利用人神经干细胞模型研究遗传及表观遗传调控在环境化学物所致神经发育毒性中的作用机制

The temporally and spatially restricted nature of the proliferation and differentiation capacity of neural stem cells plays a vital role in the development of nervous system, but can also be influenced by neurotoxic environmental chemicals. The current project is aimed to assess the sensitivity of human neural stem cells (hNSCs) at different developmental stages to a panel of neurotoxic (methylmercury, chlorpyrifos, and bisphenol A) compounds, and try to explicit the potential common pathway among them. In addition, we will investigate the roles of cytokine-Jak-STAT signaling and epigenetic modifications in the developmental neurotoxicity (DNT) induced by neurotoxic compounds. This work will provide not only valuable endpoints of human in vitro models for DNT assessment, but also genetic and epigenetic information for DNT mechanisms, which will contribute to the environmental chemicals management and intervention.

神经干细胞的增殖和分化具有严格的时序性，是保证神经系统正常发育的重要前提，同时也是环境化学物产生毒性作用的重要阶段，但其具体作用机制尚不明确。本项目拟以体外培养的人神经干细胞为模型，以神经干细胞增殖和分化过程中各个关键时期的特异性基因作为检测终点，选择环境化学物中的甲基汞、毒死蜱、双酚A作为研究对象，阐明不同类型化学物暴露对神经干细胞增殖和分化的影响，并探讨潜在共同作用通路。并在此基础上，进一步探讨细胞因子-Jak-STAT信号通路和表观遗传学修饰在化学物所致神经发育毒性中的作用。项目的实施不仅可以为环境化学物的神经发育毒性评价模型提供新的检测指标，更能为神经发育毒性机制研究提供深入的遗传性和表观遗传性信息，为环境化学物的科学管理和干预提供理论依据。