title: Barrier formation: potential molecular mechanism of enamel fluorosis.
abstract: 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.
authors.affiliation: Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam, University of Amsterdam, and MOVE Research Institute, VU University Amsterdam, Amsterdam, Netherlands.
authors.forename: D M
authors.initials: DM
authors.lastname: Lyaruu
authors.forename: J F
authors.initials: JF
authors.lastname: Medina
authors.forename: S
authors.initials: S
authors.lastname: Sarvide
authors.forename: T J M
authors.initials: TJ
authors.lastname: Bervoets
authors.forename: V
authors.initials: V
authors.lastname: Everts
authors.forename: P
authors.initials: P
authors.lastname: Denbesten
authors.forename: C E
authors.initials: CE
authors.lastname: Smith
authors.forename: A L J J
authors.initials: AL
authors.lastname: Bronckers
mesh_terms: D000565:Ameloblasts / Q000187:drug effects / Q000473:pathology; D000566:Amelogenesis / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001639:Bicarbonates / Q000032:analysis; D027963:Chloride-Bicarbonate Antiporters / Q000032:analysis / Q000187:drug effects* / Q000235:genetics; D002712:Chlorides / Q000032:analysis; D004396:Coloring Agents; D003743:Dental Enamel / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D003746:Dental Enamel Proteins / Q000032:analysis; D004058:Diffusion; D005260:Female; D005459:Fluorides / Q000009:adverse effects*; D009050:Fluorosis, Dental / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D006579:Heterozygote; D006720:Homozygote; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D051379:Mice; D018345:Mice, Knockout; D008903:Minerals / Q000032:analysis; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D014074:Tooth Calcification / Q000187:drug effects / Q000235:genetics
chemical_list: D001639:Bicarbonates; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides; D004396:Coloring Agents; D003746:Dental Enamel Proteins; D007202:Indicators and Reagents; D008903:Minerals; C109069:enamel matrix proteins; D005459:Fluorides
keywords: Slc4a2; chloride; hypermineralization; hypomineralization; pH regulation; quantitative X-ray microanalysis