Researchers combined genetic epidemiology, transcriptomics, molecular docking, and mouse experiments to show how common endocrine-disrupting chemicals affect biological pathways associated with major depressive disorder.
Study: Bisphenol A exposure and major depressive disorder: an integrated analysis combining network toxicology, molecular docking, genetic epidemiology, and transcriptomic validation. Image credit: monticello / Shutterstock
New research published in journal translational psychiatry Shedding light on the potential molecular relationship between the common environmental chemical bisphenol A (BPA) and major depressive disorder (MDD). Using an integrative multi-omics approach, researchers identified six common molecular targets linking BPA exposure and depression-related pathways.
These findings highlight perturbations in synaptic signaling, neurodevelopment, and cognition and indicate potential molecular targets that may inform future research on diagnosis and targeted treatment strategies for MDD.
Risk factors for major depressive disorder and BPA
MDD is a debilitating mental health condition with far-reaching public health implications, including an increased risk of suicidal behavior. Complex interactions between genetic, biological, and environmental factors drive its development.
Among them, exposure to endocrine-disrupting chemicals such as BPA, which is widely used in plastics, food containers, and medical materials, has emerged as a contributor to neurodevelopmental and neurobehavioral disorders. Although there is increasing evidence linking BPA exposure to depression and related symptoms, the exact molecular mechanisms remain unclear.
This gap highlights the need for an integrative approach to understanding the pathways linking environmental exposures and MDD.
Integrated multi-omics research design
In this study, researchers adopted an integrated multi-omics strategy to investigate the potential impact of BPA on MDD.
The team compiled BPA-related targets from ChEMBL, STITCH, and SwissTargetPrediction, used PubChem to obtain structural information, and standardized target names using UniProt. They identified overlapping targets associated with MDD and prioritized key molecular targets using protein-protein interaction network analysis.
Biological roles were investigated through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis.
The researchers then applied Mendelian randomization (MR) and summary database MR (SMR) to assess causality. They used expression quantitative trait locus (eQTL) data from genome-wide association studies (GWAS).
Gene expression patterns were analyzed using single-cell ribonucleic acid sequencing (scRNA-seq) datasets. Molecular docking evaluated the predicted binding interactions between BPA and the core target.
Validation includes bulk RNA sequencing, enzyme-linked immunosorbent assay (ELISA) in human blood samples, and experimental testing in a BPA-induced mouse model. Behavioral assessments included the elevated zero maze (EZM) and forced swim test (FST).
Transcriptional changes were confirmed using quantitative real-time polymerase chain reaction (qRT-PCR). Some validation datasets were small, with limited ELISA analysis of 5 MDD patients and 5 controls, and scRNA-seq samples.
Shared molecular targets and validation results
This analysis identified 571 protein targets common to BPA exposure and MDD, enriched in pathways related to synaptic plasticity, neurodevelopment, and cognition.
Six targets have emerged as central regulators: SRC proto-oncogene tyrosine kinase (SRC), estrogen receptor 1 (ESR1), AKT serine/threonine kinase 1 (AKT1), epidermal growth factor receptor (EGFR), Janus kinase 3 (JAK3), and phospholipase C gamma 2 (PLCG2).
Transcriptome analysis showed upregulation of SRC, PLCG2, AKT1, JAK3, and ESR1 in MDD, while EGFR was downregulated. MR and SMR analyzes supported the potential causal role of several targets, with EGFR appearing to be protective. ESR1 was identified as a core target, but no significant causal relationship was shown.
Enhancements have linked these targets to neuronal development, synaptic signaling, and cognitive dysfunction. scRNA-seq analysis reveals disease-associated transcriptional signatures across neuronal subtypes. Molecular docking showed strong binding affinity between BPA and core proteins, especially AKT1 and ESR1.
Experimental validation demonstrated that mice exposed to BPA exhibited anxiety and depression-like behaviors. The gene expression pattern was consistent with human findings. Additional targets include blood-brain barrier (BBB) interactions, estrogen receptor alpha signaling, and cytochrome P450 enzymes, supporting the potential for BPA to disrupt neuronal function.
BPA, Depression, and Public Health Impact
This study highlights BPA as a potential environmental factor associated with MDD, with implications for research and public health. The findings support further investigation into how environmental exposures contribute to mental health risk, prevention, and management.
They also emphasize the importance of policies aimed at reducing exposure to endocrine disrupting chemicals.
Future studies should validate these findings in larger populations and investigate longitudinal associations between BPA exposure and mental health outcomes. Expanding multi-omics approaches and investigating cell type-specific mechanisms is essential to advance precision interventions.
Reference magazines:
- Lu, Z., Shi, W. (2026). Bisphenol A exposure and major depressive disorder: An integrated analysis combining network toxicology, molecular docking, genetic epidemiology, and transcriptomic validation. Translational psychiatry. DOI: 10.1038/s41398-026-03862-5, https://www.nature.com/articles/s41398-026-03862-5
