Mechanism of fluoride-induced neurotoxicity: Dissecting a multi-target organelle signaling network

Fluoride is a widely distributed environmental contaminant, and excessive exposure has been associated with adverse neurological outcomes. However, the underlying mechanisms of fluoride-induced neurotoxicity remain incompletely understood. In this review, we integrate current evidence to propose a multilevel, multi-target mechanistic framework of fluoride-induced neurotoxicity. We highlight that fluoride exerts neurotoxic effects not via isolated pathways but through the coordinated disruption of multiple organelles, particularly mitochondria, the endoplasmic reticulum (ER), and lysosomes. Dysfunction of these organelles converges via inter-organelle crosstalk, leading to impaired energy metabolism, calcium dyshomeostasis, defective protein folding, and impaired lysosomal degradation. We further identify oxidative stress as a central integrative relay and amplifier, linking organelle dysfunction to downstream pathological processes, including neuroinflammation, neuronal cell death, and synaptic impairment. Emerging evidence also suggests that epigenetic reprogramming, including aberrant DNA methylation and non-coding RNA network remodeling, contributes to long-term gene expression changes. These molecular and cellular disturbances ultimately converge on impaired neurogenesis, synaptic dysfunction, and cognitive deficits. Finally, we discuss current limitations, including the dependence on high-dose experimental models, and propose future directions emphasizing multi-target strategies to restore organelle homeostasis and redox balance. This integrative framework provides a comprehensive perspective on fluoride-induced neurotoxicity and may facilitate the development of more effective intervention strategies.