Assessing male reproductive toxicity of environmental pollutant di-ethylhexyl phthalate with network toxicology and molecular docking strategy

Abstract

Environmental pollutants, especially endocrine-disrupting chemicals (EDCs) like di-ethylhexyl phthalate (DEHP), pose serious threats to human health, with DEHP widely implicated in male reproductive toxicity. However, the complex molecular interactions remain unknown. We employed a network toxicology approach combined with molecular docking analysis to identify potential targets and mechanisms of DEHP's toxic effects. Databases such as ChEMBL, STITCH, OMIM, and GeneCards were utilized to gather data, and Cytoscape software was used to construct protein-protein interaction networks. A total of 51 potential targets were identified, with eight core targets, including PTGS2, CASP3, and ESR1, highlighted for their roles in oxidative stress, apoptosis, and hormonal dysregulation. KEGG pathway enrichment analysis revealed significant associations with pathways in cancer, cytokine-mediated signaling, and the hypothalamic-pituitary-gonadal axis. Additionally, gene expression datasets from the Gene Expression Omnibus (GEO) database were analyzed to identify differentially expressed genes overlapped with DEHP targets in testicular diseases. Molecular docking results confirmed strong binding affinities between DEHP and the core target proteins, suggesting a robust interaction mechanism. This study underscores the need for further investigation into DEHP's toxic mechanisms and its combined effects with other environmental pollutants, paving the way for comprehensive risk assessments and the development of targeted intervention strategies.