Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Environ Pollut. 2023 Oct 15;335:122278. doi: 10.1016/j.envpol.2023.122278. Epub 2023 Jul 28.
Environmental methylmercury (MeHg) exposure has gained global attention owing to its serious health hazards, especially neurotoxicity. Ferroptosis is a novel form of programmed cell death characterized by lipid peroxidation and iron overload. However, the occurrence of ferroptosis and its underlying mechanisms have not been fully elucidated in the methylmercury-induced neurotoxicity and the role of Nrf2 in MeHg-induced ferroptosis remains unexplored. In this study, we verified that MeHg decreased cell viability in a dose- and time-dependent manner in the Rat Brain Astrocytes cells (CTX cells). MeHg (3.5 μmol/L) exposure induced CTX cells to undergo ferroptosis, as evidenced by glutathione (GSH) depletion, lipid peroxidation, and iron overload, which was significantly rescued by the ferroptosis-specific inhibitors Ferrostatin-1 and Deferoxamine. MeHg directly disrupted the process of GSH metabolism by downregulating of SLC7A11 and GPX4 and interfered with intracellular iron homeostasis through inhibition of iron storage and export. Simultaneously, the expression of Nrf2 was upregulated by MeHg in CTX cells. Hence, the inhibition of Nrf2 activity further downregulated the levels of GPX4, SLC7A11, FTH1, and SLC40A1, which aggravated MeHg-induced ferroptosis to a greater extent. Overall, our findings provided evidence that ferroptosis played a critical role in MeHg-induced neurotoxicity, and suppressing Nrf2 activity further exacerbated MeHg-induced ferroptosis in CTX cells.
环境甲基汞（MeHg）暴露因其严重的健康危害而引起全球关注，尤其是神经毒性。铁死亡是一种新型的程序性细胞死亡形式，其特征为脂质过氧化和铁过载。然而，铁死亡的发生及其潜在机制在甲基汞诱导的神经毒性中尚未完全阐明，Nrf2 在 MeHg 诱导的铁死亡中的作用也尚未得到探索。在本研究中，我们验证了甲基汞以剂量和时间依赖的方式降低 CTX 细胞（大鼠脑星形胶质细胞）中的细胞活力。甲基汞（3.5 μmol/L）暴露诱导 CTX 细胞发生铁死亡，这表现在谷胱甘肽（GSH）耗竭、脂质过氧化和铁过载，而铁死亡特异性抑制剂 Ferrostatin-1 和 Deferoxamine 则显著挽救了这一过程。甲基汞通过下调 SLC7A11 和 GPX4 直接破坏 GSH 代谢过程，并通过抑制铁储存和输出干扰细胞内铁稳态。同时，甲基汞在 CTX 细胞中上调 Nrf2 的表达。因此，Nrf2 活性的抑制进一步下调了 GPX4、SLC7A11、FTH1 和 SLC40A1 的水平，这在更大程度上加剧了 MeHg 诱导的铁死亡。总的来说，我们的研究结果表明，铁死亡在 MeHg 诱导的神经毒性中起关键作用，抑制 Nrf2 活性进一步加重了 MeHg 诱导的 CTX 细胞铁死亡。
