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 (CdCl2) for 72 h (h), and male mice (C57BL/6J, 8 weeks) were orally administered CdCl2 (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 CdCl2 for 72 h compared with controls, and inhibition of lnc-Gm10532 significantly antagonized CdCl2-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.
Keywords: Environmental heavy metal; Epigenetic modification; Long noncoding RNAs; Memory disorder; Mitochondrial homeostasis.
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