孕前EE暴露致下丘脑ARC区Leptin/NPY通路改变引起子代糖代谢失衡的机制

Ethinyl estradiol (EE) has been widely used in women at childbearing age for its function on contraception and regulation of menstrual cycles. Whether taking EE before pregnancy affects development of the offspring becomes a social concern. Our pilot study showed that preconceptional EE exposure could result in impaired glucose homeostasis in offspring in rats and leptin / NPY pathway in hypothalamic ARC region was involved. But the mechanism underlying is unclear. This project intends to use rats with preconceptional EE exposure as the model and analyze estrogen metabolism spectrum at different periods, leptin LEP gene methylation levels, leptin and its receptor expression in different tissues, neonatal leptin peak characteristics and ARC leptin / NPY pathway establishment to elaborate how EE exposure alters gestational leptin function and thus impaires leptin/NPY pathway in the hypothalamic ARC area. And this project will check whether the impaired glucose homeostasis would be alleviated by applying leptin and NPY receptor agonists during the neonatal period. Meanwhile, the results from the animal model will be verified based on a large-size mother-child cohort study which has already been built up in our lab. This project aims to provide theoretical basis on prevention, early diagnosis and treatment of impaired glucose homeostasis in children caused by preconceptional EE exposure to improve population quality and promote children's health.

炔雌醇(EE)因为有避孕、调节生理周期和辅助受孕的功能，被越来越多的育龄妇女使用。因此孕前服用EE是否会影响子代发育成为社会所关注的问题。我们的预实验结果显示大鼠孕前EE暴露能导致子代幼年期糖代谢失衡，并提示与脑ARC区leptin/NPY通路相关，但具体机制尚不清楚。本项目拟采用EE孕前暴露大鼠模型，通过分析不同时段雌激素代谢谱、leptin基因LEP甲基化水平、不同组织leptin及其受体表达和ARC区leptin/NPY通路完整性，去阐明孕前EE暴露改变孕期leptin功能，进而引起脑ARC区leptin/NPY代谢通路受损的机制。同时，对已建立的大样本母亲儿童队列进行回访，验证动物模型结果。本项目旨在为孕前EE暴露引起子代幼年期糖代谢失衡的预防、早期诊断和治疗提供依据，促进儿童健康。

炔雌醇(EE)因为有避孕、调节生理周期和辅助受孕的功能，被越来越多的育龄妇女使用。因此孕前服用EE是否会影响子代发育成为社会所关注的问题。我们的科学假说为大鼠孕前EE暴露能导致子代幼年期糖代谢失衡，并与脑ARC区leptin/NPY通路相关。本项目采用EE孕前暴露大鼠模型，通过分析孕期不同时段尿液小分子雌激素代谢谱发现孕前EE暴露可以影响到孕晚期母代体内雌激素代谢；与科学假说不同的是，胎盘中LEP甲基化未有改变，而NPY甲基化状态明显改变；子代脑ARC中NPY蛋白表达也证实孕前EE暴露会影响NPY表达，降低ARC区leptin/NPY通路完整性，这说明阐明孕前EE暴露改变孕期NPY功能，进而引起脑ARC区leptin/NPY代谢通路受损的机制；通过新生期补充leptin，可适当缓解子代幼年期糖代谢失衡。本项目旨在为孕前EE暴露引起子代幼年期糖代谢失衡的预防、早期诊断和治疗提供依据，促进儿童健康。