.Google Scholar
  46. Laws, S.C., Carey, S.A., Kelce, W.R., Cooper, R.L., Gray, L.E., 1996. Vinclozolin does not alter progesterone receptor (PR) function in vivo despite inhibition of PR binding by its metabolites in vitroToxicology.112(3): 173–82.PubMedCrossRefGoogle Scholar
  47. Mably T., Moore. R.W., Peterson, R.E., 1992a. In utero and lactational exposure of male rats to 2,3,7,8tetrachlorodibenzo-p-dioxin. 1. Effects on Androgenic statusToxicol Appl Pharmacol.114: 97–107.CrossRefGoogle Scholar
  48. Mably, T., Bjerke, D.L., Moore, R.W., Gendron-Fitzpatrick, A., Peterson, R.E.,1992c. In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin. 3. Effects on spermatogenesis and reproductive capabilityToxicol Appl Pharmacol.114: 118–126.CrossRefGoogle Scholar
  49. Mably, T., Moore, R.W., Goy, R.W, Peterson, R.E., 1992b. In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin. 2. Effects on sexual behavior and the regulation of luteinizing hormone secretion in adulthoodToxicol Appl Pharmacol.114: 108–117.CrossRefGoogle Scholar
  50. McIntyre, B.S., Barlow, N.J., Wallace, D.G., Maness, S.C., Gaido, K.W., Foster, PM., 2000. Effects of in utero exposure to linuron on androgen-dependent reproductive development in the male Crl:CD(SD)BR ratToxicol Appl Pharmacol.1;167(2): 87–99.CrossRefGoogle Scholar
  51. McIntyre, B.S, Barlow, N.J., Foster, P.M., 2001. Androgen-mediated developmentin male rat offspring exposed to flutamide in utero: permanence and correlation of early postnatal changes in anogenital distance and nipple retention with malformations in androgen-dependent tissuesToxicol Sci.62(2): 236–249.PubMedCrossRefGoogle Scholar
  52. McLachlan, J.A., Newbold, R.R., Bullock, B.,1975. Reproductive tract lesions in male mice exposed prenatally to diethylstilbestrolScience.190(4218): 991–2.PubMedCrossRefGoogle Scholar
  53. McLachlan, J.A., Newbold, R.R., Burow, M.E., Li, S.F., 2001. From malformations to molecular mechanisms in the male: three decades of research on endocrine disruptersAPMIS.109(4): 263–72.PubMedCrossRefGoogle Scholar
  54. Murray, F.J., Smith, F.A., Nitschke, K.D., Humiston, C.G., Kociba, R.J., and Schwetz, B.A., 1979. Three-generation reproduction study in rats given 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) in the dietToxicol Appl Pharmacol.50: 241–252.PubMedCrossRefGoogle Scholar
  55. Mylchreest, E., Cattley, R., Foster, P.M.D., 1998. Male reproductive tract malformations in rats following gestational and lactational exposure to DBP: An antiandrogenic mechanismToxicol Sciences.43: 47–60.Google Scholar
  56. Mylchreest, E., Sar, M., Cattley, R.C. and Foster, P.M., 1999. Disruption of androgen-regulated male reproductive development by DBP during late gestation in rats is different from flutamideToxicol Appl Pharmacol.1556(2): 81–95.CrossRefGoogle Scholar
  57. Nagao, T., Wada, K., Marumo, H., Yoshimura, S., Ono, H., 2001. Reproductive effects of nonylphenol in rats after gavage administration: a two-generation studyReprod Toxicol.15(3): 293–315.PubMedCrossRefGoogle Scholar
  58. Noriega, N., Gray, L.E., Ostby, J., Lambright, C., and Wilson, V., 2003. Prenatal exposure to the fungicide prochloraz alters the onset of parturition in the dam and sexual differentiation in male rat offspringThe Toxicologist. 72: S1, A 1375, p 283.Google Scholar
  59. North, K., Golding, J., 2000. A maternal vegetarian diet in pregnancy is associated with hypospadias. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood.BJU Int.85(1): 107–13.PubMedCrossRefGoogle Scholar
