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MASCULINIZATION OF FEMALE RATS BY PRENATAL TESTOSTERONE PROPIONATE IS PARTIALLY ATTENUATED BY VINCLOZOLIN
Citation:
Wolf, C J., G. LeBlanc, A. K. Hotchkiss, J. R. Furr, AND L. E. Gray Jr. MASCULINIZATION OF FEMALE RATS BY PRENATAL TESTOSTERONE PROPIONATE IS PARTIALLY ATTENUATED BY VINCLOZOLIN. Presented at Triangle Consortium for Reproductive Biology, RTP, NC, January 27, 2001.
Description:
MASCULINIZATION OF FEMALE RATS BY PRENATAL TESTOSTERONE PROPIONATE IS PARTIALLY ATTENUATED BY VINCLOZOLIN
Cynthia Wolf1,2, Gerald LeBlanc2, Andrew Hotchkiss3, Jonathan Furr1, L Earl Gray, Jr.1
1USEPA, Reproductive Toxicology Division, RTP, NC 27711, 2Dept. Molecular and Environmental Toxicology, NCSU, Raleigh, NC 27695, 3USEPA/NCSU Cooperative Training Agreement, Raleigh, NC, 27695.
Exposure to testosterone during fetal development can result in masculinization of the female reproductive system. Masculinizing effects include agenesis of nipples and a vaginal orifice, and development of the male internal reproductive organs, prostate, levator ani, and bulbourethral glands (BUG). Testosterone (T) induces these androgen-dependent processes 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. V administration to the dam during sexual differentiation of the fetus results in antiandrogenic effects. Here, we sought to counter the androgenic actions of testosterone propionate (TP) in female offspring with V co-administration to support the assertion that vinclozolin acts by binding and inhibiting the AR. We dosed the rat dam 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 (control= 53.1 g) was reduced by both V (28.1 g; p< 0.005) and TP (35.4 g; p< 0.05) alone, while weight gain was further reduced by the combination of V and TP (21.9 g; p< 0.0005). Litter size was not reduced by V or TP alone (control, V and TP = 13-14), but was reduced significantly by V+TP (5.6; p< 0.001). Anogenital distance (AGD) in female offspring on postnatal day (PND) 2 was unaffected by V as expected (control=1.73 mm; V=1.62 mm), but was increased by TP (2.51 mm; p< 0.001). V co-administration completely abolished the increase in AGD by T (1.62 mm). Areola number on PND 13 was unaffected by V (mean = 12) but reduced by TP (mean = 3.7; p 0.0001). V co-administration completely restored areola number reduced by TP. Adult female offspring in the TP group displayed prostates (100%), levator ani (35.4%), BUG (40.1%) and agenesis of the vaginal orifice (94.4%). V did not induce these effects. V co-administration attenuated the masculinizing effect 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.
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