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.
