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MASCULINIZATION OF FEMALE RATS BY PRENATAL TESTOSTERONE PROPIONATE IS ATTENUATED BY VINCLOZOLIN.
Wolf, Cynthia1,2, Furr, Jonathan1, LeBlanc, Gerald2, Gray, L. Earl1, 1 2
ABSTRACT- Fetal exposure to testosterone can masculinize the female reproductive system. Masculinizing effects include agenesis of nipples and the vaginal orifice, and development of male reproductive organs such as prostate, levator ani, and bulbourethral glands (BUG). Testosterone acts by binding and activating the androgen receptor (AR) in the target tissue. Metabolites of vinclozolin (V) competitively and reversibly bind the AR to inhibit receptor binding to DNA, thus inhibiting androgen-dependent processes. Here, we sought to counter the androgenic actions of testosterone propionate (TP) in female offspring with V to determine whether co-administration of chemicals with antagonistic mechanisms of action have antagonistic effects in vivo. Sprague-Dawley dams (n = 7/ treatment group) were dosed on gestational day (GD) 14-19 with corn oil (oral gavage), TP (1 mg/0.1 l/rat; sc), V (200 mg/kg; gavage) or V+TP. Maternal weight gain was slightly reduced by V or TP alone (p < 0.05), but was further reduced by the combination of V+TP (p < 0.0005). Litter size was not reduced by V or TP alone, but was reduced significantly by V+TP (p < 0.001). Anogenital distance (AGD) in female offspring on postnatal day (PND) 2 was unaffected by V (control = 1.73 mm; V = 1.62 mm) and increased by TP (2.51 mm; p < 0.001), while V co-administration completely abolished the increase in AGD by TP (1.62 mm). Areola number in females on PND 13 (control = 12 areolas) was unaffected by V and reduced by TP (3.7; p < 0.0001) while V co-administration with TP completely restored areola number. TP induced prostates (100%), levator ani (35.4%), BUG (40.1%) and agenesis of the vaginal orifice (94.4%) in female offspring. V did not induce these effects. V co-administration attenuated these masculinizing effects of TP by significantly reducing or eliminating the incidences of prostates (21.6%), levator ani (0%), BUG (0%), and agenesis of the vaginal orifice (0%). We conclude that V co-administration on GD 14-19 attenuates the androgenicity of TP in the female offspring, and despite opposing action on the AR, adds to maternal toxicity. These effects are consistent with the hypothesis that V metabolites act as AR antagonists in fetal tissues. This work does not necessarily reflect EPA policy.
KEY WORDS: testosterone propionate, masculinization, antiandrogen, female reproductive tract
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