<p class="first" id="d2611282e132">Fluoride is becoming an ineluctable environmental
pollutant and its longterm exposure
would cause fluorosis and irreversible brain damage, but the molecular mechanisms
remain far from fully understood. In the present study, we firstly evaluated the glycogen
synthase kinase 3β (GSK-3β)/β-catenin pathway in the hippocampus of rats exposed to
fluoride, given the well-established role of GSK-3β/β-catenin pathway in neuronal
death and survival. Our data showed that sustained exposure to 50 mg/L and 100 mg/L
NaF in drinking water dose-dependently induced neuronal loss and apoptosis in rat
hippocampus. Neurogenesis was also weakened by fluoride administration in the hippocampal
dentate gyrus region. Additionally, the synaptic markers, synaptophysin (SYP) and
post-synaptic density 95 (PSD95) protein levels, were decreased by 100 mg/L NaF treatment,
whereas 50 mg/L NaF only reduced SYP expression, indicating a compromised synaptic
function. We further demonstrated that NaF, especially the higher dose, induced GSK-3β
activity, with decreased inactive phosphorylated GSK-3β levels and increased GSK-3β,
the active form of the kinase. Correspondingly, downstream β-catenin signaling was
undermined by NaF treatment as evidenced by the fact that both two doses of NaF decreased
nucleus β-catenin status and the higher dose of NaF also reduced cytoplasmic β-catenin
protein expression. Taken together, the present study firstly showed the aberrant
changes of GSK-3β/β-catenin signaling in the fluoride-exposed brain, highlighting
the involvement of GSK-3β/β-catenin signaling in the fluoride-induced neurotoxicity.
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