Beyond the Nucleus: Plastic Chemicals Activate G Protein-Coupled Receptors

Abstract

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 as 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). We further confirm that polyvinyl chloride and polyurethane products contain ADORA1 or MTNRA1 agonists using a confirmatory secondary screen and 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. This work highlights that signaling disruption caused by plastic chemicals is broader than that previously believed and demonstrates the relevance of nongenomic pathways, which have, thus far, remained unexplored.

Regrettable Substitutes and the Brain: What Animal Models and Human Studies Tell Us about the Neurodevelopmental Effects of Bisphenol, Per- and Polyfluoroalkyl Substances, and Phthalate Replacements

“…Any or all of these are potentially relevant to neurodevelopment and behavior as these receptors are expressed in the brain [47]. Recently, certain G-protein-coupled receptors were identified as being activated by plastics including BPA and diethyl phthalate [48]. Although the half-lives of bisphenols are short, their persistence in the environment yields detectable levels in most humans.…”

Moldable Plastics (Polycaprolactone) can be Acutely Toxic to Developing Zebrafish and Activate Nuclear Receptors in Mammalian Cells

“…Evidence shows that everyday consumer plastic products leach and expose us to bioactive compounds, − many of whose bioactivity is unknown . These exposures can result from volatilized chemicals (e.g., new car smell), the migration of chemicals into the foods and beverages we consume, and the inhalation of household dust, among other routes.…”