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INTERACTIVE EFFECTS OF VINCLOZOLIN AND TESTOSTERONE PROPIONATE ON PREGNANCY AND SEXUAL DIFFERENTIATION OF THE MALE AND FEMALE SD RAT
Citation:
Wolf, C J., G. A. LeBlanc, AND L E. Gray Jr. INTERACTIVE EFFECTS OF VINCLOZOLIN AND TESTOSTERONE PROPIONATE ON PREGNANCY AND SEXUAL DIFFERENTIATION OF THE MALE AND FEMALE SD RAT. TOXICOLOGICAL SCIENCES 78(1):135-143, (2003).
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ABSTRACT
Sufficient levels of androgens during fetal sexual differentiation in the mammal produces the male phenotype, and the absence of androgens or the dysfunction of the androgen receptor can produce the female phenotype. In previous studies in our laboratory, administration of vinclozolin (V), an androgen receptor inhibitor, on gestational days (GD) 14 ?19 affected male offspring by inducing female-like genitalia and reducing prostate, seminal vesicle, glans penis and levator ani/bulbocavernosus weights. Administration of testosterone propionate (TP) to rat dams on gestational days (GD) 14 ?19 affected female offspring by inducing male reproductive organs and male-like external genitalia. Each of these chemicals can produce adverse effects on pregnancy. In the current study we investigated the effects of a combination of V and TP on pregnancy and on sexual differentiation in the Sprague-Dawley rat. We hypothesized that V and TP will antagonize the effects of the other on sexual differentiation, but may add to the adverse effects of each other on pregnancy and neonatal health.
Dams were dosed daily on GD 14 ? 19 with corn oil vehicle (Control; 2.5 ml/kg-bw; oral gavage), V (200 mg/kg/2.5 ml; oral gavage), TP (1 mg/rat/0.1 ml; sc), or V+T. Dams and their offspring were monitored from GD 14 through adulthood. V and TP both individually reduced maternal weight gain, although V+TP further reduced maternal weight gain. Litter size on postnatal day (PND) 2 was reduced significantly only by V+TP. Pup body weight was reduced by V alone at p < 0.05 and by TP or V+TP at p < 0.0001. In the female, TP increased anogenital distance (AGD), reduced the number of areolae and nipples, induced cleft phallus, vaginal agenesis, prostate, bulbourethral glands and levator ani muscle, whereas V+TP completely reversed these effects. In the male, V increased the number of nipples, and induced ectopic testes, vaginal pouch and cleft phallus, whereas V+TP almost completely attenuated these responses. However, whereas V reduced AGD and reduced weights of the epididymis, ventral prostate, seminal vesicle, levator ani and bulbourethral glands, TP did not attenuate these responses. We have observed that the combination of two EDCs with opposing action, V and TP, can antagonize some of the effects of the other on sexual differentiation in male and female offspring, and may have cumulative effects on maternal and neonatal toxicity and on some androgen-dependent development of the male offspring.