2021: Fluoride Stimulates Anxiety- and Depression-like Behaviors Associated with SIK2-CRTC1 Signaling Dysfunction

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2021: Fluoride Stimulates Anxiety- and Depression-like Behaviors Associated with SIK2-CRTC1 Signaling Dysfunction

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An interesting study was pre-published today (Nov. 4, 2021) documenting that fluoride stimulated anxiety- and depression-like behaviours in rats, and was associated with SIK2-CRTC1 signaling dysfunction (Zhou et al., 2021).
  • Zhou G, Hu Y, Wang A, Guo M, Du Y, Gong Y, Ding L, Feng Z, Hou X, Xu K, Yu F, Li Z, Ba Y - "Fluoride Stimulates Anxiety- and Depression-like Behaviors Associated with SIK2-CRTC1 Signaling Dysfunction" J Agric Food Chem (2021) doi: 10.1021/acs.jafc.1c04907. Epub ahead of print. PMID: 34735150
    https://pubmed.ncbi.nlm.nih.gov/34735150/
"NaF elevated the expression of SIK2 and reduced the expression of CRTC1, brain-derived neurotrophic factor (BDNF), and VGF."

All are mediated/regulated by thyroid hormone and/or TSH. We list some of the related literature below.


Thyroid & VGF

Lewis JE, Brameld JM, Hill P, Wilson D, Barrett P, Ebling FJ, Jethwa PH - "Thyroid hormone and vitamin D regulate VGF expression and promoter activity" J Mol Endocrinol 56(2):123-34 (2016)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705542/

Kamyshna I, Kamyshnyi A - "Transcriptional Activity of Neurotrophins Genes and Their Receptors in the Peripheral Blood in Patients with Thyroid Diseases in Bukovinian Population of Ukraine" Macedonian Journal of Medical Sciences 9(A):208-216 (2021)
https://oamjms.eu/index.php/mjms/article/view/6037

Gentile F, Calì G, Zurzolo C, Corteggio A, Rosa P, Calegari F, Levi A, Possenti R, Puri C, Tacchetti C, Nitsch L - "The neuroendocrine protein VGF is sorted into dense-core granules and is secreted apically by polarized rat thyroid epithelial cells" Exp Cell Res 295(1):269-80 (2004)
https://pubmed.ncbi.nlm.nih.gov/15051509/

Molnár I, Bokk A - "Decreased nerve growth factor levels in hyperthyroid Graves' ophthalmopathy highlighting the role of neuroprotective factor in autoimmune thyroid diseases" Cytokine 35(3-4):109-14 (2006)
https://pubmed.ncbi.nlm.nih.gov/17008110/


Thyroid/TSH & CREB/CRTC
Note: CRTC1 is also called TORC1 -->target of rapamycin complex 1
CREB = cAMP responsive element-binding protein


López-Márquez A, Fernández-Méndez C, Recacha P, Santisteban P - "Regulation of Foxe1 by Thyrotropin and Transforming Growth Factor Beta Depends on the Interplay Between Thyroid-Specific, CREB and SMAD Transcription Factors" Thyroid 29(5):714-725 (2019)
"This study shows that Foxe1 is the final target of TSH/cAMP and TGF-β regulation that mediates expression of thyroid differentiation genes, and provides evidence of an interplay between CRE-binding proteins, thyroid transcription factors, and Smad proteins in its regulation. Thus, Foxe1 plays an important role in the complex transcriptional network that regulates thyroid follicular cell differentiation."

Moon MK, Kang GH, Kim HH, Han SK, Koo YD, Cho SW, Kim YA, Oh BC, Park do J, Chung SS, Park KS, Park YJ - "Thyroid-stimulating hormone improves insulin sensitivity in skeletal muscle cells via cAMP/PKA/CREB pathway-dependent upregulation of insulin receptor substrate-1 expression" Mol Cell Endocrinol 436:50-8 (2016)
https://pubmed.ncbi.nlm.nih.gov/27452800/
"Thyroid-stimulating hormone (TSH) receptor is expressed in extrathyroidal tissues such as hepatocytes, adipocytes, and skeletal muscle, which suggests a possible novel role of TSH in various metabolic processes in extrathyroidal tissues independent of thyroid hormones....TSH also stimulated Irs1 promoter activation; this stimulation was abolished by protein kinase A (PKA) inhibition using H89 or by mutation of the cAMP-response element site located at -1155 to -875 bp of the Irs1 promoter region, supporting a novel role of TSH activated-cAMP/PKA/CREB signaling in the regulation of Irs1 expression. In conclusion, TSH improves insulin sensitivity in skeletal muscle by increasing Irs1 gene expression. This regulatory effect is mediated by a PKA-CREB-dependent pathway."

Kang HS, Kumar D, Liao G, Lichti-Kaiser K, Gerrish K, Liao XH, Refetoff S, Jothi R, Jetten AM - "GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation" J Clin Invest 127(12):4326-4337 (2017)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707155/

Gnocchi D, Ellis ECS, Johansson H, Eriksson M, Bruscalupi G, Steffensen KR, Parini P - "Diiodothyronines regulate metabolic homeostasis in primary human hepatocytes by modulating mTORC1 and mTORC2 activity" Mol Cell Endocrinol 499:110604 (2020)
https://pubmed.ncbi.nlm.nih.gov/31580898/

Craps J, Joris V, De Jongh B, Sonveaux P, Horman S, Lengelé B, Bertrand L, Many MC, Colin IM, Gérard AC - "Involvement of mTOR and Regulation by AMPK in Early Iodine Deficiency-Induced Thyroid Microvascular Activation" Endocrinology 157(6):2545-59 (2016)
https://pubmed.ncbi.nlm.nih.gov/27035650/

