Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China; Department of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou, 510440, China.
Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China.
Environ Pollut. 2023 Aug 15;331(Pt 2):121887. doi: 10.1016/j.envpol.2023.121887. Epub 2023 May 24.
Cadmium is an environmental pollutant that has extensive deleterious effects. However, the mechanisms underlying the hepatotoxicity induced by long-term exposure to cadmium remained undefined. In the present study, we explored the role of m6A methylation in the development of cadmium-induced liver disease. We showed a dynamic change of RNA methylation in liver tissue from mice administrated with cadmium chloride (CdCl) for 3, 6 and 9 months, respectively. Particularly, the METTL3 expression was declined in a time-dependent manner, associated with the degree of liver injury, indicating the involvement of METTL3 in hepatotoxicity induced by CdCl. Moreover, we established a mouse model with liver-specific over-expression of Mettl3 and administrated these mice with CdCl for 6 months. Notably, METTL3 highly expressed in hepatocytes attenuated CdCl-induced steatosis and liver fibrosis in mice. In vitro assay also showed METTL3 overexpression ameliorated the CdCl-induced cytotoxicity and activation of primary hepatic stellate cells. Furthermore, transcriptome analysis identified 268 differentially expressed genes both in mice liver tissue treated with CdCl for 3 months and 9 months. Among them, 115 genes were predicted to be regulated by METTL3 determined by m6A2Target database. Further analysis revealed the perturbation of metabolic pathway, glycerophospholipid metabolism, ErbB signaling pathway, Hippo signaling pathway, and choline metabolism in cancer, and circadian rhythm, led to hepatotoxicity induced by CdCl. Collectively, our findings reveal new insight into the crucial role of epigenetic modifications in hepatic diseases caused by long-term exposure to cadmium.
镉是一种环境污染物，具有广泛的有害影响。然而，长期暴露于镉所引起的肝毒性的机制仍不清楚。在本研究中，我们探讨了 m6A 甲基化在镉诱导的肝病发展中的作用。我们显示了分别用氯化镉（CdCl）处理 3、6 和 9 个月的小鼠肝组织中 RNA 甲基化的动态变化。特别是，METTL3 的表达呈时间依赖性下降，与肝损伤的程度相关，表明 METTL3 参与了 CdCl 诱导的肝毒性。此外，我们建立了肝脏特异性过表达 Mettl3 的小鼠模型，并对这些小鼠给予 CdCl 处理 6 个月。值得注意的是，在肝细胞中高度表达 METTL3 可减轻 CdCl 诱导的小鼠脂肪肝和肝纤维化。体外实验也表明，METTL3 过表达可改善 CdCl 诱导的原代肝星状细胞的细胞毒性和激活。此外，转录组分析鉴定了在小鼠肝组织中用 CdCl 处理 3 个月和 9 个月后表达差异的 268 个基因。其中，通过 m6A2Target 数据库预测有 115 个基因受到 METTL3 的调控。进一步分析表明，代谢途径、甘油磷脂代谢、ErbB 信号通路、Hippo 信号通路和胆碱代谢在癌症中的紊乱，以及昼夜节律的改变，导致了 CdCl 引起的肝毒性。总之，我们的研究结果揭示了表观遗传修饰在长期暴露于镉引起的肝脏疾病中的关键作用。
