DEVELOPMENTAL EFFECTS OF AN ENVIRONMENTAL ANTIANDROGEN - THE FUNGICIDE VINCLOZOLIN ALTERS SEX-DIFFERENTIATION OF THE MALE-RAT

In humans and rodents, exposure to hormonally active chemicals during sex differentiation can produce a wide range of abnormal sexual phenot ypes including masculinized and defeminized females and feminized and demasculinized males. Although numerous ''environmental estrogens,'' i ncluding pesticides, toxic substances (PCBs), and plant and fungal est rogens, have been shown to alter mammalian sex differentiation, simila r information on environmental androgens is lacking. Recently, the fun gicide vinclozolin (V) was found to inhibit sexual differentiation in male rats in an antiandrogenic manner. In the present study, V was adm inistered to pregnant rats (po) at 0, 100, or 200 mg/kg/day in corn oi l during the period of sex differentiation (Gestational Day 14 to Post natal Day 3) to examine the demasculinizing effect of this fungicide m ore closely. In both groups of V-treated male offspring, anogenital di stance was female like at birth, and nipple development was prominent at 2 weeks of age. After puberty, most of the V-treated male offspring were unable to attain intromission even though they all mounted sexua lly receptive females. The V-treated male offspring that appeared to a chieve intromission, failed to ejaculate normally, as no sperm were fo und in the uterus after overnight matings. A factor in the abnormal ej aculation was that all V-treated male offspring had cleft phallus with hypospadias. In addition, a number of unusual reproductive malformati ons were noted when the males were necropsied at 1 year. Many V-treate d male offspring had suprainguinal ectopic scrota/testes, a vaginal po uch, epididymal granulomas, and small to absent sex accessory glands. During the study, about 25% of the V-treated males died as a result of bladder stones, hydroureter, or hydronephrosis, while other males dis played these lesions at necropsy. While some of the above malformation s in male offspring can also be produced by perinatal administration o f a potent estrogen, like DES, V-treated female offspring did not disp lay any estrogen-like alterations of reproductive development or fecun dity. The only change seen in the female offspring was a reduced anoge nital distance during neonatal life. Our observation of perinatal-indu ced agenesis of the prostate and blocked testicular descent, a pattern of malformations nearly identical to that reported for the antiandrog en flutamide, is consistent with other recent evidence that this fungi cide is an androgen-receptor antagonist. (C) 1994 Academic Press, Inc.