Abstract：
Exposure to nicotine by cigarette smoking have shown strongly defectives on the physiological function of ovaries, which in turn leads to disorders of fertility in women. However, the potential molecular mechanisms remain to be elucidated. In this study, we notably found that nicotine was likely to specifically raise the expression of histone deacetylase 3 (HDAC3) to promote the apoptosis and autophagy of granulosa cells (GCs) and block follicular maturation. Moreover, prostaglandin E2 (PGE2) inhibited the apoptosis of GCs and facilitated follicular maturation, and nicotine appeared to inhibit PGE2 secretion by freezing the expression of cyclooxygenase 1 (COX1), which was the rate-limiting and essential enzyme for PGE2 synthesis. Epigenetically, the nicotine was observed to diminish the histone H3 lysine 9 acetylation (H3K9ac) level and compact the chromatin accessibility in -1776/-1499 bp region of COX1 by evoking the expression of HDAC3, with the deactivated Cas9-HDAC3/sgRNA system. Mechanistically, the COX1 protein was found to pick up and degrade the autophagy related protein beclin 1 (BECN1) to control the autophagy of GCs. These results provided a potential new molecular therapy to recover the damage of female fertility induced by nicotine from cigarette smoking.
摘要：
吸烟暴露于尼古丁对卵巢的生理功能表现出强烈的缺陷，这反过来又导致女性生育障碍。然而,潜在的分子机制仍有待阐明。在这项研究中,我们特别发现,尼古丁可能特异性提高组蛋白去乙酰化酶3(HDAC3)的表达,从而促进颗粒细胞(GCs)的凋亡和自噬并阻断卵泡成熟.此外，前列腺素E2(PGE2)抑制GCs细胞凋亡,促进卵泡成熟,尼古丁似乎通过冻结环氧合酶1（COX1）的表达来抑制PGE2的分泌，是PGE2合成的限速酶和必需酶。表观遗传,观察到尼古丁降低组蛋白H3赖氨酸9乙酰化（H3K9ac）水平，并通过失活的Cas9-HDAC3/sgRNA系统引起HDAC3的表达来压缩COX1的-1776/-1499bp区域的染色质可及性。机械上,发现COX1蛋白可吸收并降解自噬相关蛋白beclin1（BECN1）以控制GCs的自噬。这些结果为恢复吸烟引起的尼古丁对女性生育能力的损害提供了潜在的新分子疗法。
