Barrier formation: potential molecular mechanism of enamel fluorosis

J Dent Res. 2014 Jan;93(1):96-102. doi: 10.1177/0022034513510944. Epub 2013 Oct 29.


Enamel fluorosis is an irreversible structural enamel defect following exposure to supraoptimal levels of fluoride during amelogenesis. We hypothesized that fluorosis is associated with excess release of protons during formation of hypermineralized lines in the mineralizing enamel matrix. We tested this concept by analyzing fluorotic enamel defects in wild-type mice and mice deficient in anion exchanger-2a,b (Ae2a,b), a transmembrane protein in maturation ameloblasts that exchanges extracellular Cl(-) for bicarbonate. Defects were more pronounced in fluorotic Ae2a,b (-/-) mice than in fluorotic heterozygous or wild-type mice. Phenotypes included a hypermineralized surface, extensive subsurface hypomineralization, and multiple hypermineralized lines in deeper enamel. Mineral content decreased in all fluoride-exposed and Ae2a,b(-/-) mice and was strongly correlated with Cl(-). Exposure of enamel surfaces underlying maturation-stage ameloblasts to pH indicator dyes suggested the presence of diffusion barriers in fluorotic enamel. These results support the concept that fluoride stimulates hypermineralization at the mineralization front. This causes increased release of protons, which ameloblasts respond to by secreting more bicarbonates at the expense of Cl(-) levels in enamel. The fluoride-induced hypermineralized lines may form barriers that impede diffusion of proteins and mineral ions into the subsurface layers, thereby delaying biomineralization and causing retention of enamel matrix proteins.

Keywords: Slc4a2; chloride; hypermineralization; hypomineralization; pH regulation; quantitative X-ray microanalysis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Ameloblasts / drug effects
  • Ameloblasts / pathology
  • Amelogenesis / drug effects
  • Amelogenesis / genetics
  • Animals
  • Bicarbonates / analysis
  • Chloride-Bicarbonate Antiporters / analysis
  • Chloride-Bicarbonate Antiporters / drug effects*
  • Chloride-Bicarbonate Antiporters / genetics
  • Chlorides / analysis
  • Coloring Agents
  • Dental Enamel / chemistry
  • Dental Enamel / drug effects
  • Dental Enamel / pathology
  • Dental Enamel Proteins / analysis
  • Diffusion
  • Female
  • Fluorides / adverse effects*
  • Fluorosis, Dental / etiology*
  • Fluorosis, Dental / genetics
  • Fluorosis, Dental / pathology
  • Heterozygote
  • Homozygote
  • Hydrogen-Ion Concentration
  • Indicators and Reagents
  • Mice
  • Mice, Knockout
  • Minerals / analysis
  • Phenotype
  • Rats
  • Rats, Wistar
  • Tooth Calcification / drug effects
  • Tooth Calcification / genetics


  • Bicarbonates
  • Chloride-Bicarbonate Antiporters
  • Chlorides
  • Coloring Agents
  • Dental Enamel Proteins
  • Indicators and Reagents
  • Minerals
  • enamel matrix proteins
  • Fluorides