Plasticizer mixture exposure-induced preeclampsia pathogenesis: Integrated single-cell and bulk transcriptomics, network toxicology, and molecular docking insights.

PURPOSE: While plasticizers are known preeclampsia (PE) risk factors, the mechanisms of combined exposure to ATBC, DEP, DMP, and DOP remain unclear. This study aims to elucidate their biological targets and pathogenic mechanisms in PE. METHODS: PE/toxin gene targets were predicted from databases. Biomarkers were identified via differential expression analysis, machine learning, expression verification, and ROC analysis. GSEA, immune infiltration analysis, molecular dynamics simulation, and scRNA-seq elucidated mechanisms and cell subsets. RT-qPCR and IHC validated target expression. PRINCIPAL RESULTS: We identitified three key targets (BCL6, FLT1, and INHA) enriched in the ribosome pathway and correlated with activated dendritic cells (p < 0.01). Compared with other targets, FLT1 exhibited the lowest binding energies with DEP, DMP, and DOP, all of which were ≤5.8 kcal/mol. The scRNA-seq analysis identified villous cytotrophoblast (VCT) as a key cell type with dynamic expression of BCL6 and FLT1 during differentiation. RT-qPCR and IHC confirmed the upregulation of BCL6, FLT1, and INHA in PE placental tissues, and their differential expression in VCT cells between the control and experimental groups. MAJOR CONCLUSION: The findings clarify plasticizer toxicity and provide novel insights into PE pathogenesis, offering a theoretical basis for improved clinical treatments.