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 phenotypes including masculinized and defeminized females and feminized and demasculinized males. Although numerous "environmental estrogens," including pesticides, toxic substances (PCBs), and plant and fungal estrogens, have been shown to alter mammalian sex differentiation, similar information on environmental androgens is lacking. Recently, the fungicide vinclozolin (V) was found to inhibit sexual differentiation in male rats in an antiandrogenic manner. In the present study, V was administered to pregnant rats (p.o.) at 0, 100, or 200 mg/kg/day in corn oil during the period of sex differentiation (Gestational Day 14 to Postnatal Day 3) to examine the demasculinizing effect of this fungicide more closely. In both groups of V-treated male offspring, anogenital distance 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 sexually receptive females. The V-treated male offspring that appeared to achieve intromission, failed to ejaculate normally, as no sperm were found in the uterus after overnight matings. A factor in the abnormal ejaculation was that all V-treated male offspring had cleft phallus with hypospadias. In addition, a number of unusual reproductive malformations were noted when the males were necropsied at 1 year. Many V-treated male offspring had suprainguinal ectopic scrota/testes, a vaginal pouch, 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 displayed these lesions at necropsy. While some of the above malformations in male offspring can also be produced by perinatal administration of a potent estrogen, like DES, V-treated female offspring did not display any estrogen-like alterations of reproductive development or fecundity. The only change seen in the female offspring was a reduced anogenital distance during neonatal life. Our observation of perinatal-induced agenesis of the prostate and blocked testicular descent, a pattern of malformations nearly identical to that reported for the antiandrogen flutamide, is consistent with other recent evidence that this fungicide is an androgen-receptor antagonist.
Developmental Reproductive Toxicology Section, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711.
L E
LE
Gray
J S
JS
Ostby
W R
WR
Kelce
D000284:Administration, Oral; D000704:Analysis of Variance; D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003198:Computer Simulation; D004542:Ejaculation / Q000187:drug effects; D005314:Embryonic and Fetal Development / Q000187:drug effects; D004702:Endocrine Glands / Q000187:drug effects; D004785:Environmental Pollutants / Q000633:toxicity; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity*; D005835:Genitalia / Q000002:abnormalities; D008297:Male; D010080:Oxazoles / Q000008:administration & dosage / Q000633:toxicity*; D010641:Phenotype; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011897:Random Allocation; D051381:Rats; D012733:Sex Differentiation / Q000187:drug effects*; D012741:Sexual Maturation / Q000187:drug effects
D000726:Androgen Antagonists; D004785:Environmental Pollutants; D005659:Fungicides, Industrial; D010080:Oxazoles; C025643:vinclozolin