Abstract

Fluoride ions are highly reactive, and their incorporation in forming dental enamel at low concentrations promotes mineralization. In contrast, excessive fluoride intake causes dental fluorosis, visually recognizable enamel defects that can increase the risk of caries. To investigate the molecular bases of dental fluorosis, we analyzed the effects of fluoride exposure in enamel cells to assess its impact on Ca²⁺ signaling. Primary enamel cells and an enamel cell line (LS8) exposed to fluoride showed decreased internal Ca²⁺ stores and store-operated Ca²⁺ entry (SOCE). RNA-sequencing analysis revealed changes in gene expression suggestive of endoplasmic reticulum (ER) stress in fluoride-treated LS8 cells. Fluoride exposure did not alter Ca²⁺ homeostasis or increase the expression of ER stress–associated genes in HEK-293 cells. In enamel cells, fluoride exposure affected the functioning of the ER-localized Ca²⁺ channel IP₃R and the activity of the sarco-endoplasmic reticulum Ca²⁺-ATPase (SERCA) pump during Ca²⁺ refilling of the ER. Fluoride negatively affected mitochondrial respiration, elicited mitochondrial membrane depolarization, and disrupted mitochondrial morphology. Together, these data provide a potential mechanism underlying dental fluorosis.

How too much fluoride derails dentition

Excessive fluoride ingestion during childhood results in defective tooth enamel mineralization, which can lead to dental problems later in life. Aulestia et al. investigated the molecular mechanisms underlying fluorosis in enamel-forming cells isolated from rats and in an enamel cell line. Exposure of enamel cells to fluoride resulted in decreases in ER Ca²⁺ content and store-operated Ca²⁺ entry into the ER, reduced the expression of genes encoding ER stress–response proteins, and resulted in mitochondrial dysfunction. These effects were not seen in HEK-293 cells (which are derived from kidney epithelium). These data may explain how fluorosis affects Ca²⁺ homeostasis in enamel-forming cells and highlight cell type–specific stress responses.

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* Supplementary Materials at http://fluoridealert.org/wp-content/uploads/aulestia-2020.supplementary-materials.pdf

* Original abstract online at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173621/

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