  60. Odum, J., Lefevre, P.A., Tinwell, H., Van Miller, J.P., Joiner, R.L., Chapin, R.E., Wallis, N.T., Ashby, J., 2002. Comparison of the developmental and reproductive toxicity of diethylstilbestrol administered to rats in utero, lactationally, preweaning, or postweaningToxicol Sci.68(1): 147–63.PubMedCrossRefGoogle Scholar
  61. Ostby, J., Kelce, W.R., Lambright, C., Wolf, C.J., Mann, P., Gray, L.E. Jr., 1999. The fungicide procymidone alters sexual differentiation inthe male rat by acting as an androgen-receptor antagonist in vivo and in vitroToxicol. Ind. Health.15: 80–93.PubMedGoogle Scholar
  62. Parks, L.G., Ostby, J.S., Lambright, C.R., Abbott, B.D., Klinefelter, G.R, Barlow, N.J., Gray, L.E. Jr., 2000. The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male ratToxicol. Sci.58: 339–349.PubMedCrossRefGoogle Scholar
  63. Pepper, G., Brenner, S., Gabrilove, J., 1990. Ketoconazole use in the treatment of ovarian hyperandrogenismFertil Steril.54: 38–444.Google Scholar
  64. Roberts, D., Veeramachaneni, D.N., Schlaff, W.D., Awoniyi, C.A., 2000. Effects of chronic dietary exposure to genistein, a phytoestrogen, during various stages of development on reproductive hormones and spermatogenesis in ratsEndocrine.13(3): 281–6.PubMedCrossRefGoogle Scholar
  65. Rosen, M., Wilson, V., Schmid, J. and Gray, L.E., 2003. Gene array analysis of the ventral prostate in rats exposed to either vinclozolin or procymidoneThe Toxicologist. 72: SI A454, p 94.Google Scholar
  66. Schurmeyer, T., Nieschlag, E., 1984. Effect of ketoconazole and other imidazole fungicides on testosterone biosynthesisActa Endocrinologica.105: 275–280.PubMedGoogle Scholar
  67. Sharpe, R.M., 2003. The ‘oestrogen hypothesis’- where do we stand now?Int JAndrol.26(1): 2–15.CrossRefGoogle Scholar
  68. Staub, C., Hardy, V.B., Chapin, R.E., Harris, M.W., Johnson, L., 2002. The hidden effect of estrogenic/antiandrogenic methoxychlor on spermatogenesisToxicol Appl Pharmacol.180(2): 129–35.PubMedCrossRefGoogle Scholar
  69. Tyl, R.W., Myers, C.B., Marr, M.C., Thomas, B.F., Keimowitz, A.R., Brine, D.R., Veselica, M.M., Fail, P.A., Chang, T.Y., Seely, J.C., Joiner, R.L., Butala, J.H., Dimond, S.S., Cagen, S.Z, Shiotsuka, R.N., Stropp, G.D., Waechter, J.M., 2002. Three-generation reproductive toxicity study of dietary bisphenol A in CD Sprague-Dawley ratsToxicol Sci.68(1): 121–46.PubMedCrossRefGoogle Scholar
  70. Tyl, R.W., Myers, C.B., Marr, M.C., Brine, D.R., Fail, P.A., Seely, J.C., Van Miller, J.P., 1999. Two-generation reproduction study with para-tert-octylphenol in ratsRegul Toxicol Pharmacol.30(2 Pt 1): 81–95.PubMedCrossRefGoogle Scholar
  71. Vannier, B. and Raynaud, J.P., 1980. Long-termeffects of prenatal oestrogen treatment on genital morphology and reproductive function in the ratJournal of Reproduction and Fertility.59: 43–49.PubMedCrossRefGoogle Scholar
  72. Vinggaard, A. M., Hnida, C., Breinholt, V. and Larsen, J. C., 2000. Screening of selected pesticides for inhibition of CYP19 aromatase activity in vitroToxicol ln Vitro.14: 227–34.CrossRefGoogle Scholar
  73. Vinggaard, A. M., Nellemann, C., Dalgaard, M., Jorgensen, E. B. and Andersen, H. R., 2002. Antiandrogenic effects in vitro and in vivo of the fungicide prochlorazToxicol Sci.69: 344–53.PubMedCrossRefGoogle Scholar
  74. Waller, C.L., Oprea, T.I., Chae, K., Park, H.K., Korach, K.S., Laws, S.C., Wiese, T.E., Kelce, W.R., Gray, L.E.Jr., 1996a. Ligand-based identification of environmental estrogensChem Res Toxicol.9(8): 1240–8.CrossRefGoogle Scholar
