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Metabolic shift as a compensatory response to impaired hippocampal neurogenesis after developmental exposure to sodium fluoride in rats.Abstract
Highlights
- NaF decreased type-3 NPCs, but increased type-1 NSCs and type-2a NPCs on weaning.
- NaF increased ARC+ granule cells and upregulated Ptgs2 in the DG on weaning.
- NaF upregulated granule cell lineage and anti-apoptosis markers on weaning.
- NaF altered expression of OXPHOS and glycolysis-related genes on weaning.
- NaF-induced changes in granule cell lineages disappeared by adulthood.
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.
Introduction
… Several recent studies have demonstrated neurotoxic effects of fluoride, including cognitive dysfunction and anxiety and depression-like behaviors in mice (Liu et al., 2014), that preferentially target the hippocampus (National Research Council NRC, 2006). Developmental exposure to fluoride in rats impaired hippocampal synaptogenesis by disrupting the brain-derived neurotrophic factor–tyrosine kinase B signaling pathway (Chen et al., 2018), and caused degeneration of hippocampal neurons by suppression of glucose utilization (Jiang et al., 2014). In addition, because the blood–brain barrier is immature in fetuses and infants, the risk of neurotoxicity from fluoride exposure during development is a major concern (Grandjean and Landrigan, 2006). Fluoride concentrations in fluoridated public water supplies in the United States have been reported to range from 0.7 to 1.2 mg/L (National Research Council NRC, 2006). However, when groundwater with high fluoride concentrations is used for drinking, residents may be exposed to high concentrations of fluoride. In Shanxi, China, where fluoride concentrations in groundwater are high, drinking water has been reported to contain up to 11.5 mg/L of fluoride (Choi et al., 2012). Notably, in regions of China with high fluoride levels in drinking water, such as Shanxi and Shandong, epidemiological studies have reported decreased intelligence in children (Choi et al., 2012).
The mammalian hippocampal dentate gyrus (DG) is a unique brain region that continues to undergo neurogenesis after birth. This neurogenesis occurs in the subgranular zone (SGZ) of the DG and has been suggested to play an important role in neural plasticity and hippocampus-specific functions such as learning, memory and emotional regulation in the adult brain (Epp et al., 2013). Hippocampal neurogenesis is a complex process that starts with type-1 neural stem cells (NSCs), which exhibit a radial glial morphology in the SGZ. Type-1 NSCs slowly differentiate into intermediate neural progenitor cells (NPCs), which in turn differentiate into type-2a, type-2b and type-3 NPCs. Type-3 NPCs then transition through the immature granule cell stage before differentiating into mature granule cells that integrate into the granule cell layer (GCL; Hodge et al., 2008). This process is regulated by a complex series of interactions, with ?-aminobutyric acid (GABA)-ergic interneurons in the DG hilus playing a key regulatory role in neurogenesis in the SGZ (Freund and Buzsáki, 1996). Neurogenesis is also regulated by neurotransmitter signaling by glutamatergic neurons that control NPC proliferation and differentiation (Jansson and Åkerman, 2014).
Because adult neurogenesis in the hippocampus is a highly complex process involving all stages of neuronal development, developmental neurotoxins often affect neurogenesis in the DG. In particular, the self-renewal of NSCs, proliferation and migration of NPCs, neuritogenesis, synaptogenesis and myelinogenesis are thought to be highly sensitive to chemical toxins. Therefore, exposure during the developmental period, when neurogenesis is active, followed by analysis of the DG may be useful for evaluating the developmental neurotoxicity (DNT) of a chemical. The Organization for Economic Co-operation and Development (OECD) has established guidelines for DNT testing in rodents; Test No. 426: Developmental Neurotoxicity Study (Organization for Economic Co-operation and Development OECD, 2007). These guidelines recommend the use of rats as experimental animals and the period from implantation [gestational day (GD) 6] to the end of nursing, on postnatal day (PND) 21, for the administration time window of the test substance. We have conducted developmental exposure studies to detect DNT following the exposure scheme of OECD Test Guidelines 426 in rats using various substances. We examined substances, such as sterigmatocystin, ethanol, lead acetate, glyphosate and glyphosate-based herbicide, which may be developmentally neurotoxic when ingested orally. We found that these substances impaired neurogenesis in the hippocampus by acting on cholinergic signaling, glutamatergic signaling and synaptic plasticity (Takashima et al., 2021, Takahashi et al., 2021, Yamashita et al., 2021, Ojiro et al., 2023).
In the present study, we investigated the effects of developmental exposure to sodium fluoride (NaF) on hippocampal neurogenesis in rat offspring at the end of exposure, as well as its effects after maturation, according to the exposure scheme of the OECD guidelines for the testing of chemicals (Test No. 426; Organization for Economic Co-operation and Development OECD, 2007). We examined the distribution of granule cell lineages, cell proliferation, apoptosis and synaptic plasticity in the SGZ/GCL of the DG during weaning and adult stages. We also examined changes in the distribution of GABAergic interneuron subpopulations, mossy cell populations, astrocytes and microglial populations in the DG hilus. Changes in gene expression associated with inhibition of neurogenesis and oxidative stress levels were also examined in the hippocampus.
https://www.sciencedirect.com/science/article/abs/pii/S0065128124000722?via%3Dihub