Department of Obstetrics and Gynecology, Xiangya Third Hospital, Central South University, Changsha, Hunan, People's Republic of China.
Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.
Endocrinology. 2019 Oct 1;160(10):2471-2484. doi: 10.1210/en.2019-00389.
Prenatal testosterone (T)-treated sheep, similar to women with polycystic ovary syndrome (PCOS), manifest oligo-/anovulation, hyperandrogenism, and polyfollicular ovary. The polyfollicular ovarian morphology, a result of persistence of antral follicles, arises, in part, by transcriptional changes in key mediators of follicular development that, in turn, are driven by epigenetic mechanisms. We hypothesized that prenatal T excess induces, in a cell-specific manner, transcriptional changes in key mediators of follicular development associated with relevant changes in epigenetic machinery. Expression levels of key mediators of follicular development, DNA methyltransferases (DNMTs), and histone de-/methylases and de-/acetylases were determined in laser-capture microdissection-isolated antral follicular granulosa and theca and ovarian stromal cells from 21 months of age control and prenatal T-treated sheep (100 mg IM twice weekly from gestational day 30 to 90; term: 147 days). Changes in histone methylation were determined by immunofluorescence. Prenatal T treatment induced the following: (i) cell-specific changes in gene expression of key mediators of follicular development and steroidogenesis; (ii) granulosa, theca, and stromal cell-specific changes in DNMTs and histone de-/methylases and deacetylases, and (iii) increases in histone 3 trimethylation at lysine 9 in granulosa and histone 3 dimethylation at lysine 4 in theca cells. The pattern of histone methylation was consistent with the expression profile of histone de-/methylases in the respective cells. These findings suggest that changes in expression of key genes involved in the development of the polyfollicular phenotype in prenatal T-treated sheep are mediated, at least in part, by cell-specific changes in epigenetic-modifying enzymes.
产前睾酮（T）处理的绵羊与多囊卵巢综合征（PCOS）女性相似，表现为少/无排卵、高雄激素血症和多囊卵巢。多囊卵巢的形态学是由于窦前卵泡持续存在而产生的，部分原因是卵泡发育关键介质的转录变化，而这些变化又是由表观遗传机制驱动的。我们假设，产前 T 过多以细胞特异性的方式诱导卵泡发育关键介质的转录变化，这些变化与表观遗传机制相关。从 21 月龄的对照组和产前 T 处理的绵羊（从妊娠第 30 天至第 90 天，每周两次 IM 注射 100mg；足月：147 天）的激光捕获显微切割分离的窦前卵泡颗粒细胞和膜细胞以及卵巢基质细胞中测定了卵泡发育的关键介质、DNA 甲基转移酶（DNMTs）、组蛋白去/甲基化酶和去/乙酰化酶的表达水平。通过免疫荧光测定组蛋白甲基化的变化。产前 T 处理诱导了以下变化：（i）卵泡发育和类固醇生成关键介质的基因表达在细胞特异性方面的变化；（ii）颗粒细胞、膜细胞和基质细胞特异性的 DNMTs 和组蛋白去/甲基化酶和去/乙酰化酶的变化；（iii）颗粒细胞中组蛋白 3 赖氨酸 9 三甲基化和膜细胞中组蛋白 3 赖氨酸 4 二甲基化的增加。组蛋白甲基化的模式与相应细胞中组蛋白去/甲基化酶的表达谱一致。这些发现表明，产前 T 处理的绵羊多囊表型发育中关键基因表达的变化至少部分是由表观遗传修饰酶的细胞特异性变化介导的。
