UBE3C介导的PINK1降解在邻苯二甲酸单-2-乙基己酯（MEHP）神经毒性中的作用及机制研究

邻苯二甲酸二-2-乙基己酯（DEHP）是一种综合性能良好的增塑剂，因其环境内分泌干扰效应受到学界关注，邻苯二甲酸单-2-乙基己酯（MEHP）是其主要代谢产物及毒作用物质。目前MEHP的毒性终点多集中于发育、生殖和免疫系统等，关于其神经毒性及机制知之甚少。已知PTEN诱导假定激酶1（PINK1）对于维持线粒体和神经系统功能有重要意义，但其蛋白稳定性的调控机制不明。本项目初步发现，MEHP暴露诱导PINK1降解，且可能由泛素连接酶E3C（UBE3C）介导，故拟设计细胞实验阐明UBE3C调控PINK1降解的分子机制，探究UBE3C-PINK1轴在MEHP暴露致神经细胞线粒体损伤和凋亡中的作用，并采用野生型和Pink1、Ube3c基因编辑小鼠构建亚急性染毒模型加以验证，以期完善邻苯二甲酸酯类化合物毒理学安全性评价方面的内容，开创性地探讨其神经毒作用机制，寻找关键蛋白。

Di-2-ethylhexyl phthalate (DEHP) is one of the most widely used and studied phthalate esters which are plasticizers to improve the plasticity and strength of plastics and have been reported to possess endocrine disrupting properties. As the major toxic metabolic derivative of DEHP, mono-2-ethylhexyl phthalate (MEHP) is capable of interfering with functions of several systems such as reproductive system and immune system, but its neurotoxicity and mechanism remain elusive. PTEN-induced putative kinase 1 (PINK1) regulates mitochondrial quality control and neuronal cell survival, and the mutation of PINK1 is implicated in various human diseases such as neurodegenerative diseases. However, the molecular mechanisms regulating PINK1 stability and the corresponding modulator(s) have not been elucidated. Preliminary data from our laboratory indicate that MEHP induces PINK1 degradation, which is probably mediated by the ubiquitin protein ligase E3C (UBE3C). In this project, we aim to investigate the neurotoxicity of MEHP with a focus on UBE3C-PINK1 axis in cell culture and mice models. This study will uncover a previously uncharacterized toxic mechanism of phthalate esters, thereby providing reference for better health risk assessment and intervention management.