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ANTIANDROGENIC EFFECTS OF VINCLOZOLIN ON MALE RATS ARE PARTIALLY ATTENUATED BY TESTOSTERONE PROPIONATE
Citation:
Wolf, C J., J S. Ostby, J. R. Furr, G. A. LeBlanc, AND L E. Gray Jr. ANTIANDROGENIC EFFECTS OF VINCLOZOLIN ON MALE RATS ARE PARTIALLY ATTENUATED BY TESTOSTERONE PROPIONATE. Presented at Triangle Consortium for Reproductive Biology, (NIEHS)RTP, NC, February 2, 2002.
Description:
ANTIANDROGENIC EFFECTS OF VINCLOZOLIN ON MALE RATS ARE PARTIALLY ATTENUATED BY TESTOSTERONE PROPIONATE
Cynthia Wolf1,2 , Joe Ostby1, Jonathan Furr 1, Gerald A. LeBlanc2, and L. Earl Gray, Jr.1
1 US Environmental Protection Agency, NHEERL, RTD, RTP, NC 27711, 2 Department of Environmental and Molecular Toxicology, NC State University, Raleigh, NC 27695
Development of the male phenotype is dependent on activation of the androgen receptor by androgens, primarily testosterone, during fetal development. The fungicide Vinclozolin (V), an androgen receptor antagonist, administered to the rat dam on gestational days (GD) 14-19 compromises masculine development, resulting in nipple formation, cleft phallus, ectopic testes, and reduced prostate, seminal vesicle and levator ani/bulbocavernosus (LA/BC) weights in the male offspring. Testosterone propionate (TP) administered to the dam during the same gestational period does not affect the male offspring but masculinizes female offspring, resulting in increased anogenital distance (AGD) and development of male sex glands. Since both androgenic and antiandrogenic chemicals exist in the environment, and combinations of chemicals may have different or greater effects than individual compounds, the study of combinational exposure to these chemical is important for risk assessment. In the current study, we sought to determine whether co-administration of an androgen, TP, with an antiandrogen, V, attenuates the action of V on sexual development of the male. Sprague-Dawley rats were dosed on GD 14-19 with corn oil (vehicle; 2.5 ml/kg; oral gavage), TP (1 mg/0.1 l/rat; sc), V (200 mg/kg; oral gavage) or V+TP. Male offspring were monitored throughout life and necropsied on postnatal day (PND) 170 - 186. Litter size on PND 2 was reduced significantly only by V+TP (5.6; p< 0.001), although sex ratio was not affected in any treatment group. Consistent with previous results, V reduced AGD on PND 2 (p < 0.0001), induced nipples (mean n = 11.68), induced malformations cleft phallus (95 %), vaginal pouch (84%), and ectopic testes (59.%), and reduced prostate, seminal vesicle and LA/BC weights in male offspring. TP alone had no effect on any of these endpoints. Co-administration of TP with V significantly reduced the number of nipples induced by V (n = 9.50; p < 0.005 compared to V) and reduced the incidence of malformations induced by V (cleft phallus = 75%, p < 0.01; vaginal pouch = 48%, p < 0.05; ectopic testes = 12.5%, p < 0.01 compared to V). Conversely, V+TP failed to reverse the reduction in AGD or restore weights of ventral prostate, seminal vesicle and LA/BC reduced by V. We conclude that co-administration of TP with V at the doses used attenuates some of the antiandrogenic effects induced by V during fetal development in male rat offspring. This abstract does not necessarily reflect USEPA policy.