Hypomineralized teeth as biomarkers of exposure to Endocrine Disruptors

MIH for Molar Incisor Hypomineralization is a recently described pathology affecting around 18% of six year old children. Although a number of putative factors have been hypothesized, etiology of MIH remains unknown. The parallel increase of exposure to endocrine disruptors (EDs) and the prevalence of MIH led us to investigate a possible relationship between both events. Rats were orally exposed daily to low dose of bisphenol A (BPA), genistein, vinclozolin, alone (for BPA) or in combination, from the conception to the sacrifice, mimicking human environmental exposure. Macroscopic observation of male rat incisors showed that the phenotype induced by BPA was the most evident with 75% of rats presenting random opaque white spots comparable to those observed in human MIH, whereas only 50% of GEN and VINCLO treated rats shared similar phenotype. Human MIH and BPA treated rat teeth were analyzed in parallel by scanning electron microscopy (SEM) - Energy dispersive X-ray (EDX) and histology. Both of them exhibited the same hypomineralization phenotype. BPA targeted specifically the expression of two major enamel genes, enamelin and kallikrein 4 (Klk4) at the transcriptional level. Rat ameloblastic HAT-7 cells were stably transfected with plasmids containing KLK4 promoter, and treated with 1 nM BPA, 1 nM GEN, 1 nM VINCLO. BPA decreased both KLK4 mRNA level and KLK4 promoter activity. Conversely, GEN increased KLK4 expression whereas VINCLO had no effect on this gene, a possible reason for the lesser effect on enamel hypomineralization. Our data strongly support a role for EDs acting as BPA in MIH pathology. In conclusion, MIH teeth may represent a much needed early biomarker, easily accessible, for ED exposure in humans.