@article{wolf_leblanc_gray_2004, title={Interactive effects of vinclozolin and testosterone propionate on pregnancy and sexual differentiation of the male and female SD Rat}, volume={78}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfh018}, abstractNote={In mammals, androgens are essential in directing mammalian sexual differentiation of the male phenotype. Administration of testosterone during this period alters female development in a male-like direction, whereas exposure to an androgen receptor antagonist like vinclozolin (V) demasculinizes and feminizes the male offspring. In the current study, we administered V (gavage at 200 mg/kg/day) and/or testosterone propionate (TP, sc, at 1 mg/rat/day), alone and in combination to Sprague-Dawley (SD) rats on days 14 through 19 of pregnancy, to determine if V would antagonize the effects of TP in the female and, conversely, if TP would antagonize the effects of V in the male offspring. These doses of TP and V were selected because they significantly alter sexual differentiation in the majority of female and male rat offspring, respectively, without producing severe toxicity in the dam or offspring. The study design is a 2 x 2 factorial (7 dams per group) including vehicle control, V, TP, and V + TP groups. As expected, individually, both V and TP reduced maternal weight gain and the V + TP group was affected in a cumulative fashion. Litter size on postnatal day (PND) 2 was reduced only by V + TP, whereas pup body weight was reduced in all three treated groups, the effect of V + TP again being cumulative. In female offspring, TP-induced alterations (i.e., increased anogenital distance [AGD] and fewer nipples, vaginal agenesis, hydrometrocolpos, induced prostate and bulbourethral glands, and levator ani muscle tissues) were all reversed by coadministration of V. In male offspring, V-induced alterations were only modestly antagonized by TP. At the dosage levels used herein, V + TP-treated male offspring had less well-developed nipples as infants and adults and a lower incidence of ectopic testis than did the V group. However, V-induced changes in reproductive organ weights, AGD, atrophic testes, vaginal pouch, and agenesis of the sex accessory tissues were not antagonized by concurrent TP treatment in male offspring. We observed that the combination of V and TP, two chemicals with opposing endocrine action, antagonized one another during sexual differentiation, especially in the female offspring and induced cumulative effects on maternal and neonatal toxicity. We suspect that antagonism of V by TP would be enhanced in the male if lower dose levels of V were used, but then the antagonism of TP by V in the female would likely be attenuated.}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Wolf, CJ and LeBlanc, GA and Gray, LE}, year={2004}, month={Mar}, pages={135–143} }
 @article{wolf_hotchkiss_ostby_leblanc_gray_2002, title={Effects of prenatal testosterone propionate on the sexual development of male and female rats: A dose-response study}, volume={65}, ISSN={["1096-6080"]}, DOI={10.1093/toxsci/65.1.71}, abstractNote={Testosterone plays a major role in male sexual development. Exposure of females to testosterone in utero can induce masculine characteristics such as anovulation, increased anogenital distance (AGD), absence of nipples, retention of male-like tissues, and agenesis of the lower vagina. In addition, high levels of androgens during fetal development can lead to toxic effects such as reduced litter size and viability. The study of the effects of testosterone administration during sexual differentiation provides a foundation for understanding the effects of environmental androgens on fetuses, a sensitive subpopulation. In the current study, we investigated the ability of a range of concentrations of testosterone propionate (TP) administered prenatally to masculinize female and alter male offspring, and measured maternal and fetal T levels. Pregnant Sprague-Dawley rats were dosed by sc injection on gestational day (GD) 14-19 (GD 1= day of plug) with either corn oil (vehicle; 0.1 ml/rat) or with 0.1 ml of TP solution at 0.1, 0.5, 1, 2, 5, or 10 mg/0.1 ml. Parturition was delayed at 2, 5, and 10 mg TP, litter size was reduced at 5 and 10 mg TP, and pup weight was significantly reduced in both sexes at 0.5 mg TP and higher doses. Viability of offspring was unaffected at any dosage level. Androgenic effects seen at 0.5 mg TP in females included increased AGD at weaning and adulthood, reduced number of areolas and nipples, cleft phallus, small vaginal orifice, and presence of prostate tissue. This dose of TP elevated maternal T levels 10x but had no effect on fetal T levels. At 1 mg TP and above, female AGD on postnatal day (PND) 2 (or postcoital day 24 [gestation length = 22(1/2)]) was increased; areolas and nipples were virtually eliminated; levator ani muscle, bulbourethral glands, and seminal vesicles (2 mg TP and above) were present; none of the females developed a vaginal orifice and many females in the 1 and 2 mg TP dose groups developed a greatly distended, fluid-filled uterus after puberty. Maternal T levels at 1 mg TP were elevated 30x, and female fetal T levels showed an 80% increase. Male offspring displayed a reduced AGD and body weight on PND 2 at 0.5 mg TP and higher doses. These effects were not evident by weaning and male offspring displayed no malformations. We conclude that gestational administration of 0.5 and 1 mg TP masculinizes female offspring without greatly affecting pup viability or pregnancy of the dam. This study provides a useful model for in utero testing of environmental androgens for their potential to induce developmental abnormalities.}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Wolf, CJ and Hotchkiss, A and Ostby, JS and LeBlanc, GA and Gray, LE}, year={2002}, month={Jan}, pages={71–86} }
 @article{wolf_leblanc_ostby_gray_2000, title={Characterization of the period of sensitivity of fetal male sexual development to vinclozolin}, volume={55}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/55.1.152}, abstractNote={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.}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Wolf, CJ and LeBlanc, GA and Ostby, JS and Gray, LE}, year={2000}, month={May}, pages={152–161} }
 @article{wolf_ostby_gray_1999, title={Antiandrogenic effects of prenatal vinclozolin exposure in the male rat: And investigation of possible involvement of EGF.}, volume={60}, number={1999}, journal={Biology of Reproduction}, author={Wolf, C. J. and Ostby, J. S. and Gray, L. E.}, year={1999}, pages={138} }
 @article{gray_price_lambright_wolf_hotchkiss_parks_ostby_1999, title={Environmental antiandrogens: The malformation pattern varies with the mechanism of antiandrogenic action.}, volume={60}, number={1999}, journal={Biology of Reproduction}, author={Gray, L. E. and Price, M. and Lambright, C. and Wolf, C. and Hotchkiss, A. and Parks, L. and Ostby, J.}, year={1999}, pages={201} }