Effects of long-term fluoride exposure on cognitive ability and the underlying mechanisms: Role of autophagy and its association with apoptosis

Autophagy and apoptosis are two important cellular processes that are crucial for neurodevelopment. Evidence shows that apoptosis is implicated in fluoride neurotoxicity. However, the biological roles of autophagy, especially its interplay with apoptosis in the neurotoxicity induced by long-term fluoride exposure remain unclear. Here we present in vivo and in vitro evidence that fluoride-induced defective autophagy elicits excessive apoptosis, thus inducing neurotoxicity. Using Sprague-Dawley rats exposed to sodium fluoride from 60 days before pregnancy until 6 months post-delivery as in vivo model, we showed that fluoride impaired the learning and memory abilities of offspring rats, with decreased neuronal number, suppressed autophagy and enhanced apoptosis in hippocampus. These results were validated in human neuroblastoma SH-SY5Y cells in vitro. Mechanistically, mTOR signaling, responsible for autophagy induction, was activated in vivo and in vitro, and targeting inhibition of mTOR with rapamycin protected SH-SY5Y cells from defective autophagy and excessive apoptosis, thereby enhancing neuronal survival. Furthermore, circulating levels of autophagy markers were low in children with higher fluoride body burden and lower intelligence quotient scores. Collectively, our results suggest that defective autophagy plays a pivotal role in fluoride neurotoxicity, and mTOR might be a promising target for the prevention and treatment of fluoride neurotoxicity.