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EFFECTS OF PRENATAL TESTOSTERONE PROPIONATE ON THE SEXUAL DEVELOPMENT OF MALE AND FEMALE RATS: A DOSE-RESPONSE STUDY
Citation:
Wolf, C J., A. K. Hotchkiss, J S. Ostby, G. A. LeBlanc, AND L. E. Gray Jr. EFFECTS OF PRENATAL TESTOSTERONE PROPIONATE ON THE SEXUAL DEVELOPMENT OF MALE AND FEMALE RATS: A DOSE-RESPONSE STUDY. TOXICOLOGICAL SCIENCES 65(1):71-86, (2002).
Description:
Effects of Prenatal Testosterone Propionate on the Sexual Development of Male and Female Rats: A Dose-Response Study
Cynthia J. Wolf1,2, Andrew Hotchkiss3, Joseph S. Ostby1, Gerald A. LeBlanc2 and
L. Earl Gray1,4, Jr.
ABSTRACT
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) and absence of nipples. 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 and antiandrogens on a sensitive subpopulation, fetuses. In the current study, we investigated the ability of a range of concentrations of testosterone propionate (TP) administered prenatally to masculinize females and possibly alter males without compromising number of offspring, in order to select a suitable dose for future mechanistic studies. Pregnant Sprague-Dawley rats were dosed by subcutaneous 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 significantly delayed at 2, 5 and 10 mg TP. Litter size was significantly reduced at 5 and 10 mg TP. Pup weight was significantly reduced in both sexes at 0.5 mg TP and higher doses. Viability of offspring was unaffected at any dose. A multitude of androgenic effects were seen at 0.5 mg TP, including in males, reduced AGD on postnatal day (PND) 2 (or postcoital (pc) day 24 [gestation length = 22?]), and in females, increased AGD at weaning and adulthood, reduced number of areolas, cleft phallus, small vaginal orifice and presence of prostate tissue. At 1 mg TP and above, female AGD on PND 2 had increased and male AGD had further decreased, areolas in females were virtually eliminated, levator ani muscle and bulbourethral glands were present in females, 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. 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 screening of environmental androgens.