Key Takeaways & Executive Findings
- •• • Identified six key toxic proteins (TP53, HSP90AA1, HSP90AB1, INS, BCL2, AKT1) common to BPA-induced AD, PD, and HD; BCL2 is the most central hub, indicating a convergent apoptotic mechanism across diseases. • • BPA exposure induces oxidative stress and cell cycle arrest in SVGP12 astrocytes, leading to mitochondrial apoptosis via inhibition of INS-AKT1-BCL2 and activation of TP53-HSP90 pathways, disrupting neural homeostasis. • • The study integrates network toxicology, molecular docking, and molecular dynamics simulations, providing a multi-scale approach to predict and validate BPA neurotoxicity, surpassing traditional single-target analyses. • • The findings establish a mechanistic link between BPA and three major neurodegenerative diseases, offering a unified target set for therapeutic intervention and risk assessment of BPA-related neurotoxicity.
Abstract
Bisphenol A (BPA), a high-volume industrial chemical, is implicated in neurotoxicity and chronic neurodegenerative diseases. This study integrates network toxicology, molecular docking, and molecular dynamics simulations to systematically delineate the common mechanisms linking BPA to Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Using the human astrocyte cell line SVGP12 as an in vitro model, we identified six key toxic functional proteins—TP53, HSP90AA1, HSP90AB1, INS, BCL2, and AKT1—that mediate BPA's effects across these diseases, with BCL2 emerging as the most central node. Experimental validation demonstrated that BPA induces oxidative stress and cell cycle arrest, suppresses the INS-AKT1-BCL2 anti-apoptotic pathway, and activates the TP53-HSP90 pro-apoptotic pathway, culminating in mitochondrial apoptosis of astrocytes and disruption of neural microenvironment homeostasis. These findings reveal a convergent mechanism by which BPA accelerates neurodegeneration, filling a critical gap in understanding BPA's role in AD, PD, and HD. The study provides a novel theoretical framework and experimental evidence for BPA neurotoxicity risk assessment and informs preventive and therapeutic strategies for BPA-related neurodegenerative disorders.
1. Introduction
Bisphenol A (BPA) is a ubiquitous environmental contaminant used in plastics and resins, with global production exceeding 6 billion pounds annually. Despite its widespread use, BPA is a known endocrine disruptor linked to reproductive and metabolic disorders. Emerging evidence implicates BPA in neurodevelopmental and neurodegenerative processes, yet the molecular mechanisms underlying its neurotoxicity remain incompletely understood. Traditional toxicological assessments often focus on single endpoints or pathways, failing to capture the systemic and convergent effects of BPA on chronic diseases such as Alzheimer's, Parkinson's, and Huntington's.
This study addresses this bottleneck by employing a network toxicology framework combined with molecular docking and molecular dynamics simulations to systematically map BPA's interactions with disease-related protein networks. Using the human astrocyte SVGP12 cell model, we validate the predicted mechanisms, revealing that BPA disrupts critical survival and apoptotic pathways, leading to mitochondrial dysfunction and neurodegeneration. This integrative approach not only identifies shared molecular targets across multiple neurodegenerative diseases but also provides a robust platform for assessing environmental chemical risks and developing targeted interventions.
Loading authentic research manuscript (Pages 1–5)...
XU Jin, CHEN Xingxing, DENG Shan, LEI Zhigang, LIU Quanhui, HUANG Ben, ZHANG Dandan (2026). Network Toxicology and Molecular Dynamics Simulation Elucidate Bisphenol A-Induced Neurotoxicity in SVGP12 Astrocytes: Mechanistic Insights and Risk Assessment for Chronic Neurodegenerative Diseases. Environmental Chemistry. https://doi.org/10.7524/j.issn.0254-6108.2026030601
Research & Educational Purpose Only: The translations, structured abstracts, analytical annotations, and data reports provided by SinoGreenTechare intended exclusively for academic research, internal corporate R&D, and educational benchmarking. They do not constitute formal engineering, chemical safety, legal, or professional advice.
Copyright & Intellectual Property Notice: Original copyright of the underlying source articles and experimental data remains with the respective authors, institutions, and original publishing journals. SinoGreenTech claims intellectual property only over its proprietary translations, analytical syntheses, and AEO structured enhancements in accordance with international fair use and academic citation principles.
Frequently Asked Questions
What are the specific molecular pathways through which BPA induces neurotoxicity in astrocytes, and how do they converge across AD, PD, and HD?
BPA induces oxidative stress and cell cycle arrest in SVGP12 astrocytes, leading to mitochondrial apoptosis. Mechanistically, it inhibits the INS-AKT1-BCL2 anti-apoptotic pathway while activating the TP53-HSP90 pro-apoptotic pathway. These pathways converge on BCL2, a central regulator of apoptosis, which is consistently implicated across AD, PD, and HD, indicating a common mechanism of BPA neurotoxicity.
