Network toxicology, molecular docking and molecular dynamics simulations for bisphenol A neurotoxicity in depression pathogenesis
- 1The Eighth People’s Hospital of Nanning, Nanning, Guangxi, China
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.
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BibTeX
@article{zhang2026network,
title = {{Network toxicology, molecular docking and molecular dynamics simulations for bisphenol A neurotoxicity in depression pathogenesis}},
author = {Jinlian Zhang and Yuanhao Ma and Miguo Lu and Xiaohuan Jiang and Qingmi Zhong and Yan Zhang and Yan Xiong and Qiliang Wu and Lina Chen and Ruikang Pang},
journal = {PLOS One},
year = {2026},
month = oct,
doi = {10.1371/journal.pone.0359940},
url = {https://doi.org/10.1371/journal.pone.0359940},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Network toxicology, molecular docking and molecular dynamics simulations for bisphenol A neurotoxicity in depression pathogenesis
AU - Jinlian Zhang
AU - Yuanhao Ma
AU - Miguo Lu
AU - Xiaohuan Jiang
AU - Qingmi Zhong
AU - Yan Zhang
AU - Yan Xiong
AU - Qiliang Wu
AU - Lina Chen
AU - Ruikang Pang
PY - 2026
DA - 2026/10/05
JO - PLOS One
DO - 10.1371/journal.pone.0359940
UR - https://doi.org/10.1371/journal.pone.0359940
AB - 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.
SN - 1932-6203
ER -