ToxSci Advance Access published online on June 29, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp137
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Published by Oxford University Press 2009.
Cumulative and antagonistic effects of a mixture of the antiandrogens vinclozolin and iprodione in the pubertal male rat
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* Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC 27695, USA
United States Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratories, Reproductive Toxicology Division, Endocrinology Branch, Research Triangle Park, NC 27711, USA
To whom correspondence should be addressed: L. Earl Gray, Jr, U.S. Environmental Protection Agency, MD-72, RTD, NHEERL, ORD, RTP, NC 27711, Email: Gray.Earl{at}EPA.gov, Phone: 919-541-7750, Fax: 919-541-4017
Received May 12, 2009; revision received June 17, 2009; accepted June 18, 2009
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Abstract |
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Vinclozolin and iprodione are dicarboximide fungicides that display anti-androgenic effects in the male rat, which suggests a mixture would lead to cumulative effects on androgen-sensitive endpoints. Iprodione is a steroid synthesis inhibitor, but AR antagonist activity, which is displayed by vinclozolin, has not been fully evaluated. Here, we demonstrate that iprodione binds to the hAR (IC50 = 86.0 µM), reduces androgen-dependent gene expression, and reduces androgen sensitive tissue weights in castrated male rats (Hershberger assay). Since vinclozolin and iprodione affect common targets in the pubertal male rat, we tested the hypothesis that a mixture would have cumulative anti-androgenic effects. An iprodione dose, that does not significantly affect androgen-dependent morphological endpoints, was combined with vinclozolin doses (2x5 factorial design). Sprague-Dawley rats were dosed by gavage with vinclozolin at 0, 10, 30, 60, and 100 mg/kg/d with and without 50 mg iprodione/kg/d from postnatal day (PND) 23 to 55-57 (n = 8/group). The age at puberty (preputial separation (PPS)), organ weights, serum hormones, and ex vivo testis steroid hormone production were measured. Vinclozolin delayed PPS, reduced androgen sensitive organ weights, and increased serum testosterone. The addition of iprodione enhanced the vinclozolin inhibition of PPS (PND 47.5 vs 49.1; 2-way ANOVA: iprodione main effect p = 0.0002). The dose response for several reproductive and non-reproductive organ weights was affected in a cumulative manner. In contrast, iprodione antagonized the vinclozolin-induced increase in serum testosterone. These results demonstrate these fungicides interact on common targets in a tissue-specific manner when co-administered to the pubertal male rat.
Key Words: Iprodione; Vinclozolin; Mixture; Puberty; Testosterone; Androgen Receptor; Endocrine Disruption.
Current address: National Toxicology Program, NIEHS, NIH, Research Triangle Park, NC 27711, USA. ¶ Current address: Nicholas School of the Environment, Duke University, Durham, NC 27708.