How could bisphenol A raise depression risk? Study identifies six key molecular targets

By Pooja Toshniwal PahariaReviewed by Susha Cheriyedath, M.Sc.Mar 31 2026

Researchers combined genetic epidemiology, transcriptomics, molecular docking, and mouse experiments to show how a common endocrine-disrupting chemical may influence biological pathways tied to major depressive disorder.

Study: Bisphenol a exposure and major depressive disorder: an integrative analysis combining network toxicology, molecular docking, genetic epidemiology, and transcriptomic validation. Image Credit: monticello / Shutterstock

A new study published in the journal Translational Psychiatry sheds light on potential molecular links between bisphenol A (BPA), a common environmental chemical, and major depressive disorder (MDD). Using an integrative, multi-omics approach, researchers identified six shared molecular targets connecting BPA exposure with depression-related pathways.

These findings highlight disruptions in synaptic signaling, neurodevelopment, and cognition, and point to potential molecular targets that may inform future research on diagnosis and targeted treatment strategies for MDD.

Major Depressive Disorder and BPA Risk Factors

MDD is a debilitating mental health condition with far-reaching public health implications, including an increased risk of suicidal behaviors. Complex interactions between genetic, biological, and environmental factors drive its development.

Among these, exposure to endocrine-disrupting chemicals such as BPA, widely used in plastics, food containers, and medical materials, has emerged as a contributor to neurodevelopmental and neurobehavioral disturbances. While growing evidence links BPA exposure to depression and related symptoms, the precise molecular mechanisms remain unclear.

This gap underscores the need for integrative approaches to understand the pathways connecting environmental exposures to MDD.

Integrated Multi-Omics Study Design

In the present study, researchers adopted an integrated, multi-omics strategy to investigate the potential effects of BPA on MDD.

The team compiled BPA-associated targets from ChEMBL, STITCH, and SwissTargetPrediction, while using PubChem to retrieve structural information and UniProt to standardize target names. They identified overlapping targets associated with MDD and used protein-protein interaction network analysis to prioritize key molecular targets.

Biological roles were explored through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses.

The investigators then applied Mendelian randomization (MR) and summary-data-based MR (SMR) to evaluate causal associations. They used expression quantitative trait loci (eQTL) data from genome-wide association studies (GWAS).

Gene expression patterns were analyzed using single-cell ribonucleic acid sequencing (scRNA-seq) datasets. Molecular docking assessed predicted binding interactions between BPA and core targets.

Validation included 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, including ELISA analyses in five patients with MDD and five controls, and limited scRNA-seq samples.

Shared Molecular Targets and Validation Results

The analysis identified 571 protein targets shared between BPA exposure and MDD, with enrichment in pathways related to synaptic plasticity, neurodevelopment, and cognition.

Six targets 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).

Transcriptomic analyses showed upregulation of SRC, PLCG2, AKT1, JAK3, and ESR1 in MDD, while EGFR was downregulated. MR and SMR analyses supported potential causal roles for several targets, with EGFR appearing protective. ESR1 was identified as a core target but did not show a significant causal effect.

Functional enrichment linked these targets to neuronal development, synaptic signaling, and cognitive dysfunction. scRNA-seq analysis revealed disease-associated transcriptional signatures across neuronal subtypes. Molecular docking showed strong binding affinities between BPA and core proteins, particularly AKT1 and ESR1.

Experimental validation demonstrated that BPA-exposed mice exhibited anxiety- and depression-like behaviors. Gene expression patterns aligned with human findings. Additional targets included blood-brain barrier (BBB) interactions, estrogen receptor alpha signaling, and cytochrome P450 enzymes, supporting BPA’s potential to disrupt neurological function.

BPA, Depression, and Public Health Implications

The 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 underscore the importance of policies aimed at reducing exposure to endocrine-disrupting chemicals.

Future research should validate these findings in larger populations and explore longitudinal associations between BPA exposure and mental health outcomes. Expanding multi-omics approaches and investigating cell-type-specific mechanisms will be essential for advancing precision interventions.