COHR researchers found that fluoride targets Androgen Receptor (AR) and Progesterone Receptor (PR) driven Klk4 transcription in maturation ameloblasts

Kallikrein related peptidase 4 (KLK4) is thought to play important role in the final stage of dental enamel formation by allowing for enamel crystal growth. In humans having a mutated KLK4 gene and in mice lacking Klk4 expression, the enamel becomes hypomineralized or hypomatured with discoloration and/or flaking. Similar hypomature enamel is also seen in enamel fluorosis, suggesting decreased KLK4 activity in the fluorosed enamel.

Researchers from COHR recently found that fluoride targets steroid hormone receptors, androgen receptor (AR) and progesterone receptor (PR), driven Klk4 transcription in maturation ameloblasts, inhibiting the activation process of AR and PR regulated by Hsp90 (heat shock protein 90). These findings suggest an effect of fluoride on the molecular function of ameloblasts, which in turn, becomes an etiological factor for enamel fluorosis.

In recent years, dental endocrinology has been highlighted in association with the endocrine-disrupting chemicals (EDC, such as bisphenol A /BPA). Steroid hormone receptors possibly mediate the effect of EDC during enamel formation. Further investigation of AR and PR signaling, enamel fluorosis and tooth development will reveal the environmental influence on tooth formation.

The report was accepted for publication in Frontiers in Physiology in June 2017, and  is currently available here.

Image: Fluoride inhibits the activation/nuclear translocation of the androgen receptor (AR) in ameloblasts.  A) non fluoride exposed (control) mice show that AR is localized in the ameloblast cell nucleus (red staining as indicated by the blue arrow) B) ameloblasts from a fluoride exposed mouse show reduced (almost no) AR in the cell nucleus, suggesting the fluoride inhibits AR activation, which occurs when AR is translocated to the cell nucleus.