2022: PFAS interact directly with TSH receptor

There are more than 7 million PFAS and over 21 million fluorinated compounds listed in PubChem (2023).
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2022: PFAS interact directly with TSH receptor

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NOTE: Since 1999, we have been saying that fluorides - both inorganic and organic - may interfere with TSH receptor signaling. Fluoride is known as the "universal G protein activator", meaning it can act on all G protein families, depending on dose and duration. The only known receptor in humans, that is capable of doing the same, is the TSH receptor.
De Toni L, Di Nisio A, Rocca MS, Pedrucci F, Garolla A, Dall'Acqua S, Guidolin D, Ferlin A, Foresta C - "Comparative Evaluation of the Effects of Legacy and New Generation Perfluoralkyl Substances (PFAS) on Thyroid Cells In Vitro" Front Endocrinol (Lausanne) 13:915096 (2022) doi: 10.3389/fendo.2022.915096
https://www.frontiersin.org/articles/10 ... 15096/full

Abstract
Background: Per- and poly-fluorinated alkyl substances (PFAS) are environment-persistent emerging endocrine-disrupting chemicals raising health concerns worldwide. Exposure to PFAS has been associated with the imbalance of thyroid hormones. However, available studies addressing the cell mechanism underlying thyroid disrupting feature of legacy PFAS, such as perfluoro-octanoic acid (PFOA), perfluoro-octane-sulfonic acid (PFOS), and the new generation substitutes, such as C6O4, are still lacking. In this study the potential disrupting effect of PFOA, PFOS, and C6O4 on a murine thyroid cell model was assessed.

Methods: A rat FRTL-5 cell line was used as the normal thyroid follicular cell model. Cell iodide uptake, induced by thyroid stimulating hormone (TSH), was used to assess the functional impact of PFAS exposure on cell function. Tetrazolium salt-based cell viability assay and merocyanine 540-based cell staining were used to address the possible involvement of cell toxicity and membrane biophysical properties on altered cell function. The possible direct interaction of PFAS with TSH-receptor (TSH-R) was investigated by computer-based molecular docking and analysis of molecular dynamics. Evaluation of intracellular cAMP levels and gene expression analysis were used to validate the direct impairment of TSH-R-mediated downstream events upon PFAS exposure.

Results: Different from PFOS or C6O4, exposure to PFOA at a concentration ≥ 10 ng/mL was associated with significant impairment of the iodide uptake upon TSH stimulation (respectively: basal 100.0 ± 19.0%, CTRL + TSH 188.9 ± 7.8%, PFOA 10 ng/mL + TSH 120.4 ± 20.9%, p= 0.030 vs CTRL + TSH; PFOA 100 ng/mL + TSH 115,6 ± 12,3% p= 0.017 vs CTRL + TSH). No impairment of cell viability or membrane stability was observed. Computational analysis showed a possible direct differential interaction of C6O4, PFOA, and PFOS on the same binding site of the extracellular domain of TSH-R. Finally, exposure to PFOA was associated with a significant reduction of downstream intracellular cAMP levels and both sodium-iodide transporter and thyroperoxidase gene expression upon TSH-R stimulation.

Conclusions: Our data suggest that legacy and new generation PFAS can differentially influence TSH dependent signaling pathways through the direct interaction with TSH-R.

Keywords: C6O4; PFOA; PFOS; endocrine disruptors; iodide; thyreocyte.
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