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LATE GESTATIONAL EXPOSURE TO THE FUNGICIDE PROCHLORAZ DELAYS THE ONSET OF PARTURITION AND CAUSES REPRODUCTIVE MALFORMATIONS IN MALE RAT OFFSPRING
Citation:
Noriega, N C., J S. Ostby, C R. Lambright, V S. Wilson, AND L E. Gray Jr. LATE GESTATIONAL EXPOSURE TO THE FUNGICIDE PROCHLORAZ DELAYS THE ONSET OF PARTURITION AND CAUSES REPRODUCTIVE MALFORMATIONS IN MALE RAT OFFSPRING. Presented at Society for the Study of Reproduction, Cincinnati, OH, July 19-22, 2003.
Description:
Late gestational exposure to the fungicide prochloraz delays the onset of parturition and causes reproductive malformations in male rat offspring.
Nigel C. Noriega, Joseph Ostby, Christy Lambright, Vickie S. Wilson, and L. Earl Gray Jr.,
Prochloraz (PZ) is an imidazole fungicide that displays multiple endocrine activities. It affects steroidogenesis via P450 inhibition and acts as an AR antagonist (Vinggaard et al. 2002). However, effects on sexual differentiation of the male reproductive system have not been described for PZ or other conazole fungicides. We have demonstrated that PZ exposure from gestational day (GD) 14-18 decreased testosterone while increasing progesterone in fetal rat testes (Lambright et al. 2003). In the current study, PZ treatment above 1[:mgr:]M caused a dose-dependent inhibition of DHT-induced androgen receptor (AR)-mediated activity in MDA-kb2 cells containing endogenous AR and stably transfected with a MMTV-luc reporter. Cytotoxicity was observed at 100[:mgr:]M. Prochloraz inhibited R1881 binding to the rat AR (IC50 approx 60[:mgr:]M). In vivo, pregnant rats received daily PZ administration (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, AGD was reduced at birth (but was highly correlated to reduced bodyweight) and female-like areolas were observed in 13 day old male offspring at frequencies of 31%, 43%, 41% and 71% in 31.25, 62.5, 125 and 250 mg/kg groups, respectively. All males in the 250 mg/kg and some males in the 125 mg/kg treatment groups showed permanent phallus abnormalities. In animals without malformations, treatment did not affect age at preputial separation. Prochloraz appears to alter sexual differentiation via two independent mechanisms; it inhibits steroidogenesis, similarly to other antifungal imidazoles, and acts as an AR antagonist. This is an abstract of a proposed presentation and does not necessarily reflect EPA policy.
Parturition, sexual differentiation, Androgen receptor antagonist, steroidogenesis
fungicide, hypospadias, prochloraz