Characterization of the period of sensitivity of fetal male sexual development to vinclozolin.
Vinclozolin is a fungicide whose metabolites are androgen receptor (AR) antagonists. Previous work in our laboratory showed that perinatal administration of vinclozolin to rats results in malformations of the external genitalia, permanent nipples, reduced anogenital distance (AGD), and reduced seminal vesicle, ventral prostate, and epididymal weights. The objectives of this study were to determine the most sensitive period of fetal development to antiandrogenic effects of vinclozolin and to identify a dosing regime that would induce malformations in all of the male offspring. Pregnant rats were dosed with 400 mg vinclozolin/kg/day on either GD 12-13, GD 14-15, GD 16-17, GD 18-19, or GD 20-21, or with corn oil (2.5 ml/kg) from GD 12 through GD 21 (Experiment 1). All 2-day periods in which significant effects were produced were included in an extended dosing period, GD 14 through GD 19, in which pregnant rats were dosed with 200 or 400 mg vinclozolin/kg (Experiment 2). In Experiment 1, significant effects of vinclozolin were observed in rats dosed on gestation days (GD) 14-15, GD 16-17, and GD 18-19, while the most significant effects were observed in rats treated on GD 16-17. These effects include reduced AGD; presence of areolas, nipples, and malformations of the phallus; and reduced levator ani/bulbocavernosus weight. In contrast, ventral prostate weight was reduced only in the GD 18-19 group. The expanded dosing regime (Experiment 2) increased the percentage of male offspring with genital malformations (> 92%), and retained nipples (100%), further reduced the weight of the ventral prostate, and reduced the weight of the seminal vesicles. In addition, malformations were more severe and included vaginal pouch and ectopic/undescended testes. The latter was induced only in the 400 mg/kg group. These data indicate that the reproductive system of the fetal male rat is most sensitive to antiandrogenic effects of vinclozolin on GD 16 and 17, although effects are more severe and 100 % of male offspring are affected with administration of vinclozolin from GD 14 through GD 19.
Wolf
C J
CJ
Endocrinology Branch, MD 72, Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
LeBlanc
G A
GA
Ostby
J S
JS
Gray
L E
LE
D000726:Androgen Antagonists / Q000633:toxicity; D000818:Animals; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects; D005659:Fungicides, Industrial / Q000633:toxicity*; D005837:Genitalia, Male / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010080:Oxazoles / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D020318:Rats, Long-Evans; D012741:Sexual Maturation / Q000187:drug effects*; D013737:Testis / Q000002:abnormalities; D015430:Weight Gain / Q000187:drug effects
D000726:Androgen Antagonists; D005659:Fungicides, Industrial; D010080:Oxazoles; C025643:vinclozolin