Thyroid/parathyroid function and fluoride: role of mitochondrial DNA and SOD genetic variations

Emerging evidence indicates excessive fluoride exposure damage thyroid/parathyroid, with oxidative stress and mitochondrial dysfunction as crucial mechanisms. However, epidemiological research on their involvement in fluoride-induced thyroid/parathyroid dysfunction and modification of oxidative stress-related SNPs are insufficient. Therefore, we conducted a cross-sectional study (n = 401) among children aged 7-13 in areas with drinking water fluoride exposure in Tongxu County, Henan Province, China. This study examined the associations between urinary fluoride (UF) levels and thyroid/parathyroid function in children, as well as mediation effect of DNA copy number (mtDNA-CN) and interactions between UF and superoxide dismutase (SOD) SNPs. The population was divided into two groups based on children safety guidance of UF (WS/T 256-2005), with respective UF levels of 0.73 mg/L and 2.21 mg/L. Results revealed that for each 1 mg/L increase in children UF, thyroid volume (Tvol) increased by 0.34 cm³ (95%CI: 0.21, 0.46), parathyroid hormone (PTH) levels decreased by 1.40 ng/L (95%CI: -0.21, 0.17), mtDNA-CN reduced by 0.13 unit (95%CI: -0.22, - 0.04). Notably, in girls, the UF-Tvol association was partially mediated by relative mtDNA-CN (mediation proportion = 33.08%). Additionally, the GG genotype carriers of SOD2 rs4880 exhibited a larger Tvol (P = 0.017). The TT carriers of SOD3 rs13306703 exhibited higher PTH levels (P < 0.001). GMDR analysis identified an interaction between SOD2 rs4880, SOD3 rs10370 polymorphisms, and UF on Tvol. These findings linked fluoride exposure to thyroid function change in children. mtDNA-CN partially mediating the UF-Tvol association in girls. Genetic variants in SOD2 and SOD3 may modify the effect of fluoride exposure on thyroid.