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

• Published in: Endocrinology (Philadelphia) 2011-05, Vol.152 (5), p.2048-2059
• Main Authors: Hogg, Kirsten, McNeilly, Alan S, Duncan, W. Colin
• Format: Article
• Language: English
• Subjects: Androgen receptors; Androgens; Androgens - pharmacology; Animals; Aromatase; Biological and medical sciences; Cell differentiation; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Cell size; Cholesterol Side-Chain Cleavage Enzyme - genetics; Enzyme inhibitors; Estrogen receptors; Estrogens; Female; Females; Fetuses; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental - drug effects; Gestational Age; Id1 protein; Immunohistochemistry; Inhibitor of Differentiation Proteins - genetics; Inhibitor of Differentiation Proteins - metabolism; Injection; Intrauterine exposure; Ki-67 Antigen - metabolism; Male; mRNA; Ovaries; Ovary - anatomy & histology; Ovary - embryology; Ovary - metabolism; Phenotypes; Phosphoproteins - genetics; Polycystic ovary syndrome; Pregnancy; Prenatal experience; Protein structure; Proteins; Receptor mechanisms; Receptors; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Receptors, LH - genetics; Reverse Transcriptase Polymerase Chain Reaction; Sheep; Steroid 17-alpha-Hydroxylase - genetics; Steroid hormone receptors; Structure-function relationships; Testosterone; Testosterone propionate; Testosterone Propionate - pharmacology; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2010-1219

Direct fetal injection of testosterone propionate enables bypass of interference from products of placental aromatization such as estrogens. 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.