Interactive effects of vinclozolin and testosterone propionate on pregnancy and sexual differentiation of the male and female SD rat.
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.
Wolf
Cynthia J
CJ
U.S. Environmental Protection Agency, Office of Research and Development, NHEERL, Reproductive Toxicology Division, Research Triangle Park, North Carolina 27711, USA.
LeBlanc
Gerald A
GA
Gray
L Earl
LE
D000014:Abnormalities, Drug-Induced / Q000453:epidemiology / Q000473:pathology; D000726:Androgen Antagonists / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D001724:Birth Weight / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D005260:Female; D005328:Fetal Viability / Q000187:drug effects; D005333:Fetus / Q000378:metabolism; D005835:Genitalia / Q000187:drug effects / Q000254:growth & development; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010080:Oxazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000633:toxicity*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D012733:Sex Differentiation / Q000187:drug effects*; D012741:Sexual Maturation / Q000187:drug effects; D013723:Teratogens / Q000633:toxicity; D043343:Testosterone Propionate / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects
D000726:Androgen Antagonists; D010080:Oxazoles; D013723:Teratogens; C025643:vinclozolin; D043343:Testosterone Propionate