PFPC Fluoride Education Project

Xu K, Feng Z, Afrim FK, Ma J, Yang S, Zhang X, Niu Z, An N, Du Y, Yu F, Zhou G, Ba Y - "Interaction of fluoride exposure and CREB1 gene polymorphisms on thyroid function in school-age children" Chemosphere 303(Pt 2):135156 (2022) doi: 10.1016/j.chemosphere.2022.135156
https://www.sciencedirect.com/science/a ... 3522016496

Abstract

Objectives

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 assay and 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 was 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.

Results

Negative and positive associations between serum TT4 level (β = −0.721, 95%CI: −1.209, −0.234) and Tvol (β = 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).

Conclusions

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

PFPC Commentary

This is yet another study on the Kaifeng cohort. Again, the authors conduct a faulty investigation, and fail to account for iodine intake appropriately.

Here, the authors claim:

"Almost all children had appropriate iodine intake, which may be due to the diversity of food and the implementation of iodized salt policy."

However, table 1 shows that the children had excessive iodine intake. Mean UIC was 346.95 μg/L- according to WHO guidelines indicative of excessive iodine consumption.

CREB & Gq/11

Olianas MC, Dedoni S, Onali P - "Coincidence signaling of dopamine D1-like and M1 muscarinic receptors in the regulation of cyclic AMP formation and CREB phosphorylation in mouse prefrontal cortex" Neurosignals 21(1-2):61-74 (2013) doi: 10.1159/000335208
https://karger.com/nsg/article/21/1-2/6 ... ike-and-M1

Abstract

In the prefrontal cortex, dopamine D1-like and M1 muscarinic receptors are both involved in the regulation of attentional, cognitive and emotional processes but so far no information has been provided on their functional interaction. In the present study we show that in mouse medial prefrontal cortex, concomitant activation of M1 muscarinic receptors potentiated D1-like receptor-induced cyclic AMP formation through a mechanism involving activation of Gq/11 and the release of G protein βγ subunits. Immunohistochemical studies indicated that the adenylyl cyclase isoforms AC2 and AC4 are expressed in mouse prefrontal cortex and that they colocalize with D1-like receptors with a greater association for AC4. In primary cultures of frontal cortex neurons, D1-like receptor-induced Ser133 phosphorylation of the transcription factor cyclic AMP-responsive element binding protein (CREB) was potentiated by concurrent stimulation of M1 receptors. Suppression of AC4 expression with small interfering RNA transfection reduced D1 stimulation of cyclic AMP formation and CREB phosphorylation and abolished the M1 potentiation, whereas knockdown of AC2 had no significant effects. These data indicate that in mouse prefrontal cortex Gq/11-coupled M1 receptor and Gs-coupled D1-like receptor inputs converge on AC4 with a consequent enhancement of cyclic AMP formation and signaling to the nucleus.

More-than-adequate iodine intake in the mother results in subclinical hypothyroidism.

Zhang Y, Fan Y, Yu X, Wang X, Bao S, Li J, Fan C, Shan Z, Teng W - "Maternal Subclinical Hypothyroidism Impairs Neurodevelopment in Rat Offspring by Inhibiting the CREB Signaling Pathway" Mol Neurobiol 52(1):432-41 (2015) doi: 10.1007/s12035-014-8855-x
https://link.springer.com/article/10.10 ... 014-8855-x

Abstract

Thyroid hormone is indispensable for fetal brain development, and maternal thyroid hormone deficiency is thought to result in severe and irreversible brain impairments in learning and memory. Epidemiological and animal studies by our group had shown that maternal subclinical hypothyroidism had significant negative impact on neurodevelopment. But, the underlying mechanisms responsible for these neurological alterations remain unclear. In the present study, we performed thyroidectomy and injected L-T4 daily in Wistar rats to induce maternal subclinical hypothyroidism. Our data indicated that the pups from subclinical group showed prolonged latencies during the learning process in the Morris water maze as compared to the control group. Transcription factor cAMP response element-binding protein (CREB) signaling pathway is closely associated with synaptic plasticity, learning, and memory. Consistent with behavioral results, Western blotting also showed decreased activation of three important upstream modulators of CREB signaling pathway: phospho-mitogen-activated protein kinases (P-ERK1/2), phospho-calcium-dependent-calmodulin kinase IV (P-CaMKIV), phospho-serine/threonine protein kinase AKT(P-AKT), as well as total CREB and phospho-CREB as compared to the control at postnatal day 7 (PND 7) in hippocampus. Our findings suggested that decreased activation of the CREB signaling pathway in pups was related to impairments of cognitive function caused by maternal subclinical hypothyroidism.