School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
Department of Medicine, Renal Electrolyte and Hypertension Division, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Chemosphere. 2021 Jun;273:129727. doi: 10.1016/j.chemosphere.2021.129727. Epub 2021 Jan 24.
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）是新烟碱类杀虫剂中最重要的化合物之一，也是目前全球应用最广泛的杀虫剂之一。此前，TMX 被认为是一种对哺乳动物无毒的新烟碱类杀虫剂。然而，最近有报道称 TMX 具有遗传毒性、细胞毒性和肝毒性。迄今为止，TMX 对小鼠肝脏的影响及其详细机制尚不清楚。NNMT 在肝脏中强烈表达，在机体能量消耗中发挥关键作用。为了证实 TMX 引起肝损伤的潜在发病机制，我们将 ICR 小鼠以 4mg/kg 和 20mg/kg 的剂量经灌胃染毒 12 周。结果显示，慢性 TMX 暴露可导致小鼠发生血脂异常和非酒精性脂肪性肝病（NAFLD）。此外，TMX 处理的小鼠肝脏还观察到氧化应激加剧、功能障碍和结构紊乱。另外，TMX 处理的小鼠肝脏中还观察到 PPARγ、脂肪酸合成酶和 NNMT 表达增加，PPARα 和 GNMT 表达减少，S-腺苷甲硫氨酸缺乏以及蛋氨酸代谢紊乱。这些结果表明，慢性 TMX 暴露可诱导小鼠发生血脂异常和 NAFLD。此外，肝细胞中 NNMT 的抑制可显著逆转 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 进展的一种潜在新策略。
