Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, 700-8530, Japan.
Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, 920-0293, Japan.
Arch Toxicol. 2021 Apr;95(4):1241-1250. doi: 10.1007/s00204-021-02982-9. Epub 2021 Jan 16.
Methylmercury (MeHg), an environmental toxicant, induces neuronal cell death and injures a specific area of the brain. MeHg-mediated neurotoxicity is believed to be caused by oxidative stress and endoplasmic reticulum (ER) stress but the mechanism by which those stresses lead to neuronal loss is unclear. Here, by utilizing the ER stress-activated indicator (ERAI) system, we investigated the signaling alterations in the unfolded protein response (UPR) prior to neuronal apoptosis in the mouse brain. In ERAI transgenic mice exposed to MeHg (25 mg/kg, S.C.), the ERAI signal, which indicates activation of the cytoprotective pathway of the UPR, was detected in the brain. Interestingly, detailed ex vivo analysis showed that the ERAI signal was localized predominantly in neurons. Time course analysis of MeHg exposure (30 ppm in drinking water) showed that whereas the ERAI signal was gradually attenuated at the late phase after increasing at the early phase, activation of the apoptotic pathway of the UPR was enhanced in proportion to the exposure time. These results suggest that MeHg induces not only ER stress but also neuronal cell death via a UPR shift. UPR modulation could be a therapeutic target for treating neuropathy caused by electrophiles similar to MeHg.
甲基汞（MeHg）是一种环境毒物，可诱导神经元细胞死亡并损伤大脑的特定区域。据信，MeHg 介导的神经毒性是由氧化应激和内质网（ER）应激引起的，但这些应激导致神经元丧失的机制尚不清楚。在这里，我们通过利用内质网应激激活指标（ERAI）系统，研究了在小鼠大脑神经元凋亡之前 UPR 中未折叠蛋白反应（UPR）的信号改变。在暴露于 MeHg（25mg/kg，S.C.）的 ERAI 转基因小鼠中，检测到指示 UPR 细胞保护途径激活的 ERAI 信号。有趣的是，详细的离体分析表明，ERAI 信号主要定位于神经元。MeHg 暴露的时间过程分析（饮用水中 30ppm）表明，尽管 ERAI 信号在早期增加后在晚期逐渐减弱，但 UPR 凋亡途径的激活与暴露时间成正比。这些结果表明，MeHg 不仅诱导 ER 应激，还通过 UPR 转移诱导神经元细胞死亡。UPR 调节可能是治疗类似于 MeHg 的亲电子化合物引起的神经病变的治疗靶点。
