低剂量铅暴露导致神经元轴突发育障碍的机制研究

Heavy metal lead has obvious neural development toxicity. Low-level lead exposure (blood lead < 100 μ g/L) can also lead to children's cognitive impairment, but the toxicological mechanisms need to be clarified. Axon formation is the key stage of neuronal polarity development. Our study showed that low level lead exposure could lead to disorder of hippocampal neuron axon elongation. We also found that low-level lead exposure could increase RhoA activity in neurons, and induce upregulation of PDZ-RhoGEF, the positive regulatory molecule of RhoA. These results suggested that the PDZ-RhoGEF/RhoA pathway may be involved in neuronal axon development dsiorder induced by low-level lead exposure. In this study, we will use neurological molecular biology, tissue and cell morphology and other methods, to clarify the effect of low dose lead on the axon development, and the dynamic changes of RhoA activity in neurons. The results will clarify the role of PDZ-RhoGEF/RhoA pathway involved in low-lead induced axon development disorder. Our study will provide a new perspective for studying the molecular mechanisms of lead neurotoxicity, and lay a foundation for the prevention and control strategies of children lead neurotoxicity.

重金属铅具有很强的神经发育毒性，低铅暴露（血铅＜100μg/L）也可导致儿童认知功能损伤，其毒性机制有待阐明。轴突发育是神经元极性形成的关键，我们发现低剂量铅暴露可导致海马神经元轴突延伸障碍，还发现低铅暴露可诱导神经元内RhoA分子的活性形式增加，并可诱导其正向调节分子PDZ-RhoGEF表达增加，这提示PDZ-RhoGEF/RhoA通路极可能参与了低铅导致的神经元轴突发育障碍。本课题拟应用神经分子生物学、组织和细胞形态学等方法，阐明低剂量铅暴露对神经元轴突发育的影响，以及神经元内RhoA活性的动态变化，阐明PDZ-RhoGEF/RhoA通路在低铅导致的轴突发育障碍中的作用。这些结果将为研究铅神经毒性的分子机制提供新的视角，并为开发儿童铅神经毒性的防治策略提供研究基础。

重金属铅具有很强的神经发育毒性，铅暴露可导致儿童认知功能损伤，其毒性机制有待阐明。在项目进行过程中，我们建立了原代培养神经元铅暴露细胞模型，检测铅暴露对体外神经元发育的影响和对RhoA活性的影响，观察RhoA在低铅导致神经元发育障碍中的作用。检测阻断RhoA通路对铅暴露致神经元发育障碍的影响，观察PDZ-RhoGEF在铅暴露诱导RhoA活性改变和神经元轴突发育障碍中的作用。通过铅暴露动物模型检测PDZ-RhoGEF和RhoA在铅暴露导致神经元发育障碍中的作用。研究结果显示，1）铅暴露可影响发育期大鼠神经元突触发育；2）铅暴露是通过影响神经元内RhoA分子的活性影响神经元突触发育的；3）铅暴露通过影响RhoA激酶的正向调控分子PDZ-RhoGEF的表达影响RhoA活化；4）铅暴露影响PDZ-RhoGEF的表达与表观遗传学调控有关。本项目的研究成果对于拓展课题组研究深度，深入重金属铅神经发育毒性及防护研究具有创新意义，将为阐明铅致认知功能损伤的分子机制提供新的视角。