Fluoride Action Network



  • Serum TT4 level is negatively associated with urinary fluoride concentration.
  • Thyroid volume of children is positively related to urinary fluoride concentration.
  • CREB1 polymorphisms could modify the levels of serum TT3 and TT4.
  • Fluoride exposure and CREB1 SNPs interactions on thyroid volume are observed.
  • Interactions among CREB1 SNPs loci may modify the serum TT3 level.


To evaluate the effects of CREB1 gene polymorphisms and long-term exposure to fluoride on thyroid function of children.

Study design

A total of 424 children (including 226 boys and 198 girls) aged 7–12 years old were enrolled in Kaifeng, China by cross-sectional study in 2017. The concentrations of urinary fluoride (UF) and creatinine (UCr) were measured using fluoride ion-selective electrode essay and a creatinine assay kit (picric acid method), respectively. The concentration of UCr-adjusted UF (CUF) was calculated. Children were divided into high fluoride exposure group (HFG, CUF >1.41 mg/L) and low fluoride exposure group (LFG, CUF <1.41 mg/L) according to the median concentration of CUF (1.41 mg/L). The serum thyroid-stimulating hormone (TSH), total triiodothyronine (TT3) and total thyronine (TT4) levels were detected by the radiation immunoassay. The B-mode ultrasound was performed to test the thyroid volume (Tvol). Genotyping of CREB1 gene were conducted by a custom-by-design 48-plex SNPscan™ Kit. Associations between CUF concentration, CREB1 single nucleotide polymorphisms (SNPs) and thyroid function were assessed by multiple linear regression models.


Negative and positive associations between serum TT4 level (B = -0.721, 95%CI: -1.209, -0.234) and Tvol (B = 0.031, 95%CI: 0.011, 0.050) and CUF concentration were observed respectively. Children carrying CREB1 rs11904814 TG and rs2254137 AC genotypes had lower TT3 levels (P < 0.05). Children in HFG carrying rs11904814 TT, rs2253206 GG genotypes and rs6740584 C allele easily manifested lower serum TT4 levels (P < 0.05). Moreover, interactions between excessive fluoride exposure and CREB1 SNPs on Tvol were observed, and the interaction among different loci of CREB1 gene could modify serum TT3 level (P < 0.05, respectively).


Fluoride could alter children’s serum TT4 levels and Tvol. Interactions between fluoride exposure and CREB1 polymorphisms may modify thyroid volume of children.


Fluoride; Thyroid; CREB1 gene; SNP; Children