Cumulative and antagonistic effects of a mixture of the antiandrogens vinclozolin and iprodione in the pubertal male rat.
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 (IC(50) = 86.0 microM), 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.
Blystone
Chad R
CR
Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina 27695, USA.
Lambright
Christy S
CS
Cardon
Mary C
MC
Furr
Johnathan
J
Rider
Cynthia V
CV
Hartig
Phillip C
PC
Wilson
Vickie S
VS
Gray
Leon E
LE
D000311:Adrenal Glands / Q000187:drug effects / Q000254:growth & development; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000633:toxicity; D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005659:Fungicides, Industrial / Q000633:toxicity*; D005837:Genitalia, Male / Q000187:drug effects / Q000254:growth & development; D006728:Hormones / Q000097:blood; D006827:Hydantoins / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000254:growth & development; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010080:Oxazoles / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects; D012741:Sexual Maturation / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects
D000726:Androgen Antagonists; D004338:Drug Combinations; D005659:Fungicides, Industrial; D006728:Hormones; D006827:Hydantoins; D010080:Oxazoles; D011944:Receptors, Androgen; D018336:Receptors, Aryl Hydrocarbon; D000620:Aminoimidazole Carboxamide; C025643:vinclozolin; C033148:iprodione