Deng Ping, Zhang Huadong, Wang Liting, Jie Sheng, Zhao Qi, Chen Fengqiong, Yue Yang, Wang Hui, Tian Li, Xie Jia, Chen Mengyan, Luo Yan, Yu Zhengping, Pi Huifeng, Zhou Zhou
Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Third Military Medical University, Chongqing 400038, China.
Chongqing Center for Disease Control and Prevention, Chongqing 400042, China.
Sci Total Environ. 2023 Feb 1;858(Pt 3):159950. doi: 10.1016/j.scitotenv.2022.159950. Epub 2022 Nov 3.
Cadmium (Cd), a ubiquitous environmental contaminant, is deemed a possible aetiological cause of cognitive disorders in humans. Nevertheless, the exact mechanism by which chronic exposure to Cd causes neurotoxicity is not fully understood. In this study, mouse neuroblastoma cells (Neuro-2a cells) and primary hippocampal neurons were exposed to low-dose (1, 2, and 4 μM for Neuro-2a cells or 0.5, 1, and 1.5 μM for hippocampal neurons) cadmium chloride (CdCl) for 72 h (h), and male mice (C57BL/6J, 8 weeks) were orally administered CdCl (0.6 mg/L, approximately equal to 2.58 μg/kg·bw/d) for 6 months to investigate the effects and mechanism of chronic Cd-induced neurotoxicity. Here, chronic exposure to Cd impaired mitochondrial function by promoting excess reactive oxygen species (ROS) production, altering mitochondrial membrane potential (Δψm) and reducing adenosine triphosphate (ATP) content, contributing to neuronal cell death. Specifically, microarray analysis revealed that the long noncoding RNA Gm10532 (lnc-Gm10532) was most highly expressed in Neuro-2a cells exposed to 4 μM CdCl for 72 h compared with controls, and inhibition of lnc-Gm10532 significantly antagonized CdCl-induced mitochondrial dysfunction and neurotoxicity. Mechanistically, lnc-Gm10532 increased Fission 1 (FIS1) expression and mitochondrial fission by recruiting the m6A writer methyltransferase-like 14 (METTL14) and enhancing m6A modification of Fis1 mRNA. Moreover, lnc-Gm10532 was also required for chronic Cd-induced mitochondrial dysfunction and memory deficits in a rodent model. Therefore, data of this study reveal a new epigenetic mechanism of chronic Cd neurotoxicity.
镉（Cd）是一种普遍存在的环境污染物，被认为是人类认知障碍可能的病因。然而，长期接触镉导致神经毒性的确切机制尚未完全明确。在本研究中，将小鼠神经母细胞瘤细胞（Neuro-2a细胞）和原代海马神经元暴露于低剂量（Neuro-2a细胞为1、2和4 μM，海马神经元为0.5、1和1.5 μM）的氯化镉（CdCl）中72小时，并且对雄性小鼠（C57BL/6J，8周龄）口服给予CdCl（0.6 mg/L，约等于2.58 μg/kg·bw/d）6个月，以研究慢性镉诱导神经毒性的作用和机制。在此，长期接触镉通过促进过量活性氧（ROS）生成、改变线粒体膜电位（Δψm）和降低三磷酸腺苷（ATP）含量而损害线粒体功能，导致神经元细胞死亡。具体而言，微阵列分析显示，与对照组相比，在暴露于4 μM CdCl 72小时的Neuro-2a细胞中，长链非编码RNA Gm10532（lnc-Gm10532）表达最高，并且抑制lnc-Gm10532可显著拮抗CdCl诱导的线粒体功能障碍和神经毒性。机制上，lnc-Gm10532通过募集m6A书写器样甲基转移酶14（METTL14）并增强Fis1 mRNA的m6A修饰来增加裂变1（FIS1）表达和线粒体裂变。此外，lnc-Gm10532也是啮齿动物模型中慢性镉诱导的线粒体功能障碍和记忆缺陷所必需的。因此，本研究数据揭示了慢性镉神经毒性的一种新的表观遗传机制。
