NORIEGA, N.C.*; OSTBY, J; LAMBRIGHT, C; WILSON, V.S.; GRAY, L.E.; US EPA, RTP NC; US EPA, RTP NC; US EPA, RTP NC; US EPA, RTP NC; US EPA, RTP NC: The Fungicide Prochloraz: In vitro Androgen Antagonism, Parturition Delays, and Male Reproductive Malformations in Rats.

Prochloraz (PZ) is an imidazole fungicide that affects steroidogenesis via P-450 modulation and shows multiple endocrine activities, including AR antagonism and aromatase inhibition. In the current study, we confirmed in-vitro reports and described PZ effects on male reproductive development. PZ treatment above 1μM caused a dose-dependent inhibition of DHT-induced AR-mediated activity in MDA-kb2 cells containing endogenous AR and stably transfected with a MMTV-luc reporter. Cytotoxicity was observed at 100μM. PZ inhibited R1881 binding to the rat AR (IC₅₀ approx 60μM). In vivo, pregnant rats received daily PZ gavage from GD 14-18 at 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 statistically higher mortality at the two highest doses. In male pups, AGD was reduced at birth (but was highly correlated to reduced bodyweight) and female-like areolas were observed in 13 day old males at frequencies of 31%, 43%, 41% and 71% in 31.25, 62.5, 125 and 250 mg/kg groups, respectively. 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. In animals without malformations, PZ did not affect age at preputial separation. PZ appears to affect 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.