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Endocrine Abstracts (2022) 81 OC9.2 | DOI: 10.1530/endoabs.81.OC9.2

1University of Padova, Department of Medicine, Italy; 2University of Padova, Department of Pharmacological Sciences, Italy; 3Padova University Hospital, Italy

Perfluoroalkyl substances (PFASs) have been claimed as thyroid disrupting chemicals since the exposure to several PFASs was significantly associated with thyroid hormones derangements. Demographics such as sex, age, and disease status likely influence the associations between PFASs exposure and thyroid hormones since major hypothyroidism effects were observed among pregnant women and infants. This study aims to evaluate of the possible impact of legacy and new-generation PFAS exposure on the thyroid stimulating hormone (TSH) receptor (THSR)-mediated effects on available cell models of thyrocytes. Based on their surfactant properties, PFAS are supposed to interfere with the cell function through the alteration of the biophysical properties of plasma membrane. FRTL-5 normal rat thyroid follicular cell line was exposed to C6O4, perfluorooctanoic-acid (PFOA) or perfluoro-octan-sulphonate (PFOS) at a concentration ranging from 0 ng/ml (CTRL) to 100 ng/ml for 24 hours and the possible cell accumulation was evaluated by LC-MS/MS. The cell content of all tesetd PFAS was below the limit of detection and, accordingly, membrane fluidity evaluated by Merocyanin 540 (MC540) showed no obvious variation showed no variation compared to CTRL. The quantification of intracellular cAMP levels upon stimulation with 10 mIU/ml of TSH for 30 minutes showed a significant reduction, compared to CTRL sample, when cells were exposed for 24 hours exposure to PFAS. A dose-dependent effect detected for PFOA whilst, for C6O4 and PFOS, a sharp blunt of cAMP was observed at the lowest concentration tested. The possible interaction of TSHR with PFAS was evaluated by computational docking methods, addressing the possible binding of C6O4 or PFOA to TSHR extracellular domain. Molecular dynamics also showed that the receptor bound by C6O4 or PFOA displayed major conformational differences related to the unbound receptor. Specifically, the root-mean-square deviation (RMSF) profile of the atomic positions in LEU100-GLN170 range, the most involved in the binding to TSH, showed a modified flexibility than the unbound structure, particularly for PFOA. The cell iodide uptake upon 10 mIU/ml TSH stimulation was then evaluated with the Sandell-Kolthoff (SK) reaction. Stimulation with TSH was associated with a strong and significant increase of the intracellular iodide levels in CTRL conditions. Differently, the exposure to PFOA was associated with a significant reduction of iodide uptake at the highest concentration tested of 10 ng/ml, whilst C6O4 and PFOS were essentially unaffected. Further gene expression experiments are planned to clarify whether this effect is mediated by a down-regulation of downstream event related to TSHR-signaling.

Volume 81

European Congress of Endocrinology 2022

Milan, Italy
21 May 2022 - 24 May 2022

European Society of Endocrinology 

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