CXCL12/CXCR4介导孕期咖啡因暴露所致子代大鼠POI易感的宫内起源机制

Premature ovarian insufficiency (POI) which greatly influences women’s reproductive health is considered to have potential intrauterine origin epidemiologically and experimentally. But little is known about the underlying mechanism. The morbidity of POI is related with the premature depletion of follicle pool and the insufficient proliferation and excessive apoptosis of granulosa cells. Our previous data revealed that, in prenatal caffeine exposure rat model, the offspring rats over-exposed to maternal glucocorticoid (GC) and the folliculogenesis were impaired; futhermore, the abnormal reproductive hormones/behaviers and damaged compensation hypothalamus-pituitary-ovary axis were observed in adult stage, which suggested the POI-like phenotype. Moreover, we found the low expression of chemokine CXCL12, weakened proliferation and active apoptosis in fetal ovary. To prove intrauterine origin of the susceptibility of POI induced by maternal GC, we are abaut to discuss the inner link between “maternal GC → fetal ovarian expression of CXCL12 → CXCR4/MEK/ERK signaling pathway inhibition → weakened proliferation/active apoptosis in granulosa cells → POI susceptibility” in PCE model. Our research will provide a novel idea and theoretical foundation of early warning and prevention to POI.

早发性卵巢功能不全（POI）极大地影响女性的生殖健康，流行病学和动物研究提示其可能具有宫内起源。然而，POI的宫内发生机制研究尚不足。已知POI与卵泡池的过早耗竭、颗粒细胞的增殖不足与过度凋亡有关。我们前期证实，孕期咖啡因暴露（PCE）的子代大鼠过暴露于母源性糖皮质激素（GC），其卵泡发育受损；成年后内分泌及生殖行为学指标异常，下丘脑-垂体-卵巢轴代偿不足，提示生殖功能出现POI样改变。近期我们还发现，PCE胎卵巢趋化因子CXCL12表达降低，细胞增殖减弱而凋亡增加。本项目拟进一步在整体和细胞水平探讨PCE下“母源性高GC→胎卵巢低CXCL12表达→CXCR4/MEK/ERK信号通路抑制→颗粒细胞增殖减少/凋亡增加→POI易感”之间的内在联系，以阐明母源性高GC所致POI易感的宫内起源机制。本研究对于POI的预警与防治均提供了新的思路和理论依据。

早发性卵巢功能不全（POI）极大地影响女性的生殖健康，流行病学和动物研究提示其可能具有宫内起源。据报道，孕期咖啡因暴露（PCE）可导致子代卵泡数减少，然而其宫内编程机制却并未阐明。已知POI与卵泡池的过早耗竭、颗粒细胞的增殖不足与过度凋亡有关。本项目通过构建PCE大鼠模型，检测其雌性子代血、卵巢和下丘脑等内分泌相关指标，揭示了PCE子代生殖内分泌及卵巢功能的改变。具体的，我们观察到PCE子代雌性在不同发育时期卵泡发育和雌激素合成功能发生改变，卵巢功能在出生后虽出现了一定程度的追改性生长，并发现在慢性刺激（冰水游泳）后，PCE子代由GC-IGF1轴所介导的卵巢功能损伤得以加重。进一步，通过KGN细胞系我们发现咖啡因和糖皮质激素均可抑制雌激素生成，而皮质醇可促进糖皮质激素受体核转位，通过上调组蛋白去乙酰化酶10表达抑制H3K27乙酰化水平及IGF1表达，进而影响雌二醇合成。本研究发现PCE与雌性子代卵巢功能紊乱及POI样改变有关，其机制与宫内高糖皮质激素暴露导致GR及组蛋白去乙酰化酶10表达上调造成卵巢CG-IGF1轴变成改变有关。本研究对于POI的预警与防治均提供了新的思路和理论依据。