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EFFECTS OF GESTATIONAL PROCHLORAZ ADMINISTRATION ON MALE REPRODUCTIVE DEVELOPMENT IN RATS. IN VIVO ASSESSMENTS OF A FUNGICIDE WITH MULTIPLE IN VITRO EFFECTS
Citation:
Noriega, N C., J S. Ostby, C R. Lambright, V S. Wilson, AND L E. Gray Jr. EFFECTS OF GESTATIONAL PROCHLORAZ ADMINISTRATION ON MALE REPRODUCTIVE DEVELOPMENT IN RATS. IN VIVO ASSESSMENTS OF A FUNGICIDE WITH MULTIPLE IN VITRO EFFECTS. Presented at Duke Postdoctoral Association Research, Durham, NC, October 24, 2003.
Description:
Effects of Gestational Prochloraz Administration on Male Reproductive Development in Rats. In Vivo Assessments of a Fungicide with multiple In Vitro effects.
Nigel C. Noriega, Joseph Ostby, Christy Lambright, Vickie S. Wilson,and L. Earl Gray Jr.,
noriega.nigel@epa.gov
US EPA, MD-72 RTD, NHEERL, ORD, RTP, NC 27711
Prochloraz (PZ) is an imidazole fungicide thatshows multiple endocrine activities, including androgen receptor (AR) antagonism and inhibition of testosterone and estradiol synthesis via reductions in P-450 activity. In the current study, we confirmed in-vitro reports that PZ is an AR antagonist, and described PZ effects on male sex differentiation. PZ concentrations above 1?M caused a dose-dependent inhibition of DHT(0.1nM)-induced AR-mediated activity in cells (MDA-kb2) containing endogenous AR and stably expressing the MMTV-luc reporter. PZ inhibited androgen (1nM R1881) binding to the rat AR (IC50approx 60?M). In vivo, pregnant Sprague-Dawley ratswere gavaged dailyfrom GD 14-18 at PZ doses of 31.25, 62.5, 125 and 250 mg/kg bodyweight/day. Pup delivery was delayed in a dose-dependent manner and resulted in stillbirths at the two highest doses. In male pups, AGD was reduced at birth but was highly correlated with reduced bodyweight. Female-like areolas were observed in PZ-treated 13 day old males at frequencies ranging from 31% in the low-dose group, to 71% at the high dose. Males in the two highest dose groups showed reduced androgen-dependent tissue weights (testis, epididymis, seminal vesicle, ventral prostate and levator ani + bulbocavernosus) and 40% of high-dose males had vaginal pouches. All high-dose males and some in the 125 mg/kg treatment group showed permanent phallus abnormalities including hypospadias. In animals without malformations, PZ did not affect age at preputial separation.PZ appears toaffect sexual differentiation via two independent mechanisms; steroidogenesis inhibition(similarly to other antifungal imidazoles) and AR antagonism. This is an abstract of a proposed presentation and does not necessarily reflect EPA policy.