---
title: "Bisphenol A neurotoxicity in depression: network toxicology, docking, MD and in vivo validation"
id: "plos-one-4-network-toxicology-molecular-docking-and-molecular-dynamics-simulations-for"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-4-network-toxicology-molecular-docking-and-molecular-dynamics-simulations-for"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940"
published_at: "2026-10-05T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Bisphenol A neurotoxicity in depression: network toxicology, docking, MD and in vivo validation
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-one-4-network-toxicology-molecular-docking-and-molecular-dynamics-simulations-for
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940)
- **Published At:** 2026-10-05T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This study combined **network toxicology**, molecular docking, molecular dynamics (MD) simulation, public transcriptomic analysis, and in vivo mouse experiments to identify molecular targets and pathways linking **bisphenol A (BPA)** exposure to depression pathogenesis. - BPA-related targets were predicted from ChEMBL, STITCH, and SwissTargetPrediction; depression-associated genes were retrieved from GeneCards, OMIM, and TTD; overlapping targets (29 genes) were analyzed by PPI network construction and GO/KEGG enrichment. - Enrichment highlighted roles in **neural synaptic function**, **neurotransmitter binding**, and the **neuroactive ligand–receptor interaction** pathway as candidate mechanisms for BPA-associated depressive effects. - Five core hub genes were identified: **INS**, **ESR1**, **SLC6A4**, **GRIA1**, and **NTRK2**. Molecular docking and 100-ns MD simulations showed stable binding and favorable binding free energies for BPA with these hub proteins. - MM-GBSA decomposition and trajectory analyses (RMSD, RMSF, Rg, SASA, hydrogen bonds) were used to evaluate binding stability and interaction energetics; docking controls were included to support specificity claims. - GEO transcriptomic validation across multiple datasets found these five genes were markedly downregulated in major depressive disorder (MDD) patients, with concurrent suppression of neurotrophic and insulin-related pathways by GSEA. - In vivo, chronic oral BPA exposure in adult male C57BL/6J mice (50 mg/kg daily for 28 days) worsened depressive-like behaviors (sucrose preference, open field metrics) and significantly reduced mRNA and protein expression of the five core molecules in hippocampus and prefrontal cortex. - The authors conclude that BPA can target multiple neurobiology-relevant proteins and pathways linked to depression, providing a theoretical basis for further mechanistic research and potential intervention development. - Details such as exact numerical docking scores per target, full lists of the 29 overlapping genes, and quantitative behavioral results are reported in the original article and supporting files; where specifics were not restated here, they were not reported in the provided source excerpt.
## Clinical Analysis & Structured Key Points
[ Skip to main content ](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#main-content) Advertisement * [plos.org](https://plos.org/) * [Create account](https://community.plos.org/registration/new) * [Sign in](https://journals.plos.org/user/secure/login?page=%2Fplosone%2Farticle%3Fid%3D10.1371%2Fjournal.pone.0359940) * * About * Browse * Publish * [](https://journals.plos.org/plosone/ "PLOS One") * Search [advanced search](https://journals.plos.org/plosone/search) * [Browse Topics](https://journals.plos.org/plosone/subjectAreaBrowse) Browse Subject Areas ? Click through the PLOS taxonomy to find articles in your field. For more information about PLOS Subject Areas, click [here](https://github.com/PLOS/plos-thesaurus/blob/master/README.md "Link opens in new window"). [](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940) [](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940) * 0 [Save](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0359940#savedHeader) [Total Mendeley and Citeulike bookmarks.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0359940#savedHeader) * 0 [Citation](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0359940#citedHeader) [Paper's citation count computed by Dimensions.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0359940#citedHeader) * 10 [View](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0359940#viewedHeader) [PLOS views and downloads.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0359940#viewedHeader) * 0 [Share](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0359940#discussedHeader) [Sum of Facebook, Twitter, Reddit and Wikipedia activity.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0359940#discussedHeader) Open Access Peer-reviewed Research Article # Network toxicology, molecular docking and molecular dynamics simulations for bisphenol A neurotoxicity in depression pathogenesis * Jinlian Zhang , Contributed equally to this work with: Jinlian Zhang, Yuanhao Ma Roles Conceptualization, Data curation, Writing – original draft Affiliation The Eighth People’s Hospital of Nanning, Nanning, Guangxi, China ⨯ * Yuanhao Ma , Contributed equally to this work with: Jinlian Zhang, Yuanhao Ma Roles Data curation, Software, Visualization, Writing – original draft Affiliation The Eighth People’s Hospital of Nanning, Nanning, Guangxi, China ⨯ * Miguo Lu, Roles Software, Visualization Affiliation The Eighth People’s Hospital of Nanning, Nanning, Guangxi, China ⨯ * Xiaohuan Jiang, Roles Data curation Affiliation The Eighth People’s Hospital of Nanning, Nanning, Guangxi, China ⨯ * Qingmi Zhong, Roles Data curation Affiliation The Eighth People’s Hospital of Nanning, Nanning, Guangxi, China ⨯ * Yan Zhang, Roles Data curation Affiliation The Eighth People’s Hospital of Nanning, Nanning, Guangxi, China ⨯ * Yan Xiong, Roles Supervision Affiliation The Eighth People’s Hospital of Nanning, Nanning, Guangxi, China ⨯ * Qiliang Wu, Roles Software Affiliation The Eighth People’s Hospital of Nanning, Nanning, Guangxi, China ⨯ * Lina Chen, Roles Project administration, Visualization Affiliation The Eighth People’s Hospital of Nanning, Nanning, Guangxi, China ⨯ * Ruikang Pang Roles Project administration, Resources, Supervision, Writing – review & editing * E-mail: 20222110132@stu.gzucm.edu.cn Affiliation The Eighth People’s Hospital of Nanning, Nanning, Guangxi, China [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0009-0004-4859-4343 ](https://orcid.org/0009-0004-4859-4343 "ORCID Registry") ⨯ # Network toxicology, molecular