Toxicology

Late Gestational Exposure to the Fungicide Prochloraz Delays the Onset of Parturition and Causes Reproductive Malformations in Male but not Female Rat Offspring

Abstract
Prochloraz (PZ) is an imidazole fungicide that displays multiple endocrine activities. It inhibits steroid synthesis via P-450 modulation and acts as an androgen receptor (AR) antagonist, but its effects on male sexual differentiation have not been described. The purpose of the current study was to expand in vitro observations and to determine whether PZ affected sexual differentiation. PZ effects on AR-mediated gene expression were tested using a cell line (MDA-kb2) containing endogenous AR and stably transfected with a MMTV-luc reporter. PZ concentrations greater than 1µM caused a dose-dependent inhibition of DHT-induced gene expression. PZ also inhibited R1881 binding to the rat AR (IC₅₀ approx 60µM). In vivo, pregnant rats received PZ by gavage from GD 14-18 at doses of 31.25, 62.5, 125 and 250 mg/kg body weight/day. PZ delayed delivery in a dose-dependent manner and resulted in pup mortalities at the two highest doses. In male offspring, anogenital distance and body weight were slightly reduced at 3 days of age. Additionally, female-like areolas were observed at 13 days of age at frequencies of 31%, 43%, 41% and 71% from low to high dose groups, respectively. Weights of androgen-dependent tissues showed dose-dependent reductions. Hypospadias and vaginal pouches were noted in all 250 mg/kg-treated males while these defects were observed 12.5% and 6.25% respectively of 125mg/kg-treated males. Treatment did not affect age of preputial separation in animals without penile malformations. Despite severe malformations in males, no malformations were noted in females. Together, these results indicate that PZ alters sexual differentiation in an antiandrogenic manner.

Key words: Environment • Male Reproductive Tract • Toxicology • Parturition • Penis

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