Mechanistic Insights Into Cholinergic, Neurotrophic, and Glutamatergic Pathways in Fluoride Neurotoxicity

This study investigated the molecular and histopathological mechanism(s) contributing to fluoride induced neurotoxicity in male and female rats, focusing on dysregulation of cholinergic, neurotrophic, glutamatergic pathways and the accompanying structural alterations in the brain tissue. Forty male and female rats were administered sodium fluoride in water at concentrations (ppm) of 0.5 (control), 50 (low), 150 (medium), and 300 (high dose) for 90 days. The mRNA expression levels of cholinergic markers (acetylcholinesterase-AChE, butyrylcholinesterase-BChE), the brain derived neurotrophic factor (BDNF) and the metabotropic glutamate receptor 5 (mGluR5) were quantified using RT-qPCR, and histopathological alterations of different regions of brain was assessed by hematoxylin and eosin (H&E) staining. Chronic NaF exposure resulted dose-dependent neurodegenerative changes in the hippocampal CA1, CA3, and dentate gyrus (DG) regions, characterized by neuronal shrinkage, pyknosis, vacuolization, and spongiosis. The histopathological lesions were more pronounced in male rats than in females. Chronic fluoride exposure also resulted in a dose-dependent decrease of blood AChE (1.09-0.604 mU/mL) and BChE (0.575-0.311 mU/mL) activities in both genders. Furthermore, chronic NaF exposure significantly down-regulated the expression of AChE, BDNF, and mGluR5 in fluoride-treated groups compared to controls. These findings demonstrate that prolonged NaF exposure disrupts cholinergic, neurotrophic, and glutamatergic signaling pathways, thereby contributing to neurotoxicity and potential neurodegeneration. Collectively, this mechanistic evidence underlines the importance of public health to monitor environmental fluoride exposure and highlight the potential for therapeutic strategies targeting cholinergic, neurotrophic and glutamatergic pathways to mitigate fluoride-induced neuronal injury.