Prenatal Androgen Exposure Leads to Alterations in Gene and Protein Expression in the Ovine Fetal Ovary

Abstract

Exposure of a female fetus to increased androgens in utero results in an adult phenotype reminiscent of polycystic ovary syndrome. We investigated whether prenatal androgens could directly alter the structure and function of the fetal ovary. We examined fetal ovarian cell proliferation, germ cell volume, and the expression of steroid receptors and steroidogenic enzymes. In addition, we studied the inhibitors of differentiation (Ids) and the SLIT/Roundabout developmental pathways. Female fetuses were collected from ewes treated with 100 mg testosterone propionate (TP) or vehicle control (C), twice weekly from d 60 to 70 (C = 3, TP = 6) or d 90 (C = 6, TP = 8). Female fetuses were also collected at d 70 after a single injection of TP (20 mg) or vehicle C into the fetal flank at d 60 (C = 4, TP = 8). Prenatal androgenization had no effect on fetal ovarian morphology, cell proliferation, or germ cell volume. However, there was a reduction in the expression of StAR, CYP11A, CYP17, and LHR at d 90 of gestation. There was also an increase in Id1 immunostaining at d 90 and an increase in Id3 immunostaining at d 70. Direct injection of TP into the fetus down-regulated ovarian CYP11A, estrogen receptor α and β mRNA, and ROBO1 and up-regulated CYP19, androgen receptor immunostaining, and Id3 mRNA and protein. Although at d 90 prenatal androgenization does not result in structural changes of the fetal ovary, there are functional changes that may impact on ovarian development. TP has direct actions on the fetal ovary, and these may contribute to the adult ovarian phenotype in the ovine model of polycystic ovary syndrome.