Retinoic Acid Excess Impairs Amelogenesis Inducing Enamel Defects

Abstract

Abnormalities of enamel matrix proteins deposition, mineralization, or degradation during tooth development are responsible for a spectrum of either genetic diseases termed Amelogenesis imperfecta or acquired enamel defects. To assess if environmental/nutritional factors can exacerbate enamel defects, we investigated the role of the active form of vitamin A, retinoic acid (RA). Robust expression of RA-degrading enzymes Cyp26b1 and Cyp26c1 in developing murine teeth suggested RA excess would reduce tooth hard tissue mineralization, adversely affecting enamel. We employed a protocol where RA was supplied to pregnant mice as a food supplement, at a concentration estimated to result in moderate elevations in serum RA levels. This supplementation led to severe enamel defects in adult mice born from pregnant dams, with most severe alterations observed for treatments from embryonic day (E)12.5 to E16.5. We identified the enamel matrix proteins enamelin (Enam), ameloblastin (Ambn), and odontogenic ameloblast-associated protein (Odam) as target genes affected by excess RA, exhibiting mRNA reductions of over 20-fold in lower incisors at E16.5. RA treatments also affected bone formation, reducing mineralization. Accordingly, craniofacial ossification was drastically reduced after 2 days of treatment (E14.5). Massive RNA-sequencing (RNA-seq) was performed on E14.5 and E16.5 lower incisors. Reductions in Runx2 (a key transcriptional regulator of bone and enamel differentiation) and its targets were observed at E14.5 in RA-exposed embryos. RNA-seq analysis further indicated that bone growth factors, extracellular matrix, and calcium homeostasis were perturbed. Genes mutated in human AI (ENAM, AMBN, AMELX, AMTN, KLK4) were reduced in expression at E16.5. Our observations support a model in which elevated RA signaling at fetal stages affects dental cell lineages. Thereafter enamel protein production is impaired, leading to permanent enamel alterations.

Undifferentiated spermatogonia regulateCyp26b1expression through NOTCH signaling and drive germ cell differentiation

“…Because both an excess and lack of RA are detrimental for most tissues, regulation of its concentration by CYP26 enzymes needs to be appropriately controlled (56)(57)(58)(59)(60). In the seminiferous epithelium, the major CYP26 enzyme that hydrolyzes RA is CYP26B1 (18,32).…”

Nanostructured Ti surfaces and retinoic acid/dexamethasone present a spatial framework for the maturation and amelogenesis of LS-8 cells

“…In addition, the timing and dose of RA/DEX treatment should be carefully determined, as improper or excessive RA/DEX stimulation reduces LS-8 cell viability and even impairs amelogenesis and, thereby, may result in enamel defects in vivo. 78 Future improvements to our research include methods to fabricate the biomimetic surface nanostructure of biomaterials with additional chemical-biological modifications, to regulate maturation of ameloblasts via precise biomolecules and other bioactive compounds. Furthermore, primary dental epithelium and ameloblasts should be employed in further research as they possess the full range of cellular functions.…”

La sphère orale, cible et marqueur de l’exposition environnementale

“…D'ailleurs, la synthèse de l'émail est modulée par les androgènes [21] et par la vitamine D [22]. Les rétinoïdes, métabolites de la vitamine A, ont également été impliqués dans la régulation de l'amélogenèse [23]. Il a en effet été montré que des souris exposées durant la vie foetale à un excès d'acide rétinoïque présentaient une quantité d'émail dentaire réduite et un os très altéré.…”