  75. Waller, C, Juma, B, Gray, L. E., and Kelce, W., 1996b. Three dimensional Quantitative structure Activity relationships for androgen receptor ligandsToxicol Appl Pharm.137: 219–227.CrossRefGoogle Scholar
  76. Weir, P.J., Conner, M. and Johnson, C.M., 1990. Abnormal development of male urogenital sinus derivatives produced by a 5alpha-reductase inhibitorTeratology. 41: 5, A 599.Google Scholar
  77. Williams, T., 1999. Lessons from Lake Apopka,.Audubon.101(4): 64–72.Google Scholar
  78. Wilker, C., Johnson, L. and Safe, S., 1996. Effects of developmental exposure to indole-3-carbinol or 2,3,7,8tetrachlorodibenzo-p-dioxin on reproductive potential of male rat offspringToxicol ApplPharmacol.141: 68–75.Google Scholar
  79. Wilson, V.S. and LeBlanc, G.A., 2000. The contribution of hepatic inactivation of testosterone to the lowering of serum testosterone levels by ketoconazoleToxicol Sci.54: 125–137.CrossRefGoogle Scholar
  80. Wilson, V.S., Wood, C., Held, G., Lambright, C., Ostby, J., Furr, J. and Gray, L,E., 2003. Comparison of the effects of two AR antagonnists on tissue weights and hormone levels in male rats on expression of three androgen-dependent genes in the ventral prostateThe Toxicologist. 72: S1, A639 p 131.Google Scholar
  81. Wilson, V.S., Lambright, C., Furr, J., Ostby, J., Wood, C., Held, G., Gray, L.E. Jr. (in prep). Phthalate ester-induced gubernacular ligament lesions are associated with reduced Insl3 gene expression in the fetal rat testis during sexual differentiation.Google Scholar
  82. Wolf, C.J., Ostby, J.S., Gray, L.E. Jr.. 1999. Gestational exposure to 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD)severely alters reproductive function of female hamster offspringToxicol Sci.51(2): 259–64.PubMedCrossRefGoogle Scholar
  83. Wolf, C.J., LeBlanc, G.A., Ostby, J.S., Gray, L.E. Jr., 2000. Characterization of the period of sensitivity of fetal male sexual development to vinclozolinToxicol Sci.55(1): 152–61.PubMedCrossRefGoogle Scholar
  84. You, L., Casanova, M., Archibeque-Engle, S., Sar, M., Fan, L., d’A Heck, H., 1998. Impaired male sexual development in perinatal Sprague-Dawley and Longs-Evans Hooded rats exposed in utero and lactationally to p,p’-DDEToxicol Sciences.45: 162–173.Google Scholar
  85. You, L., Brenneman, K.A., Heck, H., 1999a In utero exposure to antiandrogens alters the responsiveness of the prostate to p,p’-DDE in adult rats and may induce prostatic inflammationToxicol Appl Pharmacol.161(3): 258–66.CrossRefGoogle Scholar
  86. You, L., Gazi, E., Archibewque-Engle, S., Casonova, M., Conolly and d’ AHeck, H. 1999b. Transplacental and lactational transfer ofg p,p’ DDE in Sprague-Dawley ratsToxicol Appl Pharm157: 134–144.CrossRefGoogle Scholar
  87. You, L., Casanova, M, Bartolucci, E.J., Fryczynski, M.W., Dorman, D.C., Everitt, J.I., Gaido, K. W., Ross, S.M., Heck, H., 2002. Combined effects of dietary phytoestrogen and synthetic endocrine-active compound on reproductive development in Sprague-Dawley rats: genistein and methoxychlorToxicol Sci.66(1): 91–104.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • L. Earl GrayJr.
    • 1
  • Joseph Ostby
  • Johnathan Furr
  • Carmen Wolf
  • Christy Lambright
  • Vickie Wilson
  • Nigel Noriega
  1. 1.MD-72, Endocrinology Branch, RTD, NHEERL, ORD, USEPA, RTP,USA

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