Elucidating the mechanisms of environmental pollutant BPA inducing neurotoxicity through metabolomics and network toxicology strategy

Zhongshi Xu; Anli Wang; Jiaqiang Hu; Ze Li; Yuchen Zheng; Yi Liu; Qingqing Xiang; Jiye Wang; Weixuan Yao; Chengrong Ding; Ying Zhou

doi:10.1016/j.envpol.2025.126591

Elucidating the mechanisms of environmental pollutant BPA inducing neurotoxicity through metabolomics and network toxicology strategy

Environ Pollut. 2025 Sep 15:381:126591. doi: 10.1016/j.envpol.2025.126591. Epub 2025 Jun 2.

Authors

Zhongshi Xu¹, Anli Wang², Jiaqiang Hu³, Ze Li³, Yuchen Zheng³, Yi Liu⁴, Qingqing Xiang⁵, Jiye Wang³, Weixuan Yao³, Chengrong Ding⁶, Ying Zhou⁷

Affiliations

¹ College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, 310014, China; Key Laboratory of Drug Prevention and Control Technology of Zhejiang Province, The Department of Criminal Science and Technology, Zhejiang Police College, Hangzhou, 310053, China.
² College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China.
³ Key Laboratory of Drug Prevention and Control Technology of Zhejiang Province, The Department of Criminal Science and Technology, Zhejiang Police College, Hangzhou, 310053, China.
⁴ Innovation Center of Yangtze River Delta, Zhejiang University, Jiashan, 314100, China.
⁵ School of Environment and Natural Resources, Zhejiang University of Science & Technology, Hangzhou, 310023, China.
⁶ College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, 310014, China.
⁷ College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, 310014, China. Electronic address: yingzhou@zjut.edu.cn.

PMID: 40466997
DOI: 10.1016/j.envpol.2025.126591

Abstract

Bisphenol A (BPA), a ubiquitous chemical compound in plastics and resins, is a pervasive environmental pollutant posing significant health risks to humans and animals. Despite evidence linking BPA exposure to neuronal damage and cognitive impairments, its underlying mechanisms and core targets remain poorly understood. Therefore, this study employed an integrated metabolomics and network toxicology strategy to elucidate the neurotoxic mechanisms of BPA. Zebrafish embryos were subjected to BPA exposure (0.05, 0.5, 1, and 2 mg/L) from 6 h post-fertilization (hpf) to 6 days post-fertilization (dpf). Neurotoxic effects were assessed via developmental and morphological observations, behavioral analyses, metabolomics profiling, and transcriptional examinations. BPA exposure disrupted zebrafish larval development, suppressed central nervous system (CNS) neurogenesis, altered cardiac function, and induced significant neurobehavioral deficits. In addition, metabolomics analysis identified disruptions in glutamate metabolism as a key contributor to BPA-induced neurotoxicity. Utilizing databases such as comparative toxicogenomics database (CTD), ChEMBL, and GeneCards, we identified potential neurotoxicity-associated targets, further refined through STRING and Cytoscape analyses. Enrichment analysis using Metascape and molecular docking via Autodock revealed strong binding affinities between BPA and core targets, including PRKACA, ESR2, MMP9, PTGS2, DRD1, AR, and ESR1. Moreover, the BPA-ESR2 interaction and BPA-PRKACA interaction were further validated via SPR assay. This study offers a comprehensive understanding of BPA-induced neurotoxicity through advanced metabolomics and network toxicology approaches, offering novel and valuable insights into its toxicity mechanisms and guiding the development of potential therapeutic strategies.

Keywords: Bisphenol A; Network toxicology; Neurotoxicity; Untargeted metabolomics; Zebrafish.

MeSH terms

Animals
Benzhydryl Compounds* / toxicity
Bisphenol A Compounds
Environmental Pollutants* / toxicity
Metabolomics
Phenols* / toxicity
Zebrafish

Substances

Benzhydryl Compounds
bisphenol A
Phenols
Environmental Pollutants
Bisphenol A Compounds