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ToxSci Advance Access published online on January 21, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh018
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received May 15, 2003; accepted October 10, 2003
© 2004 Society of Toxicology

Reproductive and Developmental Toxicology

Interactive Effects of Vinclozolin and Testosterone Propionate on Pregnancy and Sexual Differentiation of the Male and Female SD Rat

Cynthia J. Wolf 1, Gerald A. LeBlanc 2, and L. Earl Gray Jr.3*

1 US Environmental Protection Agency, Office of Research and Development, NHEERL, Reproductive Toxicology Division, Research Triangle Park, NC 27711; Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695
2 Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695
3 US Environmental Protection Agency, Office of Research and Development, NHEERL, Reproductive Toxicology Division, Research Triangle Park, NC 27711

* To whom correspondence should be addressed. E-mail: gray.earl{at}epa.gov.


  Abstract

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/d) and/or testosterone propionate (TP sc at 1 mg/rat/d) alone and in combination to SD rats on to days 14-19 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 the 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 plus TP groups. As expected, individually both V and TP reduced maternal weight gain and the V plus TP group was affected in a cumulative fashion. Litter size on postnatal day (PND) 2 was reduced only by V plus TP, whereas pup body weight was reduced in all three treated groups, the effect of V plus TP again being cumulative. In female offspring, TP-induced alterations (increased anogenital distance (AGD), fewer nipples, vaginal agenesis, hydrometrocolpos and 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 plus 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.


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