Dental Fluorosis Is Related With CFTR And Clc-3

Dental fluorosis (DF) is a common endemic disease affecting dental enamel. The traditional concept of DF is based on the environmental contamination effect of fluoride. More evidence have shown that genetic variations also contribute to DF. There were abundant chloride channels in tooth tissues. Here we aim to prove that some chloride channels transport fluoride and their variants contribute to DF. 884 DF cases and 833 controls was recruited from the same fluoride contamination region. The tag SNPs of CFTR and nine ClC chloride channels were screened. DF mouse model, zebrafish morpholino, patch clamp and various cellular experiments were used to test the biological functions of chloride channels and their variations. CFTR M470V and three SNPs in CLCN3 were closely related with DF. M470 and V470 had different tolerance to fluoride in Xenopus oocytes. ClC-3 helped yeast cells to against overdose fluoride and clcn3 deficiency dysregulated tooth and craniofacial development in zebrafish. The fluoride treatment altered the binding between nucleoprotein and specific SNP region and resulted in the mRNA changes in different ClC-3 transcripts. Furthermore, various CLCN3 transcripts present different fluoride conductance and coordinated together to resistant fluoride. CFTR and CLCN3 are the major protective factors involving DF through different mechanisms. The results shed new insights into the genetic risks in DF development.