Prolonged fluoride exposure induces spatial-memory deficit and hippocampal dysfunction by inhibiting small heat shock protein 22 in mice

Millions of residents in areas with high-fluoride drinking water supply ingest excessive levels of fluoride for long periods. This study investigated the mechanisms and impacts of lifelong exposure to naturally occurring moderate–high-fluoride drinking water on spatial-memory function by studying mice in controlled experiments. Spatial-memory deficits and disorders of hippocampal neuronal electrical activity were observed in mice exposed to 25-ppm or 50-ppm-fluoride drinking water for 56 weeks, but not in adult or old mice exposed to 50 ppm fluoride for 12 weeks. Ultrastructural analysis showed severely damaged hippocampal mitochondria, evidenced by reduced mitochondrial membrane potential and ATP content. Mitochondrial biogenesis was impaired in fluoride-exposed mice, manifesting as a significantly reduced mtDNA content, mtDNA-encoded subunits mtND6 and mtCO1, and respiratory complex activities. Fluoride reduced expression of Hsp22, a beneficial mediator of mitochondrial homeostasis, and decreased levels of signaling for the PGC-1α/TFAM pathway—which regulates mitochondrial biogenesis—and the NF-κβ/STAT3 pathway—which regulates mitochondrial respiratory chain enzyme activity. Hippocampus-specific Hsp22-overexpression improved fluoride-induced spatial-memory deficits by activating the PGC-1α/TFAM and STAT3 signaling pathways, while Hsp22-silencing aggravated the deficits by inhibiting both pathways. Downregulation of Hsp22 plays a vital role in fluoride-induced spatial-memory deficits by impacting mtDNA-encoding subsets and mitochondrial respiratory chain enzyme activity. [Display omitted] •Long-term high-fluoride drinking water impacts spatial memory function in mice.•Fluoride induces downregulation of Hsp22 leading to mitochondrial damage.•The Hsp22 downregulation inhibits mitochondrial biogenesis by PGC-1α/TFAM pathway.•The downregulation inhibits mitochondrial enzyme activity by NF-κβ/STAT3 pathway.