Prenatal ethanol exposure induces susceptibility to premature ovarian insufficiency
Prenatal ethanol exposure induces susceptibility to premature ovarian insufficiency
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产前乙醇暴露会导致卵巢早衰的易感性
DOI：
10.1530/joe-19-0063
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发表时间：
2019-10-01
影响因子：
4
通讯作者：
Wang, Hui
中科院分区：
文献类型：
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作者：
Ni, Yuan;Xu, Dan;Wang, Hui
产前乙醇暴露（PEE）对后代生殖系统产生不利影响。我们的目的是确认女性PEE后代卵巢功能不全（POI）的易感性，并阐明其宫内编程机制。从妊娠第9天（GD）至第20天，对妊娠Wistar雌性大鼠灌胃给予4 g/kg ×天乙醇。在GD 20、出生后6周和出生后12周检测子代的生殖参数。PEE胎儿显示卵母细胞数量减少，卵巢细胞凋亡增加，卵巢胰岛素样生长因子1（IGF 1）信号通路和类固醇生成酶的表达水平上调。成年大鼠闭锁卵泡比例增加，抗苗勒氏管抗体阳性有腔卵泡数量减少。血清雌二醇（E-2）水平降低，但卵泡刺激素水平升高。卵巢Igf 1信号通路从青春期的激活转变为成年期的相对抑制，卵巢类固醇生成酶的表达水平在成年期受到抑制。此外，我们用不同浓度的乙醇（15、30、60、120 mM）处理人颗粒细胞系KGN，发现IGF 1信号通路组分3 β-H5 D和P450 arom的表达以及E-2的产生增加。IGF 1 siRNA转染后P450 arom表达和E-2产生均下调。这些结果表明，PEE诱导POI的易感性在成年女性，这可能是由于过度激活的胎儿卵巢IgF 1信号通路和类固醇激素下PEE，导致加速卵泡发育和原始卵泡耗竭的早期发展。
Prenatal ethanol exposure (PEE) adversely affects the offspring reproductive system. We aimed to confirm the susceptibility to premature ovarian insufficiency (POI) in female PEE offspring and elucidate its intrauterine programming mechanism. The pregnant Wistar female rats were intragastrically administered with 4 g/kg x day of ethanol from gestational day (GD) 9 to 20. Offspring reproductive parameters were detected on GD20, postnatal week (PW) 6 and PW12. The PEE foetuses showed a decreased number of oocytes, increased ovarian cell apoptosis and upregulated expression levels of ovarian insulin-like growth factor 1 (IGF1) signalling pathway and steroidogenic enzymes. The proportion of atretic follicles in adult rats was increased, while the number of anti-Mullerian hormone-positive antral follicles was decreased. The serum oestradiol (E-2) levels were decreased, but the follicle stimulation hormone levels were elevated. The ovarian Igf1 signalling pathway was transformed from activation during puberty to relative inhibition in adulthood, and the expression levels of ovarian steroidogenic enzymes were inhibited in adulthood. Furthermore, we treated the human granulosa cell line KGN with different ethanol concentrations (15, 30, 60, 120 mM) and found that the expression of IGF1 signalling pathway components, 3 beta-H5D and P450arom, as well as the production of E-2, was increased. After IGF1 siRNA transfection, P450arom expression and E-2 production were downregulated. These results suggest that PEE induces POI susceptibility in adult females, which may be caused by over-activation of the foetal ovarian IgF1 signalling pathway and steroidogenesis under PEE, resulting in accelerated early development of folliculogenesis and depletion of primordial follicles.