典型药物污染物卡马西平及其代谢产物对斑马鱼的神经行为毒性和作用机制研究

The environmental pollution problem of pharmaceutically active compounds (PhACs) has become a hot topic of social concern and environmental science research. As a human psychotropic drug, Carbamazepine (CBZ) is one of the most detectable and potentially ecotoxic drug contaminants in the water environment. Studies have shown that it is neurotoxic to aquatic organisms such as fish, and the mechanism of its toxicity is still unclear. This study plans to select CBZ and its main metabolites DiOH-CBZ and EP-CBZ as exogenous compounds, zebrafish as test organisms, with neurobehavioral toxicity as the entry point, transcriptomics technology as a means, combined with early development, behavioral testing , biochemical indicators, GABA and dopamine signaling pathway gene expression and protein expression and other different levels of test indicators, the construction of fish neurobehavioral toxicity Adverse outcome pathway (AOP), would identify its toxic pathway and its molecular action sites, and clarify the neurobehavioral toxicity mechanism of CBZ and its metabolites on the early developmental stage of fish. This study will provide toxicological data an ecotoxicological basis for the ecological risk assessment of PhACs in water environment.

药物活性化合物（Pharmaceutically active compounds, PhACs）的环境污染问题已经成为社会关注焦点和环境科学研究的热点课题。作为人用精神类药物，卡马西平(Carbamazepine，CBZ)是水环境中检出率最高且具有潜在生态毒性的药物污染物之一。研究表明其对鱼类等水生生物具有神经行为毒性，而对其毒性作用机制仍不明确。本项目拟选取CBZ及其主要代谢产物DiOH-CBZ和EP-CBZ为外源化合物，斑马鱼为受试生物，以神经行为毒性为切入点，转录组学技术为手段，结合早期发育、行为测试、生化指标、GABA和多巴胺信号通路基因表达和蛋白表达等不同效应水平的测试指标，构建鱼类神经行为毒性有害结局路径框架，甄别其毒性作用通路及其分子作用位点，尝试阐明CBZ及其代谢产物对鱼类早期发育阶段的神经行为毒性作用机制，为水环境中PhACs生态风险评价提供生态毒理学基础。

药物活性化合物的环境污染问题已经成为社会关注焦点和环境科学研究的热点课题。卡马西平（CBZ）和舍曲林（SER）作为人用精神类药物，是水环境中检出率较高且具有潜在生态毒性的典型药物污染物。本项目以斑马鱼为受试生物，以神经行为毒性为切入点，结合早期发育、行为测试、生化指标、GABA和多巴胺信号通路基因表达等不同效应水平的测试指标，研究CBZ和SER对鱼类的神经行为毒性和作用机制。研究结果表明，CBZ的慢性暴露能够导致斑马鱼胚胎的早期自发运动减少，诱导幼鱼的脑组织和肝脏产生氧化应激，其潜在机制为干扰幼鱼脑组织的胆碱能系统和GABA能系统。而对于SER，其短期暴露抑制斑马鱼仔鱼的运动以及增加其焦虑性，经长期暴露后能够干扰斑马鱼幼鱼脑内的5-HT系统和胆碱酯能系统，抑制褪黑激素调节生物和睡眠的转录组通路，产生神经毒性。综上，CBZ和SER均可对鱼类产生发育毒性和神经毒性，然而其作用机制存在差异，需要进一步研究。本项目的研究为精神类药物污染物的毒性效应和作用机制研究提供了新的方法，为风险评价和化学品管理提供了生态毒理学基础。