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IPRODIONE DELAYS MALE RAT PUBERTAL DEVELOPMENT, REDUCING SERUM TESTOSTERONE AND EX VIVO TESTOSTERONE PRODUCTION
Citation:
BLYSTONE, C., C. R. LAMBRIGHT, M. C. CARDON, P. C. HARTIG, J. R. FURR, V. S. WILSON, AND L. E. GRAY. IPRODIONE DELAYS MALE RAT PUBERTAL DEVELOPMENT, REDUCING SERUM TESTOSTERONE AND EX VIVO TESTOSTERONE PRODUCTION. Presented at SOT Annual Meeting, Seattle, WA, March 16 - 20, 2008.
Impact/Purpose:
Presentation
Description:
Iprodione (IPRO) is a dichlorophenyl dicarboximide fungicide similar to the androgen receptor (AR) antagonist vinclozolin. The current studies were designed to determine if IPRO would delay male rat pubertal development like vinclozolin and to identify the mechanism(s) of action. We intend to use the dose response data obtained in the current study to determine how a mixture of IPRO and vinclozolin interact when administered during puberty. In the first study, Sprague-Dawley weanling rats were dosed by gavage with 0, 50, 100, or 200 mg/kg/day of IPRO from 23 to 51/52 days of age. The progression of preputial separation (PPS) was measured starting on day 37 and organ weights, serum hormones, and ex vivo testis hormone measured at necropsy (Blystone et al., in press). In the second study the hAR COS whole cell binding assay and an AR transcriptional activation with MDA-kb2 cells were used to determine if IPRO was an AR antagonist. In vivo, IPRO delayed PPS at 100 and 200 mg/kg/day and decreased androgen sensitive seminal vesicle and epididymides weights. As hypothesized, serum testosterone levels were decreased along with serum progesterone and 17α-hydroxyprogesterone whereas serum LH was unaffected. IPRO also reduced ex vivo testis production of testosterone, progesterone, and 17α-hydroxyprogesterone. In vitro IPRO bound to the AR and inhibited AR mediated transcription, but was considerably less potent than vinclozolin (binding IC50 = 86.0 µM vs 1.4 µM, respectively). Taken together, these results indicate that IPRO directly inhibits steroidogenesis in the rat testis, without affecting LH signaling. It is unclear at present however if IPRO’s weak AR antagonism in vitro contributes to its anti-androgen effects in the pubertal male rat. CRB supported through USEPA/NCSU Cooperative Training Agreement.