Bisphenol a exposure and major depressive disorder: an integrative analysis combining network toxicology, molecular docking, genetic epidemiology, and transcriptomic validation.

Bisphenol A (BPA) is a widely used endocrine-disrupting chemical that has been implicated in neurodevelopmental and psychiatric disorders; however, the molecular mechanisms linking BPA exposure to major depressive disorder (MDD) remain poorly understood. In this study, we systematically investigated the potential toxicological effects of BPA on MDD by integrating network toxicology, summary-data-based Mendelian randomization (SMR), single-cell RNA sequencing (scRNA-seq), molecular docking, and experimental validation. BPA-related targets were collected from multiple databases and intersected with MDD-associated genes, followed by functional enrichment analyses and construction of a protein-protein interaction network to identify core targets. Causal relationships between candidate targets and MDD were assessed using SMR analysis based on genome-wide association study (GWAS) and expression quantitative trait loci (eQTL) data. Cell-type-specific expression patterns were examined using scRNA-seq data from MDD patients, while molecular docking was employed to evaluate the binding affinities between BPA and core target proteins. Differential expression of key targets was further validated using public bulk RNA-seq datasets, Enzyme-Linked Immunosorbent Assay (ELISA), and BPA exposure were further confirmed via quantitative real-time PCR (qRT-PCR) in BPA-induced MDD mouse models, together with behavioral assessments. A total of 571 shared targets between BPA and MDD were identified, enriched in pathways related to neurodevelopment, synaptic plasticity, and cognitive function. Six core targets (ESR1, SRC, EGFR, AKT1, PLCG2, and JAK3) were highlighted. MR and SMR analyses supported causal roles for AKT1, SRC, PLCG2, and JAK3 in MDD, whereas EGFR exhibited a protective effect. These findings provide integrative evidence for molecular mechanisms underlying BPA-associated susceptibility to MDD and identify potential targets for future therapeutic intervention.