Single-cell transcriptomic analysis reveals endothelial mitochondrial dysfunction and synaptic impairment underlying...

Although arsenic (As) exposure is a well- established neurotoxicant, the cellular heterogeneity and underlying molecular mechanisms remain incompletely understood. In the present study, scRNA-seq was performed on the hippocampi of mice exposed to 50 mg/L sodium arsenite (NaAsO₂) via drinking water for 12-weeks. Nine cell types were identified based on marker genes: namely Neuron, Oligodendrocyte, NSC, OPC, Microglia, Astrocyte, Fibroblast-like cells, Endothelial-cell and Pericyte. Among these endothelial cells exhibited the most pronounced transcriptomic alterations, characterized by mitochondrial energy metabolism dysfunction. Arsenic exposure may also impair neuronal synaptic transmission. Additionally, the oxidative phosphorylation (OXPHOS) pathway was aberrantly upregulated, and lipid metabolism was disturbed across multiple cell subtypes. Furthermore, arsenic exposure may altered hippocampal intercellular communication network by reshaping ligand-receptor interaction patterns. In vitro experiments further verified mitochondrial damage in both endothelial cells and neurons. At single-cell resolution, our study demonstrates that endothelial mitochondrial dysfunction, neuronal synaptic impairment, multicellular metabolic disorders, and imbalanced intercellular crosstalk collectively may mediate arsenic-induced hippocampal neurotoxicity. These findings provide novel insights into the cellular heterogeneity of arsenic neurotoxicity and establish a foundation for the early warning and targeted intervention of arsenic-related neural injuries. Notably, the protein-level validation was not performed and that the transcriptomic findings require further confirmation.