Interrogating Environmental Contaminant Activity Against the Druggable GPCRome: A High Throughput Approach to Assess Interaction and Pathology

Abstract

<b>Abstract ID 28830</b> <b>Poster Board 56</b> From intentional production and unintended byproducts of industrialization, large amounts of anthropogenic chemicals have been produced and amassed in the environment. These environmental contaminants can disrupt physiological equilibria and cause diverse harm to human health, such as developmental disorders, immunological-mediated diseases, and neurological pathologies. Past literature and emerging data show that certain environmental contaminants can activate specific GPCRs. However, studies focus on specific contaminant-receptor pairs in detail, leaving the vast majority of the GPCR landscape unexplored. As GPCRs act as signaling nodes in many physiological processes, we hypothesized that interrogating the activity of a contaminant against the GPCRome could be used to assess biological impact while simultaneously providing insight into potential mechanisms of pathology. This work applies traditional pharmacology and drug discovery practices toward toxicology efforts. Utilizing the open-source platform (PRESTO-Tango), we developed a screening methodology capable of investigating the activity of contaminants against 314 non-olfactory GPCRs amendable to high-throughput. From our initial screen of eight compounds, we identified several interactions between polychlorinated biphenyls (PCBs) and GPCRs, including both characterized and orphan receptors. Most interesting are the relationships uncovered between specific PCB congeners (PCB95 and PCB52) and receptor isoforms involved in sphingosine-1-phosphate and melatonin signaling pathways (S1PR4 and MTb). To our knowledge, this is the first report of these interactions, highlighting the utility of our approach to quickly assess the biological impact and pathology of a contaminant at the receptor level. Additionally, while detailed pharmacological experiments are underway, these findings could potentially support the involvement of sphingosine and melatonin signaling interplay in pathologies beyond the contaminant(s) alone.