Abstract：
Trimethyltin chloride (TMT) is a potent neurotoxin widely used as a constituent of polyvinyl chloride plastic in the industrial and agricultural fields. However, the underlying mechanisms by which TMT leads to neurotoxicity remain elusive. In the present study, we constructed a dose and time dependent neurotoxic mouse model of TMT exposure to explore the molecular mechanisms involved in TMT-induced neurological damage. Based on this model, the cognitive ability of TMT exposed mice was assessed by the Morris water maze test and a passive avoidance task. The ultrastructure of hippocampus was analyzed by the transmission electron microscope. Subsequently, proteomics integrated with bioinformatics and experimental verification were employed to reveal potential mechanisms of TMT-induced neurotoxicity. Gene ontology (GO) and pathway enrichment analysis were done by using Metascape and GeneCards database respectively. Our results demonstrated that TMT-exposed mice exhibited cognitive disorder, and mitochondrial respiratory chain abnormality of the hippocampus. Proteomics data showed that a total of 7303 proteins were identified in hippocampus of mice of which 224 ones displayed a 1.5-fold increase or decrease in TMT exposed mice compared with controls. Further analysis indicated that these proteins were mainly involved in tricarboxylic acid (TCA) cycle and respiratory electron transport, proteasome degradation, and multiple metabolic pathways as well as inflammatory signaling pathways. Some proteins, including succinate-CoA ligase subunit (Suclg1), NADH dehydrogenase subunit 5 (Nd5), NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2 (Ndufa4l2) and cytochrome c oxidase assembly factor 7 (Coa7), which were closely related to mitochondrial respiratory electron transport, showed TMT dose and time dependent changes in the hippocampus of mice. Moreover, apoptotic molecules Bax and cleaved caspase-3 were up-regulated, while anti-apoptotic Bcl-2 was down-regulated compared with controls. In conclusion, our findings suggest that impairment of mitochondrial respiratory chain transport and promotion of apoptosis are the potential mechanisms of TMT induced hippocampus toxicity in mice.
摘要：
氯化三甲基锡（TMT）是一种有效的神经毒素，在工业和农业领域中广泛用作聚氯乙烯塑料的成分。然而,TMT导致神经毒性的潜在机制仍然难以捉摸。在本研究中,我们构建了剂量和时间依赖性TMT暴露的神经毒性小鼠模型，以探讨TMT引起的神经损伤的分子机制。基于这个模型,通过Morris水迷宫测试和被动回避任务评估TMT暴露小鼠的认知能力。通过透射电子显微镜分析海马的超微结构。随后，蛋白质组学结合生物信息学和实验验证，揭示了TMT诱导神经毒性的潜在机制。分别使用Metascape和GeneCards数据库进行基因本体论（GO）和途径富集分析。我们的结果表明，暴露于TMT的小鼠表现出认知障碍，海马线粒体呼吸链异常。蛋白质组学数据显示，在小鼠的海马中鉴定出总共7,303种蛋白质，其中224种与对照组相比，暴露于TMT的小鼠显示出1.5倍的增加或减少。进一步分析表明,这些蛋白主要参与三羧酸(TCA)循环和呼吸电子传递,蛋白酶体降解，和多种代谢途径以及炎症信号通路。一些蛋白质，包括琥珀酸辅酶A连接酶亚基（Suclg1），NADH脱氢酶亚基5（Nd5），NADH脱氢酶[泛醌]1α亚复合物亚基4样2（Ndufa4l2）和细胞色素c氧化酶组装因子7（Coa7），与线粒体呼吸电子传递密切相关，显示小鼠海马TMT剂量和时间依赖性变化。此外，凋亡分子Bax和裂解的caspase-3上调，而抗凋亡Bcl-2与对照组相比下调。总之,我们的发现表明线粒体呼吸链转运受损和促进细胞凋亡是TMT诱导小鼠海马毒性的潜在机制。
