Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning, China, 110122; The Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, China Medical University, Shenyang, Liaoning, China, 110122; Department of Occupational Health, School of Public Health, China Medical University, Shenyang, Liaoning, China, 110122.
Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning, China, 110122; Department of Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, China, 110122.
J Hazard Mater. 2024 Oct 5;478:135580. doi: 10.1016/j.jhazmat.2024.135580. Epub 2024 Aug 22.
Arsenic is recognized as a hazardous environmental toxicant strongly associated with neurological damage, but the mechanism is ambiguous. Neuronal cell death is one of the mechanisms of arsenic-induced neurological injury. Ferroptosis is involved in the pathophysiological process of many neurological diseases, however, the role and regulatory mechanism of ferroptosis in nerve injury under arsenic exposure remains uncovered. Our findings confirmed the role of ferroptosis in arsenic-induced learning and memory disorder and revealed miR-21 played a regulatory role in neuronal ferroptosis. Further study discovered that miR-21 regulated neuronal ferroptosis by targeting at FTH1, a finding which has not been documented before. We also found an extra increase of ferroptosis in neuronal cells conditionally cultured by medium collected from arsenic-exposed microglial cells when compared with neuronal cells directly exposed to the same dose of arsenic. Moreover, microglia-derived exosomes removal or miR-21 knockdown in microglia inhibited neuronal ferroptosis, suggesting the role of intercellular communication in the promotion of neuronal ferroptosis. In summary, our findings highlighted the regulatory role of miR-21 in ferroptosis and the contribution of microglia-derived miR-21 in exosomes to arsenic-induced neuronal ferroptosis.
砷被认为是一种环境有毒物质，与神经损伤密切相关，但具体机制尚不清楚。神经元细胞死亡是砷引起的神经损伤的机制之一。铁死亡参与了许多神经疾病的病理生理过程，然而，砷暴露下铁死亡在神经损伤中的作用和调节机制尚不清楚。我们的研究结果证实了铁死亡在砷诱导的学习和记忆障碍中的作用，并揭示了 miR-21 在神经元铁死亡中的调节作用。进一步的研究发现，miR-21 通过靶向 FTH1 来调节神经元铁死亡，这一发现以前尚未有文献报道。我们还发现，与直接暴露于相同剂量砷的神经元细胞相比，条件性培养在砷暴露的小胶质细胞培养基中的神经元细胞中，铁死亡明显增加。此外，小胶质细胞衍生的外泌体去除或小胶质细胞中 miR-21 的敲低抑制了神经元铁死亡，表明细胞间通讯在促进神经元铁死亡中的作用。综上所述，我们的研究结果强调了 miR-21 在铁死亡中的调节作用，以及小胶质细胞衍生的 miR-21 在 exosomes 中对砷诱导的神经元铁死亡的贡献。
