Interrogating the Activity of Environmental Contaminants Against the Druggable GPCR‐ome

Abstract

Exposure to environmental contaminants can result in a myriad of conditions including developmental disorders, pulmonary conditions, and neurological pathologies. Literature precedent and new, emerging data, demonstrates specific GPCRs can be activated by some classes of environmental contaminants, including PCBs, pesticides, chloropropanols, and others. When interrogating GPCR’s with small‐molecule based screens, the traditional paradigm is to test hundreds of thousands of compounds against a single target. In recent literature, an open‐source method “PRESTO‐TANGO” (Parallel Receptor‐ome Expression and Screening via Transcriptional Output – TANGO) has been described as a feasible approach to simultaneously screen the entire druggable human GPCR‐ome against a smaller collection of compounds via a G protein‐independent β‐arrestin recruitment assay. In this work, we have adopted a similar approach to the PRESTO‐TANGO methodology, enabling us to screen activity of a number of environmental contaminates against the known druggable GPCR‐ome of 314 GPCRs. From our initial screen, we identified several potential ligand‐receptor interactions. Secondary dose response experiments uncovered what we believe to be a novel ligand‐receptor relationship between PCBs and the Sphingosine‐1‐phoshpate receptor (S1PR) family. Experiments to validate the relationship between the PCBs and S1PR family, as well as investigate the relevant signaling cascades impacted are currently underway. Ultimately, this work utilizes a modified form of the PRESTO‐TANGO assay as a novel screening platform to elucidate bioactivity of environmental contaminants.Support or Funding InformationThis work was supported by the University of Iowa Environmental Health Science Research Center (NIEHS P30 ES05605 D.L.R)