Deciphering pathogenic mechanisms of BDCPP exposure in endometrial cancer progression via an integrated approach combining network toxicology, machine learning, and molecular docking.

Endometrial cancer (EC) is one of the most common gynecological malignancies globally. Increasing attention has been paid to the role of environmental pollutants in EC development. Epidemiological studies have demonstrated a significant association between elevated urinary concentrations of bis(1,3-dichloro-2-propyl) phosphate (BDCPP) and an increased risk of EC. However, the hub genes and underlying mechanisms of BDCPP-induced EC remain poorly understood. Potential targets of BDCPP and EC were retrieved from multiple databases. A protein-protein interaction network was constructed based on the common targets. Enrichment analysis was performed using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Reactome databases. Clinical and transcriptomic data of EC patients were downloaded from The Cancer Genome Atlas Program. Subsequently, 117 machine learning models were employed to screen for hub genes. A risk score for BDCPP exposure was calculated based on the hub genes. Single-gene gene set enrichment analysis (GSEA) was conducted on the hub genes, and molecular docking was performed to predict the binding affinity of BDCPP to the hub genes. We identified 165 potential targets implicated in BDCPP-induced EC. Machine learning pinpointed eight hub genes: PLA2G2A, PLAU, SIRT2, DRD2, GSK3A, THRB, CYP17A1 , and TLR9 . The BDCPP exposure risk score model offers a framework for predicting the prognosis of EC patients with moderate accuracy. Molecular docking revealed the binding potential between BDCPP and hub genes. Our findings highlight the pivotal roles of inflammatory activation, hormonal disruption, altered lipid metabolism, and epigenetic dysregulation in pathogenic mechanisms. Single-gene GSEA further emphasized the critical roles of nucleocytoplasmic transport, polycomb repressive complex, and mRNA surveillance pathway in this process. Our study investigated the hub genes and underlying mechanisms of BDCPP-induced EC. The findings not only offer novel insights into the role of environmental pollutants in EC development but also present an analytical framework for elucidating the carcinogenic mechanisms of other environmental chemicals.