Integrative Bioinformatics and Docking-Based In Silico Toxicity Assessment of Plastic Additives: Insights into Neurotoxic, Reproductive, and Carcinogenic Risks and Associated Molecular Pathways.

Abstract

Plastic additives are pervasive pollutants that readily leach into water, affecting human health; however, their toxicological risk assessment remains limited. This study used network toxicology to identify disease-associated common targets in plastic additives, including benzotriazole, Bisphenol A, 2,4-Di-tert-butylphenol, mirex, Diphenyl ether, Bisphenol S, Dibutyl phthalate, PFNA, and PFBS. The core targets identified using network toxicology for these plastic additives were AKT1, PTGS2, BCL2, ESR1, and GSK3B. In addition, an integrated in silico toxicity assessment of selected plastic additives using molecular docking, MM/GBSA analysis, and molecular dynamics simulation was performed to assess neurotoxicity, reproductive toxicity, and carcinogenic potential. Molecular docking revealed the high-scoring docked complexes as PTGS2-benzotriazole (-5.047 kcal/mol), PTGS2-bisphenol A (-5.264 kcal/mol), PTGS2-diphenyl ether (-5.078 kcal/mol), PTGS2-bisphenol S (-5.519 kcal/mol), PTGS2-2,4-di-tert-butylphenol (-5.565 kcal/mol), ESR1-benzotriazole (-5.339 kcal/mol), and ESR1-2,4-di-tert-butylphenol (-5.626 kcal/mol). The stability of highly interacting complexes was then assessed through MM/GBSA calculations and molecular dynamics simulations. A more negative ΔGBind score in MM/GBSA analysis indicated a stronger and more favourable interaction. In silico analysis of plastic additive-biological target interactions identified potential carcinogenic, reproductive, and neurological health hazards and revealed key molecular pathways underlying plastic additive-induced toxicity. Further in vitro/in vivo studies are required to validate these computational findings.