Investigating environmental contaminant interactions on the GPCRome: an unexplored landscape of activity

Abstract Improved approaches are needed to advance the field of toxicology by discovering specific targets and mechanisms through which legacy and emerging environmental contaminants act. G protein-coupled receptors (GPCRs) are critical mediators of physiological processes and have been identified as targets that mediate the harmful effects of a small number of contaminants. However, the current research on contaminant activity toward the human GPCRome is scarce and only investigates specific contaminants and receptors in detail. Our proposed project focuses on the gap in the research concerning environmental contaminant activity on GPCRs. We will leverage contemporary high throughput screening (HTS) and receptor pharmacology techniques to identify novel contaminant-GPCR pairs, giving insight into molecular mechanisms and biological consequences. To test our approach, we trialed a small, preliminary study, which yielded promising results by revealing novel and unpredictable contaminant interactions with specific GPCRs, thus supporting this research's direction. From both literature precedent and our findings, we propose to expand the effort more comprehensively and rigorously with the following research objectives: (1) Interrogate per- and polyfluoroalkyl substances (PFAS) against a focused set of GPCRs to identify PFAS-GPCR relationships that mediate effects of PFAS exposure, (2) Conduct a comprehensive screen of various contaminants against the 'druggable' GPCRome, to discover unpredictable contaminant-GPCR pairs, and finally (3) characterize the newly identified contaminant-GPCR pairs in detail regarding their impact on receptor pharmacology, and cellular consequences. To achieve success in our research objectives, the methods of our approach will draw upon the recently developed PRESTO-TANGO and TRUPATH technologies, in addition to traditional receptor pharmacology techniques. Findings generated from this proposal will include (1) the identification of GPCR-mediated effects of contaminants, (2) the discovery of specific targets acted on by environmental contaminants, and (3) characterizing molecular mechanisms of contaminant exposure in the relevant context of cellular consequences. Furthermore, the significance of this work will extend beyond the insight gathered from the tested compounds. As a 'first-in-class' study, this project would support a new framework for investigating the biological activity of xenobiotic compounds - proving valuable for current research initiatives such as the exposome and future work investigating emerging contaminants.