Developmental Programming: Gestational Exposure To Excess Testosterone Alters The Ovarian Expression Of SF1 And DAX1 Proteins,

PUTTABYATAPPA M.; MATILLER, V.; SALVETTI, N.R.; ORTEGA, H.H.; PADMANABHAN, V

Congreso; Endocrine Society's annual meeting,; 2018

Endocrine Society's annual meeting,

Prenatal exposure to excess testosterone (T) induces reproductive defects that include multifollicular ovarian phenotype, features seen in women with polycystic ovarian syndrome (PCOS). Multifollicular phenotype appear to be the result of enhanced recruitment and follicular persistence. Decreased anti-Mullerian hormone (AMH) in early growing follicles and its increased expression in antral follicles underlie, in part, the increased recruitment and follicular arrest/persistence, respectively. The mechanisms by which disruption in AMH is mediated is unclear. Considering that AMH expression is regulated by transcription factors, Splicing Factor 1 (SF1) and dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX1), with SF1 enhancing AMH expression and DAX1 antagonizing SF1?s action, the goal of this study was to determine if developmental changes in SF1 and DAX1 underlie prenatal T excess-induced changes in AMH expression. Ovaries were collected from control and prenatal T-treated (100 mg twice weekly from days 30-90 of gestation (term 147 days)) animals at fetal day 90 and 140 and 1 and 2 years-of-age with sample size of 5-8/ treatment group/developmental time point. Changes in SF1 and DAX1 levels in the granulosa cells of the primordial, primary, and small pre-antral (SPA) follicles, granulosa/theca cells of the large pre-antral (LPA) and antral (LA) follicles (5-10 follicles per follicular type) were assessed by immunohistochemistry, quantified using ImagePro Plus software, and data analyzed by ANOVA. SF1 and DAX1 were detectable in granulosa cells of all follicle classes at all ages and theca cells of LPA and LA follicles. Prenatal T-treatment (1) had no effect on SF1 and DAX1 at fetal day 90; (2) reduced SF1 in the theca cells of LPA follicles at fetal day 140; (3) increased DAX1 in granulosa cells of primordial through LPA and theca cells of LPA follicles at fetal day 140; (4) increased SF1 protein content in the granulosa cells of SPA, LPA and LA and theca cells of LPA follicles and DAX1 in the granulosa cells of LPA at 1 year-of-age and (5) had no effect on SF1 or DAX1 at year 2. These data indicate age-specific changes in SF1 and DAX1 protein. Increased expression of DAX1 in early follicular stages at day 140, increased expression of SF1 in LA follicles at 1 year and lack of changes at 2 years-of-age are consistent with decrease in AMH expression in early stages, increased expression in later stages of follicular development and no changes at 2 years-of-age (Fertil Steril 97:748, 2012). The changes in SF1/ DAX1 may therefore contribute to the enhanced follicular recruitment, follicular persistence, and multifollicular ovarian phenotype of prenatal T-treated females and thus may be of translational relevance to the ovarian phenotype of women with PCOS. Supported by NIH P01 HD44232.