docking and molecular dynamics simulations for bisphenol A neurotoxicity in depression pathogenesis * Jinlian Zhang, * Yuanhao Ma, * Miguo Lu, * Xiaohuan Jiang, * Qingmi Zhong, * Yan Zhang, * Yan Xiong, * Qiliang Wu, * Lina Chen, * Ruikang Pang ![PLOS](https://journals.plos.org/resource/img/logo-plos-full-color.svg) x * Published: October 5, 2026 * * [Article](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940) * [Authors](https://journals.plos.org/plosone/article/authors?id=10.1371/journal.pone.0359940) * [Metrics](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0359940) * [Comments](https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0359940) * [Media Coverage](http://plos.altmetric.com/details/doi/10.1371/journal.pone.0359940) * [Abstract](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#abstract0) * [1. Introduction](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#sec001) * [2. Materials and methods](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#sec002) * [3. Results](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#sec012) * [4. Discussion](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#sec021) * [5. Conclusions](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#sec022) * [Supporting information](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#sec023) * [References](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#references) * [Reader Comments](https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0359940) * [Figures](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940) ## Abstract Bisphenol A (BPA), a widespread environmental endocrine disruptor, can cross the blood-brain barrier and exert neurotoxic effects closely associated with depression pathogenesis. However, the precise molecular targets and signaling pathways mediating BPA-induced depression remain poorly understood. This study integrated network toxicology, molecular docking, molecular dynamics simulation, GEO transcriptomic dataset analysis, and in vivo experimental validation in mice to systematically investigate the potential toxicological targets and underlying mechanisms of BPA in depression. BPA-related targets were predicted from ChEMBL, STITCH, and SwissTargetPrediction, and depression-associated targets were retrieved from GeneCards, OMIM, and TTD databases. Overlapping targets were subjected to PPI network construction, as well as GO and KEGG enrichment analyses. Molecular docking and 100 ns molecular dynamics simulations were performed to verify the binding affinity and structural stability between BPA and hub targets. A total of 29 overlapping targets were screened, which were significantly enriched in neural synaptic function, neurotransmitter binding, and the neuroactive ligand‑receptor interaction pathway. Five core hub genes including INS, ESR1, SLC6A4, GRIA1, and NTRK2 were identified, all of which exhibited stable specific binding to BPA with favorable binding free energies. Further validation based on multiple GEO datasets confirmed that these five core genes were markedly downregulated in MDD patients, accompanied by significant suppression of neurotrophic and insulin-related pathways. In vivo animal experiments further demonstrated that BPA exposure aggravated depressive-like behaviors in mice and significantly downregulated both mRNA and protein expression of the five core molecules in brain tissues. Collectively, this study identifies key neurotoxicity-related targets and molecular pathways underlying BPA-induced depression, providing a theoretical foundation for future mechanistic investigation and clinical intervention strategies. ## Figures ![Fig 12](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g012) ![Fig 13](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g013) ![Fig 14](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g014) ![Fig 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g001) ![Fig 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g002) ![Fig 3](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g003) ![Fig 4](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g004) ![Table 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.t001) ![Fig 5](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g005) ![Fig 6](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g006) ![Fig 7](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g007) ![Fig 8](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g008) ![Fig 9](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g009) ![Fig 10](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g010) ![Fig 11](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g011) ![Fig 12](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g012) ![Fig 13](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g013) ![Fig 14](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g014) ![Fig 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g001) ![Fig 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g002) ![Fig 3](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0359940.g003) **Citation:** Zhang J, Ma Y, Lu M, Jiang X, Zhong Q, Zhang Y, et al. (2026) Network toxicology, molecular docking and molecular dynamics simulations for bisphenol A neurotoxicity in depression pathogenesis. PLoS One 21(10): e0359940. https://doi.org/10.1371/journal.pone.0359940 **Editor:** Abbas Farmany, Hamadan University of Medical Sciences, IRAN, ISLAMIC REPUBLIC OF **Received:** February 10, 2026; **Accepted:** September 17, 2026; **Published:** October 5, 2026 **Copyright:** © 2026 Zhang et al. This is an open access article distributed under the terms of the [Creative Commons Attribution License](http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. **Data Availability:** All relevant data are within the paper and its [Supporting Information](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#sec023) file. **Funding:** The author(s) received no specific funding for this work. **Competing interests:** The authors have declared that no competing interests exist. ## 1. Introduction Endocrine disrupting chemicals (EDCs) are ubiquitous in daily environments and consumer products and have extensive human exposure [[1](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref001)]. Chronic exposure to EDCs is associated with a plethora of adverse health outcomes, including cancer [[2](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref002)], impaired fertility [[3](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref003),[4](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref004)], metabolic disorders [[5](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref005)] and neurodevelopmental disorders [[6](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref006),[7](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref007)]. Studies have also identified EDCs as a key contributor to human mental health disorders. For instance, prenatal EDC exposure has an independent association with autism spectrum disorder and intellectual disability [[8](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref008)], and EDC levels in breast milk are significantly correlated with postpartum depression in mothers [[9](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref009)]. These findings have established a clear link between EDCs and human mental health. Given the widespread presence of EDCs in various daily commodities, the mental health issues induced by chronic EDC exposure warrant rigorous and in-depth investigation. Among the diverse classes of EDCs, bisphenol A (BPA, 2,2′-bis(4-hydroxyphenyl)) stands as a key and well-investigated member [[10](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref010)]. As a plastic monomer, it is widely present in plastic products, personal care items, household goods and other consumer products [[11](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref011)], and population biomonitoring data have confirmed widespread BPA exposure in the general population [[12](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref012)]. BPA can bind to multiple estrogen receptors and trigger various cellular responses, contributing to diverse disorders [[13](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref013)]. Accumulating evidence has demonstrated that BPA poses significant health risks, including depressive disorders [[14](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref014)], reproductive dysfunction [[15](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref015)], impaired neural development [[16](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref016)], cancer [[17](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref017)] and obesity [[10](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref010),[18](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref018)]. Importantly, BPA exhibits blood-brain barrier (BBB) permeability, enabling it to cross the BBB and accumulate in brain tissue, thereby inducing central neuroinflammation and triggering anxiety and depressive disorders [[19](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref019),[20](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref020)]. Prenatal BPA exposure correlates with elevated anxiety, depression, and hyperactivity in children [[21](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref021)], and chronic BPA exposure exacerbates depressive-like phenotypes in adult male mice, potentially via downregulation of androgen receptor and GABA(A)α2 receptor in the hippocampus and amygdala [[22](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref022)]. Despite these findings, the precise molecular targets and pathways through which BPA induces depression remain largely unknown. Depression is a prevalent and debilitating disorder with complex pathogenesis involving genetic and environmental factors [[23](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref023),[24](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref024)], and neuroinflammation mediated by microglia is an established pathological component [[25](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref025)]. In recent years, attention has turned to the association between chronic exposure to environmental pollutants, including EDCs, and depression [[26](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref026)–[28](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref028)]. However, the specific mechanisms by which BPA contributes to depression have not been systematically elucidated. In 2011, the concept of “network toxicology” was proposed, transforming traditional pharmacological databases into specialized toxicological databases to predict adverse reactions and toxicological properties of compounds [[29](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref029),[30](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref030)]. This approach is suitable for investigating multi-target toxicants and visualizing complex toxicological processes [[31](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref031),[32](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref032)]. Molecular docking simulates binding interactions between small molecules and proteins, while molecular dynamics (MD) simulation overcomes the limitations of rigid docking by capturing flexible protein-ligand interactions under physiological conditions [[33](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref033),[34](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359940#pone.0359940.ref034)]. In this study, we integrated network toxicology, molecular docking, and MD simulation to identify key genetic targets and signaling pathways mediating BPA-induced depression. Our findings provide a theoretical basis for understanding BPA neurotoxicity and for developing prevention and treatment strategies for depression associated with BPA exposure. ## 2. Materials and methods ### 2.1. Network analysis for exploring BPA toxicity We employed web-based search algorithms and toxicity prediction tools to predict the toxicological effects of BPA. Specifically, the ProTox platform ( ) and ADMETlab platform ( ) were selected as the initial screening webservers. These platforms display the molecular structure of BPA as well as its predicted toxic responses in various human systems and organs. The purpose of this step was to identify toxicity endpoints most relevant to neurotoxicity and depression (e.g., blood-brain barrier permeability, estrogen receptor activity), thereby guiding subsequent target selection. ### 2.2. Collection of BPA and depression potential targets The chemical structure and SMILES format of BPA were retrieved from the PubChem database ( ) using the keyword “bisphenol A”. Potential targets associated with BPA were obtained from the ChEMBL database ( ). To expand the search scope, the SMILES format of BPA was also queried in the STITCH database ( ) and SwissTargetPrediction ( ). To reduce false positives, we applied a prediction confidence score ≥ 0.7 (high confidence) as the screening threshold for STITCH and SwissTargetPrediction, as recommended for toxicological studies. The search results from a
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