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Per- and Polyfluoroalkyl Substances Alter GPCR Activity (Abstract ID: 227194)
Abstract   Peer reviewed

Per- and Polyfluoroalkyl Substances Alter GPCR Activity (Abstract ID: 227194)

Nathan Gentilman, Joshua Wilkinson, Hans-Joachim Lehmler and David Roman
The Journal of pharmacology and experimental therapeutics, Vol.393(5 Supplement), 104244
05/2026
DOI: 10.1016/j.jpet.2026.104244

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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. Per- and polyfluoroalkyl substances (PFAS) are a large class of chemicals used in industrial applications and have been garnering considerable attention for their apparent human exposure and potential toxicity. These "forever chemicals" are tied to a range of toxic outcomes, including but not limited to certain cancers, diabetes, impeded immune function, liver and kidney diseases, and neurological disorders. 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. Structurally, many of the compounds resemble bioactive lipids that signal through specific GPCRs. Therefore, we hypothesize that PFAS may modulate lipid-recognizing GPCRs. In this work, we conducted a focused screen of PFAS pollutants at a sub-set of GPCRs. We selected relevant PFAS representing diverse chemical space from a list prioritized by the US Environmental Protection Agency. The selected GPCRs recognize ligands that structurally resemble PFAS 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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