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Exploring the Potential Mechanism of Polyethylene Terephthalate Associated Cardiotoxicity through Network Toxicology and Molecular Docking
Summary
Researchers used computational approaches including network toxicology, molecular docking, and molecular dynamics simulations to explore how polyethylene terephthalate microplastics may affect cardiovascular function. The study identified potential molecular pathways through which PET exposure could contribute to cardiotoxicity. The findings provide a theoretical framework for understanding how plastic contaminants might interact with heart-related biological targets.
As polyethylene terephthalate (PET) is one of the most widely used plastics and a pervasive environmental contaminant, growing evidence links micro/nanoplastic exposure to cardiovascular dysfunction; however, the underlying mechanisms remain unclear. Here we aimed to explore the potential cardiotoxicity of polyethylene terephthalate (PET) using an integrative computational strategy combining network toxicology, molecular docking, and molecular dynamics simulations. This fragment-based approach examined the interactions between PET monomers, terephthalic acid (TPA) and ethylene glycol (EG) with cardiac-related proteins, to identify potential molecular initiating events. We focused on three representative cardiomyopathy subtypes hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and ischemic cardiomyopathy (ICM) to systematically explore molecular pathways that could be disrupted by PET exposure. Disease-associated targets were identified through comprehensive database mining (PubChem, ADMETlab2.0, SwissADME, and GeneCards), and core targets were extracted and visualized using Cytoscape-based network analysis. Functional characterization of these core targets was then performed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Binding affinities between PET and candidate proteins were assessed by molecular docking using AutoDock Vina, and the stability of the lowest-energy protein-ligand complexes was further examined using molecular dynamics simulations. Our analyses suggest potential mechanistic links between PET exposure and cardiomyopathy pathogenesis involving dysregulation of several critical signaling pathways, including cGMP-PKG signaling, cardiomyopathy-associated pathways, insulin resistance, and lipid metabolism/atherosclerosis-related pathways. Molecular docking and molecular dynamics simulations suggested stable interactions between PET monomers and several key proteins, particularly ERBB2 and GSK3β, suggesting plausible molecular interaction sites through which PET monomers may influence cardiomyopathy-related pathways. These findings suggest plausible mechanistic links between PET exposure and cardiomyopathy pathogenesis and provide a predictive computational framework to guide future mechanistic and toxicological studies.