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Investigating the Activity of Perfluoroalkyl Substances (PFASs) at the GPCRome (Abstract ID: 166294)
Abstract   Peer reviewed

Investigating the Activity of Perfluoroalkyl Substances (PFASs) at the GPCRome (Abstract ID: 166294)

Nathan Gentilman, Joshua Wilkinson, Hans-Joachim Lehmler and Dave Roman
The Journal of pharmacology and experimental therapeutics, Vol.392(3 Supplement), 102937
03/2025
DOI: 10.1016/j.jpet.2024.102937

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Abstract

Human exposure to synthetic chemicals is well documented, and exposure to these chemical pollutants is associated with a myriad of adverse health outcomes. However, the mechanisms of activity and the molecular initiating events that contribute to pollutant toxicity are largely unknown. G protein-coupled receptors (GPCRs) are signaling proteins that regulate a plethora of physiological activities and interact with highly chemically diverse structures, making them suitable targets for mediating the biological activity of pollutants, which our laboratory has recently demonstrated. Per- and polyfluoroalkyl substances (PFASs) are a large class of chemicals used in industrial applications and have been garnering considerable attention for their apparent human exposure and potential toxicity. Structurally, many of the compounds resemble bioactive lipids that signal through specific GPCRs. Therefore, we hypothesize that PFASs may modulate lipid GPCRs. In this work, we conducted a focused screen of PFAS pollutants at a sub-set of lipid GPCRs. We selected relevant PFASs representing diverse chemical space from a list prioritized by the US Environmental Protection Agency. The selected GPCRs recognize ligands that structurally resemble PFASs and are implicated in physiological processes adjacent to the adverse outcomes of PFAS exposure. By leveraging contemporary screening resources, we have identified novel PFAS activity at specific GPCRs, acting in an agonist or antagonist manner.

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