Unraveling the role of abnormal AMPK and CRMP-2 phosphorylation in developmental fluoride neurotoxicity: Implications for synaptic damage and neurological disorders

Abstract

Excessive fluoride exposure can be neurotoxic, although the exact mechanism remains unknown. This study aimed to investigate the neurotoxicity of continuous sodium fluoride exposure in offspring rats, focusing on the potential effects of fluoride exposure on hippocampal synaptic function and the role of AMPK and CRMP-2 in synaptic damage. We established an SD rat model of fluoride exposure (25, 50, and 100 mg/L NaF) and found that fluoride exposure damaged the learning and memory ability of F₁ generation rats and caused ultrastructural changes in the hippocampus. Additionally, after the proteomic and phosphoproteomic analysis of rat hippocampal tissues, the Gene Ontology analysis revealed that sodium fluoride was involved in the enrichment of neuronal differentiation, synaptic signaling, and cytoskeleton-related biological processes. The Kyoto Encyclopedia of Genes and Genomes analysis showed that differential genes were enriched in synapse-related signaling pathways. Thus, we screened three differentially expressed proteins related to synaptic function for validation. The Western blotting analysis showed that AMPK and CRMP-2 were hyperphosphorylated in the hippocampus of fluoride-exposed rats. Our study found that abnormal AMPK and CRMP-2 phosphorylation leads to synaptic damage. This may be an important cause of memory impairment in fluorosis, offering new insights into the mechanism of fluoride-induced neurotoxicity.