Wang H, Atkins SJ, Fernando R, Wei RL, Smith TJ - "Pentraxin-3 Is a TSH-Inducible Protein in Human Fibrocytes and Orbital Fibroblasts" Endocrinology. 156(11):4336-44 (2015)
https://pubmed.ncbi.nlm.nih.gov/26287404/

Mourouzis I, Giagourta I, Galanopoulos G, Mantzouratou P, Kostakou E, Kokkinos AD, Tentolouris N, Pantos C - "Thyroid hormone improves the mechanical performance of the post-infarcted diabetic myocardium: a response associated with up-regulation of Akt/mTOR and AMPK activation" Metabolism 62(10):1387-93 (2013)
https://pubmed.ncbi.nlm.nih.gov/23773982/

Wang Y, Wei W, Wang Y, Dong J, Song B, Min H, Teng W, Chen J - "Neurotoxicity of developmental hypothyroxinemia and hypothyroidism in rats: Impairments of long-term potentiation are mediated by phosphatidylinositol 3-kinase signaling pathway" Toxicol Appl Pharmacol 271(2):257-65 (2013)
https://pubmed.ncbi.nlm.nih.gov/23707767/


Thyroid/TSH & BDNF - ERK1/2 & Gq/11

Earlier research identified the ERK1/2 pathway (Gq/11) as the mediator of fluoride-induced disruption of BDNF (Chen et al., 2018).

Chen J, Niu Q, Xia T, Zhou G, Li P, Zhao Q, Xu C, Dong L, Zhang S, Wang A - "ERK1/2-mediated disruption of BDNF-TrkB signaling causes synaptic impairment contributing to fluoride-induced developmental neurotoxicity" Toxicology 410:222-230 (2018)
https://pubmed.ncbi.nlm.nih.gov/30130557/
  • Compare to Propofol and Gq/11:

    Zhong L, Luo F, Zhao W, Feng Y, Wu L, Lin J, Liu T, Wang S, You X, Zhang W - "Propofol exposure during late stages of pregnancy impairs learning and memory in rat offspring via the BDNF-TrkB signalling pathway" J Cell Mol Med 20(10):1920-31 (2016)
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020635/

    Jialili A, Abasi K, Maimaitizunong, Zhang L, Li XJ - "Influence of propofol on Gq/11 protein in kidney during acute respiratory distress syndrome" Chinese Critical Care Medicine 18(12):724-6 (2006)
    https://pubmed.ncbi.nlm.nih.gov/17166350/

Baek JH, Kang ES, Fava M, Mischoulon D, Nierenberg AA, Lee D, Heo JY, Jeon HJ - "Thyroid stimulating hormone and serum, plasma, and platelet brain-derived neurotrophic factor during a 3-month follow-up in patients with major depressive disorder" J Affect Disord 169:112-7 (2014)
https://www.sciencedirect.com/science/a ... via%3Dihub
"Higher TSH is associated with lower baseline and reduced the increase of serum BDNF levels during antidepressant treatment in patients with MDD."

Shabani S, Farbood Y, Mard SA, Sarkaki A, Ahangarpour A, Khorsandi L - "The regulation of pituitary-thyroid abnormalities by peripheral administration of levothyroxine increased brain-derived neurotrophic factor and reelin protein expression in an animal model of Alzheimer's disease" Can J Physiol Pharmacol (2018) 96(3):275-280. doi: 10.1139/cjpp-2016-0434. Epub 2017 Aug 28. PMID: 28846851.
https://pubmed.ncbi.nlm.nih.gov/28846851/
"These findings indicated that L-T4 increased BDNF and reelin protein expression by regulation of serum THs and TSH level in Aβ-induced AD rats."

Höpker VH, Amoureux MC, Varon S - "NGF and BDNF in the anterior pituitary lobe of adult rats" J Neurosci Res 49(3):355-63 (1997)
https://pubmed.ncbi.nlm.nih.gov/9260746/


Other studies on the effects of fluoride on CRCT1/TORC1/TOR

Kuang P, Deng H, Liu H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L - "Sodium fluoride induces splenocyte autophagy via the mammalian targets of rapamycin (mTOR) signaling pathway in growing mice" Aging (Albany NY) 10(7):1649-1665 (2018)
https://pubmed.ncbi.nlm.nih.gov/30036188/

Ma L, Zhang R, Li D, Qiao T, Guo X - "Fluoride regulates chondrocyte proliferation and autophagy via PI3K/AKT/mTOR signaling pathway" Chem Biol Interact 349:109659 (2021)
https://pubmed.ncbi.nlm.nih.gov/34536393/

Zhou G, Tang S, Yang L, Niu Q, Chen J, Xia T, Wang S, Wang M, Zhao Q, Liu L, Li P, Dong L, Yang K, Zhang S, Wang A - "Effects of long-term fluoride exposure on cognitive ability and the underlying mechanisms: Role of autophagy and its association with apoptosis" Toxicol Appl Pharmacol 378:114608 (2019)
https://pubmed.ncbi.nlm.nih.gov/31173788/

Niu Q, Chen J, Xia T, Li P, Zhou G, Xu C, Zhao Q, Dong L, Zhang S, Wang A - "Excessive ER stress and the resulting autophagic flux dysfunction contribute to fluoride-induced neurotoxicity" Environ Pollut 233:889-899 (2018)
https://pubmed.ncbi.nlm.nih.gov/29100748/
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