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Cummulative and antagonistic effects of a mixture of the antiandrogrens vinclozolin and iprodione in the pubertal male rat:
Citation:
BLYSTONE, C., C. R. LAMBRIGHT, M. C. Cardon, J. R. FURR, C. V. RIDER, P. C. HARTIG, L. E. GRAY, AND V. S. WILSON. Cummulative and antagonistic effects of a mixture of the antiandrogrens vinclozolin and iprodione in the pubertal male rat:. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 111(1):179-188, (2009).
Impact/Purpose:
A low to high dose study on the effects ofDEHP in male rat puberty and steroid hormone production.
Description:
Vinclozolin and iprodione are dicarboximide fungicides that display anti-androgenic effects in the male rat, which suggests co-exposure to these fungicides would lead to cumulative effects on androgen-sensitive endpoints. Iprodione is a steroid synthesis inhibitor, but AR antagonist activity, which is displayed by vinc1ozolin, has not been fully evaluated. Here, we demonstate that iprodione act as an AR antagonist in vitro and in vivo. Iprodione binds to the AR (ICso = 86.0 11M), reduces androgen-dependent gene expression and reduces androgen sensitive tissue weights in castrated-immature male rats given testosterone propionate (Hershberger assay). Since vinclozolin and iprodione display at least one common mechanism oftoxicity and both affect common targets in the pubertal male rat, a second in vivo studied tested the hypothesis that a mixture ofthese fungicides would have a cumulative anti-androgenic effects on male rat pubertal development. The mixture combined a dose ofiprodione that does not significantly affect androgendependent morphological endpoints with doses ofvinclozolin (a 2x5 factorial design). SpragueDawley 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, as previously reported. The addition of 50 mg iprodione/kg/d enhanced the inhibitory effect ofvinclozolin on PPS (PND 47.5 vs 49.1; 2-way ANOVA: iprodione main effect p = 0.0002). The dose response curves for several reproductive and nonreproductive (liver and adrenals) organ weights were also affected in a cumulative manner. In contrast, the vinclozolin-induced increase in serum testosterone was antagonized by iprodione. These results demonstrate these fungicides interact on common targets in a tissuespecific manner when co-administered to the pubertal male rat. Keywords: Iprodione, Vinclozolin, Mixture, Puberty, Testosterone, Androgen Receptor, Endocrine Disruption 2
