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

Publisher: American Chemical Society Country of Publication: United States NLM ID: 0213155 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5851 (Electronic) Linking ISSN: 0013936X NLM ISO Abbreviation: Environ Sci Technol Subsets: MEDLINE

Publication: Washington DC : American Chemical Society
Original Publication: Easton, Pa. : American Chemical Society, c1967-

Receptors, G-Protein-Coupled*/agonists ; Receptors, G-Protein-Coupled*/genetics ; Receptors, G-Protein-Coupled*/metabolism ; Signal Transduction*; Humans ; High-Throughput Screening Assays ; Polymers

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.

Ecotoxicol Environ Saf. 2021 Jan 15;208:111429. (PMID: 33039870)
Toxicol In Vitro. 2020 Aug;66:104871. (PMID: 32325111)
Mol Pharmacol. 2006 Jan;69(1):207-15. (PMID: 16189297)
Environ Sci Technol. 2017 Oct 3;51(19):11423-11430. (PMID: 28858478)
Curr Med Chem. 2010;17(34):4231-55. (PMID: 20939815)
Annu Rev Pharmacol Toxicol. 2016;56:361-83. (PMID: 26514204)
Sci Adv. 2020 Oct 30;6(44):. (PMID: 33127684)
Int J Mol Sci. 2020 May 30;21(11):. (PMID: 32486326)
J Vis Exp. 2020 Mar 10;(157):. (PMID: 32225148)
Obesity (Silver Spring). 2010 Sep;18(9):1861-3. (PMID: 20168308)
Nat Commun. 2021 Apr 9;12(1):2113. (PMID: 33837202)
Environ Sci Technol. 2022 Feb 15;56(4):2487-2496. (PMID: 35080176)
Biochem Pharmacol. 2004 Jun 1;67(11):2023-30. (PMID: 15135299)
Mol Psychiatry. 2021 Jul;26(7):2805-2819. (PMID: 33067580)
Environ Sci Technol. 2020 Feb 4;54(3):1720-1729. (PMID: 31935073)
Environ Health Perspect. 2010 Aug;118(8):1055-70. (PMID: 20338858)
Life Sci. 1987 Feb 9;40(6):555-61. (PMID: 3807648)
J Hazard Mater. 2018 Feb 15;344:179-199. (PMID: 29035713)
Environ Health Perspect. 2016 Jul;124(7):991-9. (PMID: 26895433)
Environ Sci Technol. 2019 Oct 1;53(19):11467-11477. (PMID: 31380625)
Nat Commun. 2022 Jan 24;13(1):454. (PMID: 35075127)
Int J Mol Sci. 2021 Dec 31;23(1):. (PMID: 35008896)
Environ Int. 2023 Oct;180:108161. (PMID: 37758599)
Neurochem Int. 2011 Oct;59(5):706-13. (PMID: 21763743)
J Pharmacol Exp Ther. 2021 Feb;376(2):306-321. (PMID: 33203660)
Annu Rev Pharmacol Toxicol. 2014;54:9-26. (PMID: 24016212)
Environ Sci Technol. 2024 Mar 19;58(11):4859-4871. (PMID: 38441001)
Nat Genet. 2000 May;25(1):25-9. (PMID: 10802651)
Environ Sci Technol. 2022 Oct 18;56(20):14627-14639. (PMID: 36173153)
Genome Biol. 2003;4(5):P3. (PMID: 12734009)
J Med Chem. 2008 Apr 24;51(8):2372-86. (PMID: 18363348)
Am J Physiol Regul Integr Comp Physiol. 2005 Dec;289(6):R1715-23. (PMID: 16109808)
Front Public Health. 2020 Sep 24;8:553850. (PMID: 33072697)
Nat Rev Drug Discov. 2018 Apr;17(4):243-260. (PMID: 29302067)
Nat Struct Mol Biol. 2015 May;22(5):362-9. (PMID: 25895059)
Sci Rep. 2020 Oct 7;10(1):16672. (PMID: 33028846)
Chem Res Toxicol. 2017 Feb 20;30(2):574-582. (PMID: 28027439)
Sci Total Environ. 2011 Aug 15;409(18):3309-24. (PMID: 21663944)
Nat Rev Drug Discov. 2013 Apr;12(4):265-86. (PMID: 23535933)
Int J Cancer. 2012 Jan 1;130(1):241-2. (PMID: 21312194)
Br J Pharmacol. 2016 Sep;173(18):2702-25. (PMID: 27314810)
Water Res. 2021 Jul 1;199:117203. (PMID: 34004441)
Elife. 2020 Mar 02;9:. (PMID: 32118583)
Environ Pollut. 2017 Dec;231(Pt 2):1609-1620. (PMID: 28964603)
Environ Health Perspect. 2020 Jul;128(7):77007. (PMID: 32700975)
PLoS One. 2015 Dec 30;10(12):e0146021. (PMID: 26717316)
Environ Sci Technol. 2021 Jul 6;55(13):9339-9351. (PMID: 34154322)
Mol Cell Endocrinol. 2020 Feb 15;502:110665. (PMID: 31760044)
Nat Struct Mol Biol. 2018 Jan;25(1):4-12. (PMID: 29323277)
Nature. 2009 May 21;459(7245):356-63. (PMID: 19458711)
Environ Sci Technol. 2015 Feb 3;49(3):1903-11. (PMID: 25556879)
Sci Adv. 2017 Jul 19;3(7):e1700782. (PMID: 28776036)
Brain Res. 2003 Apr 25;970(1-2):169-77. (PMID: 12706258)
Genetics. 2023 May 4;224(1):. (PMID: 36866529)
Sci Total Environ. 2019 Feb 15;651(Pt 2):3253-3268. (PMID: 30463173)
Environ Int. 2021 May;150:106225. (PMID: 33272655)
J Pineal Res. 2018 Apr;64(3):. (PMID: 29247541)
Sci Transl Med. 2015 Sep 16;7(305):305ra146. (PMID: 26378246)
Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19992-7. (PMID: 19066225)
Int J Mol Sci. 2020 Jan 28;21(3):. (PMID: 32012883)
Nat Rev Immunol. 2013 Mar;13(3):190-8. (PMID: 23391992)
Proc Natl Acad Sci U S A. 2016 Apr 5;113(14):3844-9. (PMID: 27001836)
Mol Med. 2012 Dec 06;18:1249-60. (PMID: 22811066)
Endocrinology. 2012 Sep;153(9):4097-110. (PMID: 22733974)
Genome Biol. 2006;7(10):R100. (PMID: 17076895)
Neuron. 2015 Mar 18;85(6):1193-9. (PMID: 25754820)

Keywords: GPCRs; PRESTO-Tango; cell surface receptor; endocrine disrupting chemicals; food packaging; plastics; screen; signaling disruption

0 (Receptors, G-Protein-Coupled)
0 (Polymers)

Date Created: 20240305 Date Completed: 20240320 Latest Revision: 20240323

20240323

PMC10956435

10.1021/acs.est.3c08392

38440973