Thiamethoxam (TMX) is one of the major compounds of neonicotinoids, the most widely used class of insecticides worldwide. Previously, TMX was considered a non-toxic neonicotinoid insecticide to mammals. However, the genotoxicity, cytotoxicity, and hepatotoxicity of TMX in mammals were recently reported. Thus far, the effects of TMX on the mouse liver and its detailed mechanism remain unclear. NNMT, strongly expressed in the liver, plays a critical role in body energy expenditure. To confirm the potential pathogenesis of liver dysfunction induced by TMX, ICR mice were exposed to TMX at a dose of 4 mg/kg and 20 mg/kg by gavage administration for 12 weeks. The data showed that chronic TMX exposure caused dyslipidemia and nonalcoholic fatty liver disease (NAFLD) in mice. Moreover, aggravated oxidative stress, dysfunction, and disorganized structure were also observed in TMX-treated mouse livers. In addition, increases of PPARγ, fatty acid synthase, and NNMT expression, as well as decreases of PPARα and GNMT expression, S-adenosylmethionine deficiency, and methionine metabolism disorder were also observed in TMX-treated mouse livers. These results suggest that chronic TMX exposure induces dyslipidemia and NAFLD in mice. Moreover, inhibition of NNMT in hepatocytes significantly reversed the effects of TMX. The molecular mechanism of TMX-induced NAFLD is mostly through NNMT-mediated methionine metabolism and methyl donor balance, which ultimately regulates PPARα signaling pathway. Inhibition of NNMT could be a potentially novel strategy for blocking the progression of NAFLD induced by TMX.

噻虫嗪（TMX）是新烟碱的主要化合物之一，新烟碱是全世界使用最广泛的杀虫剂。以前，TMX被认为对哺乳动物是无毒的新烟碱类杀虫剂。然而，最近报道了TMX在哺乳动物中的遗传毒性，细胞毒性和肝毒性。到目前为止，TMX对小鼠肝脏的作用及其详细机制尚不清楚。NNMT在肝脏中强烈表达，在人体能量消耗中起关键作用。为了证实由TMX引起的肝功能障碍的潜在发病机理，通过管饲法将ICR小鼠分别以4 mg / kg和20 mg / kg的剂量暴露于TMX中，持续12周。数据显示，长期暴露于TMX会引起小鼠血脂异常和非酒精性脂肪肝疾病（NAFLD）。此外，氧化应激加剧，功能障碍，在TMX处理的小鼠肝脏中也观察到了无序的结构。此外，还观察到在TMX处理的小鼠肝脏中PPARγ，脂肪酸合酶和NNMT表达增加，以及PPARα和GNMT表达减少，S-腺苷甲硫氨酸缺乏和甲硫氨酸代谢紊乱。这些结果表明，慢性TMX暴露可诱发小鼠血脂异常和NAFLD。此外，抑制肝细胞中的NNMT可以显着逆转TMX的作用。TMX诱导的NAFLD的分子机制主要是通过NNMT介导的蛋氨酸代谢和甲基供体平衡，最终调节PPARα信号通路。抑制NNMT可能是阻止TMX诱导的NAFLD进程的潜在新策略。还在TMX处理的小鼠肝脏中观察到脂肪酸合酶和NNMT表达，以及PPARα和GNMT表达降低，S-腺苷甲硫氨酸缺乏和甲硫氨酸代谢紊乱。这些结果表明，慢性TMX暴露可诱发小鼠血脂异常和NAFLD。此外，抑制肝细胞中的NNMT可以显着逆转TMX的作用。TMX诱导的NAFLD的分子机制主要是通过NNMT介导的蛋氨酸代谢和甲基供体平衡，最终调节PPARα信号通路。抑制NNMT可能是阻止TMX诱导的NAFLD进程的潜在新策略。还在TMX处理的小鼠肝脏中观察到脂肪酸合酶和NNMT表达，以及PPARα和GNMT表达降低，S-腺苷甲硫氨酸缺乏和甲硫氨酸代谢紊乱。这些结果表明，慢性TMX暴露可诱发小鼠血脂异常和NAFLD。此外，抑制肝细胞中的NNMT可以显着逆转TMX的作用。TMX诱导的NAFLD的分子机制主要是通过NNMT介导的蛋氨酸代谢和甲基供体平衡，最终调节PPARα信号通路。抑制NNMT可能是阻止TMX诱导的NAFLD进程的潜在新策略。在TMX处理的小鼠肝脏中也观察到了蛋氨酸和蛋氨酸代谢紊乱。这些结果表明，慢性TMX暴露可诱发小鼠血脂异常和NAFLD。此外，抑制肝细胞中的NNMT可以显着逆转TMX的作用。TMX诱导的NAFLD的分子机制主要是通过NNMT介导的蛋氨酸代谢和甲基供体平衡，最终调节PPARα信号通路。抑制NNMT可能是阻止TMX诱导的NAFLD进程的潜在新策略。在TMX处理的小鼠肝脏中也观察到了蛋氨酸和蛋氨酸代谢紊乱。这些结果表明，慢性TMX暴露可诱发小鼠血脂异常和NAFLD。此外，抑制肝细胞中的NNMT可以显着逆转TMX的作用。TMX诱导的NAFLD的分子机制主要是通过NNMT介导的蛋氨酸代谢和甲基供体平衡，最终调节PPARα信号通路。抑制NNMT可能是阻止TMX诱导的NAFLD进程的潜在新策略。TMX诱导的NAFLD的分子机制主要是通过NNMT介导的蛋氨酸代谢和甲基供体平衡，最终调节PPARα信号通路。抑制NNMT可能是阻止TMX诱导的NAFLD进程的潜在新策略。TMX诱导的NAFLD的分子机制主要是通过NNMT介导的蛋氨酸代谢和甲基供体平衡，最终调节PPARα信号通路。抑制NNMT可能是阻止TMX诱导的NAFLD进程的潜在新策略。