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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. LATE GESTATIONAL EXPOSURE TO THE FUNGICIDE PROCHLORAZ DELAYS THE ONSET OF PARTURITION AND CAUSES REPRODUCTIVE MALFORMATIONS IN MALE RAT OFFSPRING. BIOLOGY OF REPRODUCTION 72(6):1324-1335, (2005).
Description:
Abstract
Prochloraz (PZ) is an imidazole fungicide that displays multiple endocrine activities. It inhibits androgen and estrogen synthesis via CYP-19 P-450 modulation and also acts as an androgen receptor (AR) antagonist. Although PZ has been shown to display antiandrogenic effects in vitro, and in vivo, reducing androgen-dependent tissue weights in young male rats, its ability to alter sexual differentiation of the male reproductive system in an antiandrogenic manner or affect pregnancy have not been described. The purpose of the current study was to repeat and expand in vitro observations regarding the antiandrogenicity of PZ and to determine what effects, if any, it had on pregnancy and sexual differentiation. In the current study, PZ concentrations above 1iM caused a dose-dependent inhibition of DHT-induced AR-mediated gene expression in MDA-kb2 cells containing endogenous AR and stably transfected with a MMTV-luc reporter. PZ also inhibited R1881 binding to the rat AR (IC50 approx 60iM). In vivo, pregnant rats received PZ by gavage from GD 14-18 at doses of 31.25, 62.5, 125 and 250 mg/kg bodyweight/day. PZ delayed delivery in a dose-dependent manner that resulted in pup mortalities at the two highest doses. In male offspring, AGD and bodyweight were slightly reduced on at 3 days of age and female-like areolas were observed at 13 days of age 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. Males in the two highest dose groups showed vaginal pouches and reduced weights of androgen-dependent tissues (testis, epididymis, seminal vesicle, ventral prostate and levator ani plus bulbocavernosus muscles). Together, these results indicate that PZ alters sexual differentiation in an antiandrogenic manner, and at the same dosage levels, interferes with the onset of parturition, an effect that likely can be explained through inhibition of steroid hormone synthesis.