Submission Number: CYN-4-34-13

Abstract Number: 356

EFFECTS OF PRENATAL TESTOSTERONE PROPIONATE ON THE SEXUAL DEVELOPMENT OF MALE AND FEMALE RATS: A DOSE-RESPONSE STUDY.

Cynthia Wolf* ^1,2, Joseph Ostby ¹, Andrew Hotchkiss ³ and L Earl Gray Jr* ¹

USEPA, NHEERL, Reproductive Toxicology Division, Research Triangle Park, NC ¹
Dept. of Toxicology, NC State University, Raleigh, NC ²
USEPA/NCSU Cooperative Training Program, Raleigh, NC ³

Abstract:
Testosterone plays a major role in male sexual development. The study of the effects of testosterone in vivo provides a tool for the identification of environmental androgens and lends to the understanding of the effects of environmental antiandrogens. Exposure of females to testosterone during fetal development can induce male sex characteristics such as male sex behavior, increased anogenital distance (AGD), and absence of nipples. However, high levels of androgens at this stage can also lead to toxic effects such as reduced litter size and viability. In the current study, we investigated the ability of testosterone propionate (TP) over a range of concentrations to masculinize females without compromising number of offspring. Pregnant SpragueDawley rats were dosed on gestational day (GD) 14 GD 19 (GD 1= day of plug) with 0.1 ml corn oil vehicle/rat sc or with TP at 0.1, 0.5, 1, 2, 5, or 10 mg/0.1 ml/rat. Late delivery was significant 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. AGD was measured on postcoital (pc) day 24 (gestation length = 22), which was designated postnatal day (PND) 2 to standardize for age, despite day of delivery. At 0.5 mg TP, AGD was reduced in the males but was not affected in the females. At 1 mg TP and above, sexing of the pups by AGD became unreliable since many of the AGD measurements were intermediate between the typical male and female AGDs. At these higher doses, a central 'unisex' AGD was apparent in the distribution, indicating female AGD had been increased. By PND 9, sexing was performed by expressing testes. At weaning (PND 22), AGD remained significantly increased in the females at 1 mg TP. On PND 15, males and females were checked for areolas. Normally, circulating androgens in the male prevent nipple/areola development. The number of areolas in females was significantly reduced at 0.5 mg TP. Vaginal opening in the low dose groups was not affected, while females in the 1 mg TP and higher dose groups abnormally developed no vaginal orifice. 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. These doses can be used reliably in future studies.

This work does not necessarily reflect EPA policy.

Keywords: masculinization, sexual development, AGD, testosterone propionate

This abstract is being presented at: 8:00 AM in session:
Toxicology II