Toxicity and mechanism of bis(2-ethylhexyl) phthalate in premature ovarian failure: A network toxicology prediction and molecular docking analysis.

This study investigates the mechanism by which bis(2-ethylhexyl) phthalate (DEHP) induces premature ovarian failure (POF) using network toxicology analysis and molecular docking methods. The potential toxic targets of DEHP were identified using databases such as STITCH and SwissTargetPrediction. Disease-related targets associated with POF were retrieved from the GeneCards and OMIM databases. The overlapping targets related to DEHP-induced POF were identified by intersecting the 2 datasets. Furthermore, the protein-protein interaction network was constructed using the STRING database and visualized through Cytoscape software to identify key targets. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed on the overlapping targets using the DAVID database. Finally, molecular docking simulations were performed using AutoDock Vina to validate the findings. A total of 116 intersection targets associated with DEHP-induced POF were identified. Among these, 6 key core targets were screened: caspase 3, b-cell lymphoma 2 (BCL2), matrix metalloproteinase 9, peroxisome proliferator-activated receptor gamma, BCL2L1, and cyclin D1. Gene ontology analysis revealed that these targets are primarily involved in response to xenobiotic stimulus, assembly of cyclin-dependent protein kinase holoenzyme complex, and BH domain binding. Kyoto Encyclopedia of Genes and Genomes analysis indicated that these targets are predominantly associated with critical signaling pathways, including the p53 signaling pathway and apoptosis pathways. Additionally, molecular docking studies demonstrated low binding energies between DEHP and the core target proteins, supporting their potential role in the pathophysiology of DEHP-induced POF. This study indicates that caspase 3, BCL2, matrix metalloproteinase 9, peroxisome proliferator-activated receptor gamma, BCL2L1, and cyclin D1 might be potential toxic targets of DEHP-induced POF. It reveals the potential molecular mechanisms underlying DEHP-induced POF, emphasizing the synergistic roles of the p53 signaling pathway and apoptosis in its pathogenesis. These insights provide a novel theoretical framework and identify potential therapeutic targets for the prevention and management of POF.