AUTHOR=Williams Rebecca , Perez Vidal A. , Mangum Jonathan E. , Hubbard Michael J. TITLE=Pathogenesis of Molar Hypomineralisation: Hypomineralised 6-Year Molars Contain Traces of Fetal Serum Albumin JOURNAL=Frontiers in Physiology VOLUME=11 YEAR=2020 URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2020.00619 DOI=10.3389/fphys.2020.00619 ISSN=1664-042X ABSTRACT=

Molar Hypomineralisation (MH) is gaining cross-sector attention as a global health problem, making deeper enquiry into its prevention a research priority. However, causation and pathogenesis of MH remain unclear despite 100 years of investigation into “chalky” dental enamel. Contradicting aetiological dogma involving disrupted enamel-forming cells (ameloblasts), our earlier biochemical analysis of chalky enamel opacities implicated extracellular serum albumin in enamel hypomineralisation. This study sought evidence that the albumin found in chalky enamel reflected causal events during enamel development rather than later association with pre-existing enamel porosity. Hypothesising that blood-derived albumin infiltrates immature enamel and directly blocks its hardening, we developed a “molecular timestamping” method that quantifies the adult and fetal isoforms of serum albumin ratiometrically. Applying this novel approach to 6-year molars, both isoforms of albumin were detectable in 6 of 8 chalky opacities examined (corresponding to 4 of 5 cases), indicating developmental acquisition during early infancy. Addressing protein survival, in vitro analysis showed that, like adult albumin, the fetal isoform (alpha-fetoprotein) bound hydroxyapatite avidly and was resistant to kallikrein-4, the pivotal protease involved in enamel hardening. These results shift primary attention from ameloblast injury and indicate instead that an extracellular mechanism involving localised exposure of immature enamel to serum albumin constitutes the crux of MH pathogenesis. Together, our pathomechanistic findings plus the biomarker approach for onset timing open a new direction for aetiological investigations into the medical prevention of MH.