Potential mechanisms linking polyethylene terephthalate microplastic-associated exposure factors to abnormal biomineralization.

Microplastic exposure has raised health concerns. However, whether degradation products and migrants associated with polyethylene terephthalate microplastics (PET-MPs) contribute to diseases associated with abnormal biomineralization remains unclear. Here, terephthalic acid (TPA), ethylene glycol (EG), mono(2-hydroxyethyl) terephthalate (MHET), bis(2-hydroxyethyl) terephthalate (BHET), PET cyclic trimer, acetaldehyde, and antimony trioxide (Sb₂O₃) were defined as PET-MP-associated exposure factors (PAEFs). This study establishes a cross-disease biomineralization framework separates PET-MP particle exposure from associated small-molecule chemical exposure. Computational toxicology, target prediction, transcriptomics, network analysis, functional enrichment, molecular docking, and molecular dynamics (MD) simulations were integrated to assess their potential links with kidney stone disease (KSD), vascular calcification (VC), and myositis ossificans (MO). Toxicity predictions revealed heterogeneity among PAEFs in physicochemical properties, barrier permeability, and toxicological endpoints. Integration of 1747 PAEF targets with disease datasets identified 217, 101, and 25 candidate targets for KSD, VC, and MO, respectively, prioritizing 33, 12, and 7 core proteins through protein-protein interaction analysis. Functional enrichment indicated convergence on inflammation, oxidative stress, mitochondrial dysfunction, extracellular matrix remodeling, and osteogenic signaling. Molecular docking identified several PAEF-core protein pairs with binding energies below -7 kcal/mol, while TPA, MHET, BHET, and PET cyclic trimer showed broad predicted binding. Triplicate MD simulations showed mean protein and ligand root-mean-square deviations (RMSDs) of 2.06 and 3.77 Å, respectively, and 2.28 hydrogen bonds on average, supporting stable binding after ligand adjustment. These findings suggest that PAEFs may contribute to abnormal biomineralization through multi-target and multi-pathway mechanisms, providing a basis for exposure risk assessment and mechanistic validation.