Tet3在妊娠前母体高雄激素暴露致子代脂代谢紊乱中的作用研究

Most chronic adult diseases are supposed to date back to the gamete and embryo phases, during which the epigenetic regulation represented by DNA methylation plays a critical role. Hyperandrogenism among reproductive aged women can significantly increase the risks of adverse pregnancy outcomes. Intrauterine testosterone exposure can induce impaired glucose tolerance and insulin secretion in offspring not only at early age but also in adulthood. However, the long term health implications of offspring conceived by mothers with pregestational hyperandrogenism remain largely unknown. Our previous study found offspring born to maternal rats with pregestational hyperandrogenism showed dysregulation of lipid metabolism. Here, we postulate that high androgen levels induce altered epigenetic regulation in oocytes, which was transmitted to offspring through fertilization and early embryo development. Consistantly, the expression of the Tet3 DAN dioxygenase, a representative epigenetic regulator involving in oocyte reprogramming, was down regulated in oocytes of female rats with excessive androgen. In mammals, the Tet3 protein derived from the oocyte is responsible for the large-scale genomic demethylation in zygotes, and thus is on the front burner in the epigenetic reprogramming during the early embryo development. In this study, we will invesgate whether lipid metabolism disorder in the rat offspring is associated with the maternal pregestational hyperandrogenism, and how Tet3-mediated epigenetic regulation is involved so as to provide new insights into gamete origins of adult disease.

慢性成年期疾病具有配子/胚胎起源性，以DNA甲基化为代表的表观遗传调控在其中发挥关键作用。育龄期妇女病理性高雄激素症会导致明显的妊娠不良相关结局。妊娠期母体过高的雄激素水平可导致其子代发生幼年和成年期糖不耐受及胰岛功能损伤。但妊娠前高雄激素母体出生的子代的近远期健康状态还报道尚少。我们前期研究发现妊娠前母体高雄激素暴露的大鼠子代会发生脂代谢紊乱。我们推测高雄激素导致卵细胞表观遗传调控发生改变，并且此改变会通过受精卵和早期胚胎发育而传递给子代。与此一致的是我们发现高雄激素大鼠成熟卵细胞中，表观遗传调控因子Tet3 DNA双加氧酶表达下降。在哺乳动物中，来源于卵细胞的Tet3负责受精卵基因组的大规模去甲基化，在早期胚胎表观遗传重编程过程中起关键作用。本项目将利用妊娠前高雄激素暴露的大鼠模型研究子代脂代谢紊乱机理，探讨Tet3对此过程的表观遗传调控机制，为成年期代谢疾病的配子源性理论提供新线索。

慢性成年期疾病具有配子/胚胎起源性，以DNA甲基化为代表的表观遗传调控在其中发挥关键作用。育龄期妇女病理性高雄激素症会导致明显的妊娠不良相关结局。妊娠期母体过高的雄激素水平可导致其子代发生幼年和成年期糖不耐受及胰岛功能损伤。但妊娠前高雄激素母体出生的子代的近远期健康状态还报道尚少。我们前期研究发现妊娠前母体高雄激素暴露的大鼠子代会发生脂代谢紊乱。我们推测高雄激素导致卵细胞表观遗传调控发生改变，并且此改变会通过受精卵和早期胚胎发育而传递给子代。我们发现高雄激素大鼠成熟卵细胞中，表观遗传调控因子Tet3 DNA双加氧酶表达下降。来源于卵细胞的Tet3负责受精卵基因组的大规模去甲基化，在早期胚胎表观遗传重编程过程中起关键作用。本项目利用妊娠前高雄激素暴露的大鼠模型研究子代脂代谢紊乱，探讨Tet3对此过程的表观遗传调控机制，为成年期代谢疾病的配子源性理论提供新线索。我们同时发现，高雄激素暴露的母体不易受孕，子代出生率下降，推测妊娠前母体高雄激素暴露的小鼠可能同时伴随有早期流产率的升高。结合临床早期流产病例分析，可为靶基因的寻找提供参考。通过对早期流产病人子宫内膜自然杀伤细胞转录组的分析，我们找到了可能参与早期流产的关键基因和lncRNA，作为对Tet3靶基因筛选的补充。