基于肠-脑轴互作效应研究有机磷阻燃剂TCEP对斑马鱼神经毒性新机制

有机磷阻燃剂被大量应用于人类生产生活的同时也被持续释放到环境中，其引起的环境风险和健康效应近年受到了极大的关注。本项目拟以环境中普遍检出的磷酸三(2-氯乙基)酯TCEP为代表，基于肠道菌群与脑神经的调控关系探究有机磷阻燃剂对斑马鱼神经毒性新机制。该研究将先以斑马鱼的运动行为和脑组织结构等经典毒理学指标为基础，明确TCEP对斑马鱼的表观神经毒性。接着通过宏基因组测序、粪便移植和无菌斑马鱼模型建立肠道菌群与神经系统的相互联系。再利用代谢组学和分子生物学手段，阐释TCEP作用下内源性代谢物和免疫响应对肠-脑轴的调控机制。在充分掌握该毒性机制后，进一步设计益生菌或关键代谢物处理斑马鱼寻找缓解TCEP神经毒性的有效方式。该研究将从包括表观行为、菌群调控、代谢物循环和分子机制多个角度揭示有机磷阻燃剂TCEP的神经毒性机制，为预防和缓解有机磷阻燃剂对生物体的神经毒性提供新的解决思路和方法。

The environmental risks and health effects of organophosphorus flame retardants become a subject of great interest to researchers due to their wide use in materials encountered in daily living and constant release in environment. In this study, we will investigate the effects of tris(2-chloroethyl) phosphate (TCEP), a typical organophosphorus flame retardant extensively detected in environment, on the function of zebrafish nervous system based on the regulation mechanism between intestinal flora and brain. Firstly, we will verify the neuro toxic effects of TCEP by classical toxicological parameters like locomotion behavior and tissue structure. The relationship between gut flora and nervous system will be subsequently established by metagenomic sequencing, fecal transplants and free-germ zebrafish model. Finally, via metabolomics and molecular biology approaches, we will elucidate the regulatory mechanism of endogenous metabolites and immune response on gut-brain axis under TCEP exposure. Some probiotics and endogenous metabolites will also be applied to alleviate the neurotoxicity induced by TCEP. To sum up, this study will elucidate a new neurotoxic mechanism of TCEP in locomotion behavior, molecular mechanism, flora regulation and metabolite circulation, and new mild solutions will be provided for preventing the neurotoxic effects of organophosphorus flame retardants.