Melatonin protects against fluoride-induced developmental neurotoxicity by alleviating abnormal mitophagy and apoptosis via the PINK1/Parkin pathway

Feb 3, 2026Ecotoxicology and environmental safety

Melatonin may protect developing brains from fluoride damage by reducing harmful cell cleanup and death through a specific protective pathway

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Abstract

Exposure to sodium fluoride (NaF) impaired spatial learning and memory performance in offspring rats.

Fluoride exposure initiated mitophagy but disrupted autophagic flux, leading to an accumulation of autophagosomes.
Increased levels of markers associated with mitochondrial dysfunction and apoptosis were observed in the brain tissues of fluoride-exposed rats.
Melatonin treatment improved autophagic flux and reduced neurotoxic effects by activating the PINK1/Parkin pathway.
The findings suggest that fluoride-induced developmental neurotoxicity may be linked to impaired mitophagy and increased neuronal apoptosis.

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Fluoride induces developmental neurotoxicity, although the underlying mechanisms remain unclear. This study aimed to elucidate the roles of mitophagy and apoptosis mediated by the PTEN-induced kinase 1 (PINK1)/E3 ubiquitin-protein ligase Parkin (Parkin) pathway in fluoride-induced developmental neurotoxicity, as well as the protective effects of melatonin. A sodium fluoride (NaF) exposure model with melatonin intervention was established in F₁-generation Sprague-Dawley (SD) rats. Exposure to NaF impaired spatial learning and memory performance in offspring rats, promoted mitophagy initiation, but disrupted autophagic flux, resulting in accumulation of autophagosomes and subsequent neuronal apoptosis-evidenced by elevated levels of PINK1, Parkin, translocase of outer mitochondrial membrane 20 (TOMM20), Voltage-dependent anion channel (VDAC1), OMA1 zinc metallopeptidase (OMA1), microtubule-associated protein 1 light chain 3-II (LC3-II), sequestosome 1 (SQSTM1/p62), cleaved poly (ADP-ribose) polymerase (cleaved PARP), and BCL-2 Associated X protein (BAX), reduced levels of B-cell lymphoma 2 (Bcl-2) in brain tissues. Notably, melatonin treatment attenuated NaF-induced neurotoxicity by enhancing mitophagic clearance via activation of the PINK1/Parkin pathway, thereby restoring autophagic flux and suppressing apoptotic cell death. Collectively, our findings demonstrate that NaF activates the PINK1/Parkin-mediated mitophagy pathway; however, incomplete autophagic degradation leads to mitochondrial dysfunction and neuronal apoptosis, contributing to developmental neurotoxicity. Importantly, melatonin mitigates these adverse effects, suggesting its potential as a therapeutic agent for preventing fluoride-induced neurodevelopmental impairment through modulation of the PINK1/Parkin signaling axis.

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Melatonin protects against fluoride-induced developmental neurotoxicity by alleviating abnormal mitophagy and apoptosis via the PINK1/Parkin pathway

Abstract

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