Beyond the nucleus: Plastic chemicals activate G protein-coupled receptors

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/560665v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@e3b5edorg.highwire.dtl.DTLVardef@1bcf3aeorg.highwire.dtl.DTLVardef@224012org.highwire.dtl.DTLVardef@9c61ea_HPS_FORMAT_FIGEXP M_FIG C_FIG G protein-coupled receptors (GPCRs) are central mediators of cell signaling and physiological function. Despite their biological significance, GPCRs have not been widely studied in the field of toxicology. Herein, we investigated these receptors are novel targets of plastic chemicals using a high-throughput drug screening assay with 126 human non-olfactory GPCRs. In a first-pass screen, we tested the activity of triphenol phosphate, bisphenol A, and diethyl phthalate as well as three real-world mixtures of chemicals extracted from plastic food packaging covering all major polymer types. We found 11 GPCR-chemical interactions, of which the chemical mixtures exhibited the most robust activity at Adenosine receptor 1 (ADORA1) and Melatonin receptor 1 (MTNR1A) in a confirmatory secondary screen. We further confirmed that polyvinyl chloride and polyurethane products contain ADORA1 or MTNRA1 agonists using pharmacological knockdown experiments. Finally, an analysis of the associated gene ontology terms suggests that ADORA1 and MTNR1A activation may be linked to downstream effects on circadian and metabolic processes. Our findings exemplify the diversity of endpoints plastic chemicals can target and demonstrate the relevance of non-genomic pathways which have thus far remained unexplored.