The regulatory role of lncRNA-LOC680225 in fluoride-induced neurotoxicity: Insights into the miR-194–5p/Slc5a7 signaling axis

Our previous epidemiological studies showed that low-to-moderate fluoride exposure induces cholinergic dysfunction in children, but the underlying mechanisms remain unclear. Here, transcriptome sequencing of fluoride-exposed rat hippocampal tissues identified altered expression of solute carrier family 5 member 7 (Slc5a7), which encodes choline transporter 1 (Cht1), long non-coding RNA (lncRNA)LOC680225, and microRNA (miRNA) miR-194-5p. In vivo and in vitro assays confirmed that fluoride disrupted the cholinergic system and synaptic plasticity, decreased acetylcholine (ACh) content, downregulated Slc5a7, choline acetyltransferase (ChAT), postsynaptic density protein-95 (PSD-95), and synapsin-1, and increased acetylcholinesterase (AChE) expression. Fluoride also suppressed LOC680225 while elevating miR-194-5p in rat hippocampus and PC12 cells. LOC680225 overexpression or miR-194-5p inhibition partially rescued fluoride-mediated Cht1 reduction, neuronal apoptosis, and cell viability loss, whereas miR-194-5p overexpression aggravated cellular injury. Luciferase assays validated that LOC680225 and Slc5a7 are direct targets of miR-194-5p. Collectively, our findings support a potential ceRNA regulatory network, in which LOC680225 sponges miR-194-5p to modulate Slc5a7 expression. The LOC680225/miR-194-5p/Slc5a7 signaling axis represents one critical regulatory pathway underlying fluoride-induced neurotoxicity rather than the exclusive mechanism, providing novel insights into the molecular basis of fluoride-mediated cholinergic and synaptic dysfunction.