孕期双酚A暴露对印记基因Igf2/H19的影响及其致糖代谢异常的隔代遗传机制研究

Diabetes is a kind of chronic diseases with high incidence all over the world, which is associated with genetic and environmental factors. Our previous studies have shown that bisphenol A exposure during pregnancy can cause perturbed glycometabolism in offsprings, but the mechanism remains unkown. Literatures indicated that epigenetic modification and altered expression of critical imprinting gene, Igf2/H19, may play a key role in perturbed glycometabolism in offsprings. This project proposed on the basis of our previous studies, to comfirm the perturbed glycometabolism and multigenerational effects of glucose metabolic disorder in adult offsprings which are exposed by bisphenol A in uterus. We further focus on the methylation and expression of Igf2/H19 in vivo and in vitro, to verify that prenatal bisphenol A exposure lead to changes in islet function and perturbed glycometabolism in adult via maternal hyperglycemia- Igf2/H19 pathway, using the real-time PCR, western blot, gene sequencing and cell transfection technique. This project is in order to verify that the prenatal bisphenol A exposure can cause perturbed glycometabolism in offsprings and its epigenetic mechanism, and may also provide theoretical and experimental evidence for determining the long-term hazards caused by bisphenol A exposure during pregnancy.

糖尿病是全球高发的慢性疾病，与遗传和环境因素相关。本室研究显示，孕期双酚A暴露可致子代成年后糖代谢异常，但发生机制不明。文献提示，印记基因Igf2/H19 表观遗传修饰及表达改变，可能参与子代糖代谢异常的发生。本项目拟在前期研究基础上，从整体动物水平全面观察孕期双酚A暴露致子代成年后糖代谢异常及其跨代遗传效应；进一步在整体和细胞水平，以印记基因Igf2/H19甲基化状态及表达改变为切入点，采用real-time PCR，western blot，焦磷酸基因测序等技术，验证双酚A通过母源性高血糖-Igf2/H19途径引起子代胰岛功能紊乱和糖代谢异常，并通过影响性腺印迹基因的表观修饰而引起跨代遗传效应的科研假设。本研究从表观遗传学角度，阐述双酚A与DNA甲基化在胎源性糖尿病发病过程中的交互作用。为确定孕期双酚A暴露所致的远期危害，解析胎源性糖尿病的发生机制，提供理论和实验依据。

糖尿病是全球高发的慢性疾病，与遗传和环境因素相关。本室前期研究发现，孕期双酚A暴露可致子代成年后糖代谢异常，但发生机制不明。有文献报道，印记基因Igf2/H19 表观遗传修饰及表达改变，可能参与子代糖代谢异常的发生。本项目在前期研究基础上，利用孕期BPA暴露小鼠跨代模型，从整体动物水平证实孕期双酚A暴露（F0）可引起子代（F1和F2）成年后糖代谢和脂代谢异常，并具有跨代遗传效应；进一步利用体外小鼠胰岛培养体系，在细胞水平证实BPA可显著增加胰岛合成和分泌胰岛素能力；这一效应主要通过BPA增加雌激素受体GPR30的表达及改变Igf2/H19印记基因的表观遗传修饰途径，引起胰岛素合成和分泌功能紊乱，导致糖代谢异常。另外，以印记基因Igf2/H19甲基化状态及表达改变为切入点，采用real-time PCR，western blot，焦磷酸基因测序等技术，证实孕期BPA暴露可引起子代胚胎Igf2基因印记丢失，降低雄性胎鼠原始生殖细胞Igf2和H19 DMRs甲基化水平，进而引起子代糖代谢异常的跨代遗传效应。本研究从表观遗传学角度，阐述了双酚A与DNA甲基化在胎源性糖尿病发病过程中的交互作用。为确定孕期双酚A暴露所致的远期危害，解析胎源性糖尿病的发生机制，提供理论和实验依据。