Integrating network toxicology, transcriptomics and experimental validation to elucidate the potential mechanisms of...

Fluoride is a ubiquitous environmental contaminant with potential neurotoxicity. However, the molecular mechanisms underlying neurotoxicity from long-term exposure to environmentally relevant concentrations of fluoride remain incompletely understood. This study established a fluoride exposure model in zebrafish at environmentally relevant concentrations and employed an integrated approach combining network toxicology, transcriptomics, and molecular biology techniques to identify key signaling pathways underlying fluoride-induced brain tissue damage in zebrafish. The findings reveal that environmental fluoride exposure impairs swimming ability in zebrafish and induces significant brain pathology. The underlying mechanism involves fluoride activation of the TLR4/NF-κB pathway, which upregulates NLRP3 inflammasome expression. This will cause neurons to undergo pyroptosis and trigger severe neuroinflammation. Collectively, these changes result in neurological behavioral deficits in zebrafish. These findings demonstrate that the TLR4/NF-κB/NLRP3 axis constitutes a key signaling pathway for fluoride-induced neuronal pyroptosis and neurobehavioral impairment, providing crucial mechanistic insights for assessing the risks of environmental fluoride exposure to neurological health.