Metabolic shift as a compensatory response to impaired hippocampal neurogenesis after developmental exposure to sodium fluoride in rats

Abstract

Fluoride affects neurodevelopment in children. In this study, we examined the effects of developmental exposure to sodium fluoride (NaF) on hippocampal neurogenesis in rats. Dams were given drinking water containing NaF at 0 (untreated controls), 30 or 100 ppm from gestational day 6 to day 21 post-delivery upon weaning, and offspring were reared until postnatal day (PND) 77. On PND 21, NaF at 100 ppm altered the numbers in subpopulations of granule cell lineages, including a decrease in type-3 neural progenitor cells (NPCs), as well as a compensatory increase in type-1 neural stem cells (NSCs) and type-2a NPCs. NaF exposure tended to increase GluR2⁺ mossy cells in the hilus of the dentate gyrus (DG) in a dose-dependent manner, suggesting that NaF exposure induces a compensatory neurogenic response. NaF also caused a dose-dependent increase in ARC⁺ granule cells, and it upregulated Ptgs2 in the DG at 100 ppm, suggesting that NaF exposure increases synaptic plasticity in granule cells. NaF at 100 ppm upregulated granule cell lineage marker genes (Nes, Eomes and Rbfox3) and an anti-apoptotic gene (Bcl2), suggesting ameliorating responses against the impaired neurogenesis during NaF exposure. Moreover, NaF at 100 ppm downregulated oxidative phosphorylation-related genes (Atp5f1b and Sdhd) and upregulated a glycolysis-related gene (Hk3), suggesting a metabolic shift in cells undergoing neurogenesis. By PND 77, the changes in granule cell lineages were no longer detected, and GABAergic interneuron marker genes (Calb2 and Reln) were upregulated, suggesting a persistent protective response in granule cell lineages. Together, these findings suggest that developmental NaF exposure causes transient disruption of hippocampal neurogenesis, which in turn induces a metabolic shift as a compensatory response.