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.
