High-Throughput Screening of ToxCast PFAS Chemical Library for Potential Inhibitors of the Human Sodium Iodide Symporter

Evaluation of these PFAS in NIS-HEK and FRTL secondary assay. Initial single concentration and dose response testing for NIS and cytotoxicity for positive PFAS, with follow-up in secondary assay to confirm.

Impact/Purpose

The screening of these 149 ToxCast PFAS chemicals represents the first report of such a large group of structurally diverse PFASs investigated for their potential as a molecular target of NIS.  In addition to the previously observed inhibition of hNIS by PFOS and PFHxS that were repeated in the current screening set, a small set of other unique PFAS were identified as active inhibitors of iodide uptake in the hNIS RAIU with minimal interference by chemical cytotoxicity in the parallel assay.  Therefore, the chemical ranking scores incorporated here will be invaluable for further chemical prioritization in thyroid disrupting evaluations. Several of these more potent and highly ranked inhibitors may warrant additional secondary assay testing to further confirm these initial findings, especially given to the current level of priority/concern for these highly persistent chemicals in the environment. Importantly, as with all in vitro assays, considerations of absorption, distribution, metabolism, excretion (ADME) as well as potential compensatory feedback mechanisms of the thyroid system limit direct extrapolation of in vitro findings to altered thyroid synthesis in vivo. 

Citation

Stoker, T., J. Want, A. Murr, J. Bailey, AND A. Buckalew. High-Throughput Screening of ToxCast PFAS Chemical Library for Potential Inhibitors of the Human Sodium Iodide Symporter. American Chemical Society, Washington, DC, 36(3):380-389, (2023). [DOI: 10.1021/acs.chemrestox.2c00339]

DOI: High-Throughput Screening of ToxCast PFAS Chemical Library for Potential Inhibitors of the Human Sodium Iodide Symporter