Androgen Receptor Involvement in Rat Amelogenesis: An Additional Way for Endocrine-Disrupting Chemicals to Affect Enamel Synthesis

Abstract

Endocrine-disrupting chemicals (EDCs) that interfere with the steroid axis can affect amelogenesis, leading to enamel hypomineralization similar to that of molar incisor hypomineralization, a recently described enamel disease. We investigated the sex steroid receptors that may mediate the effects of EDCs during rat amelogenesis. The expression of androgen receptor (AR), estrogen receptor (ER)-α, and progesterone receptor was dependent on the stage of ameloblast differentiation, whereas ERβ remained undetectable. AR was the only receptor selectively expressed in ameloblasts involved in final enamel mineralization. AR nuclear translocation and induction of androgen-responsive element-containing promoter activity upon T treatment, demonstrated ameloblast responsiveness to androgens. T regulated the expression of genes involved in enamel mineralization such as KLK4, amelotin, SLC26A4, and SLC5A8 but not the expression of genes encoding matrix proteins, which determine enamel thickness. Vinclozolin and to a lesser extent bisphenol A, two antiandrogenic EDCs that cause enamel defects, counteracted the actions of T. In conclusion, we show, for the first time, the following: 1) ameloblasts express AR; 2) the androgen signaling pathway is involved in the enamel mineralization process; and 3) EDCs with antiandrogenic effects inhibit AR activity and preferentially affect amelogenesis in male rats. Their action, through the AR pathway, may specifically and irreversibly affect enamel, potentially leading to the use of dental defects as a biomarker of exposure to environmental pollutants. These results are consistent with the steroid hormones affecting ameloblasts, raising the issue of the hormonal influence on amelogenesis and possible sexual dimorphism in enamel quality.

Expression of Steroid Receptors in Ameloblasts during Amelogenesis in Rat Incisors

“…Concerning the AR, it has already been detected in dental pulp cells (Dale et al, 2002; Inaba et al, 2013). In addition, our past work, as well as the present study, show that AR expression in the maturation-stage ameloblasts which is higher than in the secretion-stage and mesenchymal cells, suggesting a selective role of androgens in enamel final mineralization (Jedeon et al, 2016b). Testosterone is able to modulate the expression of enamel key genes present in maturation-stage ameloblasts such as SLC26A4 (or pendrin) and KLK4 (Jedeon et al, 2016b).…”

“…In addition, our past work, as well as the present study, show that AR expression in the maturation-stage ameloblasts which is higher than in the secretion-stage and mesenchymal cells, suggesting a selective role of androgens in enamel final mineralization (Jedeon et al, 2016b). Testosterone is able to modulate the expression of enamel key genes present in maturation-stage ameloblasts such as SLC26A4 (or pendrin) and KLK4 (Jedeon et al, 2016b). Moreover, the higher level of AR expression in dental epithelium than in testis suggests that ameloblasts are responsive to plasmatic testosterone and thus androgen regulation of final enamel mineralization.…”

“…BPA exerts its anti-androgenic effects by preventing AR activation and lowering the levels of endogenous testosterone. BPA and other anti-androgenic EDCs may exert their anti-androgenic effects on final enamel mineralization through the AR expressed in maturation-stage ameloblasts (Jedeon et al, 2016b). Thus, the high testosterone levels in males following the birth, concomitant with amelogenesis, may cause a sexual dimorphism in enamel quality.…”

Disruption of Steroid Axis, a New Paradigm for Molar Incisor Hypomineralization (MIH)

“…Except PPARγ and ERβ, rodent ameloblasts express all these receptors and their expression levels vary depending on the ameloblast differentiation stage (Houari et al, 2016; Figure 1). Furthermore, we have shown that ERα is involved in pre-ameloblast proliferation (Jedeon et al, 2014b), and AR in the enamel terminal mineralization process (Jedeon et al, 2016b). Thus, mediated by these receptors, EDCs such as BPA and vinclozolin may disrupt amelogenesis.…”

“…On the other hand, premature babies were reported to be contaminated with BPA and phthalates essentially due to medical devices (Calafat et al, 2009; Duty et al, 2013). And, both class of EDCs act via steroid receptors, ERs and AR, reported to modulate enamel key genes like KLK4 (Jedeon et al, 2016b). …”