ToxSci Advance Access originally published online on June 29, 2009
Toxicological Sciences 2009 111(1):179-188; 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
,1,2,3
* Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina 27695
Reproductive Toxicology Branch, TAD, National Health and Environmental Effects Research Laboratories, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711
3 To whom correspondence should be addressed. Fax: 919-541-4017. E-mail: gray.earl{at}epa.gov.
Received May 12, 2009; accepted June 18, 2009
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Abstract |
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Vinclozolin and iprodione are dicarboximide fungicides that display antiandrogenic effects in the male rat, which suggests that a mixture would lead to cumulative effects on androgen-sensitive end points. Iprodione is a steroid synthesis inhibitor, but androgen receptor antagonist activity, which is displayed by vinclozolin, has not been fully evaluated. Here, we demonstrate that iprodione binds to the human androgen receptor (IC50 = 86.0µM), 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 antiandrogenic effects. An iprodione dose, that does not significantly affect androgen-dependent morphological end points, was combined with vinclozolin doses (2 x 5 factorial design). Sprague-Dawley rats were dosed by gavage with vinclozolin at 0, 10, 30, 60, and 100 mg/kg/day with and without 50 mg iprodione/kg/day from postnatal day (PND) 23 to 55–57 (n = 8 per 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; two-way ANOVA: iprodione main effect p = 0.0002). The dose response for several reproductive and nonreproductive organ weights was affected in a cumulative manner. In contrast, iprodione antagonized the vinclozolin-induced increase in serum testosterone. These results demonstrate that these fungicides interact on common targets in a tissue-specific manner when coadministered to the pubertal male rat.
Key Words: iprodione; vinclozolin; mixture; puberty; testosterone; androgen receptor; endocrine disruption.
1 Present address: National Toxicology Program, NIEHS, NIH, Research Triangle Park, NC 27711, USA.
2 Present address: Nicholas School of the Environment, Duke University, Durham, NC 27708.
Disclaimer: The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, Office of Research and Development, United States Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency nor does the mention of trade names or commercial products constitute endorsement or recommendation for use.