Puttabyatappa Muraly, Matiller Valentina, Stassi Antonela F, Salvetti Natalia R, Ortega Hugo H, Padmanabhan Vasantha
Department of Pediatrics and the Reproductive Sciences Program, University of Michigan, Room 7510 MSRB I, 1150 Medical Center Drive, Ann Arbor, MI, 48109-5718, USA.
Instituto de Ciencias Veterinarias del Litoral (ICiVet-Litoral), Universidad Nacional del Litoral (UNL) - Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Esperanza, Santa Fe, Argentina.
Reprod Sci. 2020 Jan;27(1):342-354. doi: 10.1007/s43032-019-00029-0. Epub 2020 Jan 1.
Prenatal testosterone (T) excess, partly via androgenic programming, enhances follicular recruitment/persistence in sheep as in women with polycystic ovarian syndrome (PCOS). Decreased anti-Mullerian hormone (AMH) in early growing and increased AMH in antral follicles may underlie enhanced recruitment and persistence, respectively. Changes in AMH may be mediated by steroidogenic factor 1 (SF1), an enhancer of AMH, and dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX1), that antagonizes SF1. Another mediator could be forkhead box 03 (FOXO3) which regulates follicular recruitment/atresia. To test if androgen-programmed changes in SF1, DAX1, and FOXO3 proteins contribute to follicular defects in prenatal T-treated sheep, ovaries from control, prenatal T-, and dihydrotestosterone (DHT)-treated (days 30-90 of gestation) animals at fetal day (FD) 90, FD140, and 1 and 2 years-of-age were studied. Prenatal T increased DAX1 in granulosa cells of primordial through large preantral and theca cells of large preantral follicles at FD140 and increased SF1 in the granulosa cells of preantral and antral and theca cells of large preantral follicle at 2 years-of-age. Prenatal T increased FOXO3 only in theca cells of preantral (FD140) and antral (2 years-of-age) follicles. Prenatal DHT increased DAX1 in granulosa cells from small preantral follicles at FD140 while increasing SF1 in granulosa cells from antral follicles at 1 year-of-age. These age-dependent changes in DAX1/SF1 partly via androgen-programming are consistent with changes in AMH and may contribute to the enhanced follicular recruitment/persistence, and multifollicular phenotype of prenatal T-treated females and may be of translational relevance to PCOS.
产前睾酮（T）过量，部分通过雄激素编程，与多囊卵巢综合征（PCOS）女性一样，会增强绵羊的卵泡募集/持续存在。早期生长卵泡中抗苗勒管激素（AMH）降低，而窦状卵泡中AMH升高，可能分别是卵泡募集增加和持续存在的基础。AMH的变化可能由类固醇生成因子1（SF1，一种AMH增强剂）和X染色体上剂量敏感的性别反转、肾上腺发育不全关键区域基因1（DAX1，其拮抗SF1）介导。另一种介质可能是叉头框03（FOXO3），它调节卵泡募集/闭锁。为了测试SF1、DAX1和FOXO3蛋白中雄激素编程的变化是否导致产前T处理绵羊的卵泡缺陷，研究了妊娠第30 - 90天接受对照、产前T和双氢睾酮（DHT）处理的动物在胎儿期第90天（FD90）、FD140以及1岁和2岁时的卵巢。产前T在FD140时使原始卵泡至大的窦前卵泡颗粒细胞以及大的窦前卵泡膜细胞中的DAX1增加，在2岁时使窦前卵泡和窦状卵泡颗粒细胞以及大的窦前卵泡膜细胞中的SF1增加。产前T仅在窦前卵泡（FD140）和窦状卵泡（2岁）的膜细胞中增加FOXO3。产前DHT在FD140时使小窦前卵泡颗粒细胞中的DAX1增加，同时在1岁时使窦状卵泡颗粒细胞中的SF1增加。这些DAX1/SF1中部分通过雄激素编程的年龄依赖性变化与AMH的变化一致，可能导致产前T处理雌性动物卵泡募集/持续存在增强以及多卵泡表型增加，并且可能与PCOS具有转化相关性。