How were the six key toxic proteins identified, and what is the evidence for their functional relevance?
The proteins TP53, HSP90AA1, HSP90AB1, INS, BCL2, and AKT1 were identified via network toxicology analysis integrating BPA target prediction and disease gene databases. Molecular docking and dynamics simulations confirmed stable binding of BPA to these proteins. In vitro experiments using SVGP12 cells validated that BPA modulates their expression and downstream signaling, confirming their functional role in BPA-induced neurotoxicity.
What is the significance of using SVGP12 cells as a model for studying BPA neurotoxicity?
SVGP12 is a human astrocyte cell line, and astrocytes are critical for maintaining neuronal homeostasis. BPA-induced astrocyte dysfunction, including mitochondrial apoptosis and disruption of the neural microenvironment, directly contributes to neurodegeneration. This model allows mechanistic studies in a human-relevant cell type, providing translational relevance for understanding BPA's impact on chronic neurodegenerative diseases.
How does this study advance beyond traditional toxicological assessments of BPA?
Traditional studies often focus on single pathways or endpoints. This study employs a network toxicology approach that integrates multiple data sources and computational simulations to identify convergent mechanisms across multiple diseases. This holistic perspective reveals common targets and pathways, offering a more comprehensive understanding of BPA's neurotoxicity and potential for cross-disease intervention.
What are the implications of these findings for risk assessment and therapeutic development?
The identification of common key proteins (e.g., BCL2) provides specific targets for therapeutic intervention. The mechanistic insights into BPA-induced apoptosis pathways can inform risk assessment by highlighting potential biomarkers of exposure and effect. Additionally, the study supports the development of strategies to mitigate BPA neurotoxicity, such as antioxidants or pathway modulators, which could be applicable across AD, PD, and HD.
Related Chinese Research & Cross-Citations
Exploring the Potential Molecular Mechanisms of Eight Environmental Pollutants in Lung Adenocarcinoma through Network Toxicology, Machine Learning, and Multi-Omics Analysis
Epidemiological studies have established a significant association between exposure to environmental pollutants (EP) and the risk of lung adenocarcinoma (LUAD). This study integrates network toxicology and multi-omics analysis to elucidate the EP-LUAD molecular regulatory network and identify key regulatory genes, thereby revealing novel mechanisms of environmental carcinogenesis. Transcriptomic data from GEO and TCGA databases yielded 4,971 and 4,488 disease-related targets, respectively. Integration of toxicology databases (TargetNet, Swiss Target Prediction, CTD, SEA) identified 24,860 potential targets for eight common pollutants (SO2, NO, CO, NO2, O3, benzene, toluene, and polycyclic aromatic hydrocarbons). Intersection of these datasets produced 1,536 EP-LUAD common target genes. Protein-protein interaction network analysis identified 247 core targets. Machine learning selected five key genes: AGER, CAV1, CD44, CEP55, and GNB3, which demonstrated robust diagnostic and prognostic efficacy. Their expression correlated with immune cell infiltration, including CD4+ memory T cells and macrophages. Single-cell RNA sequencing revealed epithelial cell-specific expression patterns. Molecular docking confirmed stable pollutant-target binding, with PAH showing highest affinity for CD44 (binding energy −9.32 kcal·mol−1) and GNB3 (−8.32 kcal·mol−1). These findings establish AGER, CAV1, CD44, CEP55, and GNB3 as core molecular mediators of pollution-related LUAD. The high-affinity binding of PAH to CD44 and GNB3 underscores its carcinogenic potential. This study constructs a multi-level regulatory network for EP-LUAD, revealing underlying molecular mechanisms and providing novel potential targets and theoretical basis for early warning and intervention.
Effects of Different Functionalized Nanoplastics on the Transformation of Extracellular Antibiotic Resistance Genes in Aquatic Environments
The rapid dissemination of antibiotic resistance genes (ARGs) in aquatic environments poses serious threats to public health and environmental safety under the 'One Health' framework. Nanoplastics (NPs), as co-occurring pollutants, can exacerbate ARG risks by promoting horizontal gene transfer (HGT), yet the influence of different functional groups on extracellular ARG (eARG) transformation remains unclear. This study investigated the effects of carboxy-modified polystyrene NPs (PS-COOH) and amino-functionalized polystyrene NPs (PS-NH2) compared to unmodified polystyrene NPs (PS) on the transformation of the extracellular resistance plasmid IE-V1955 (carrying an ampicillin resistance gene) into Escherichia coli DH5α. Results showed that PS-COOH exposure promoted plasmid transformation similarly to PS, with effects increasing over 0.1–20 mg·L−1. Low concentrations (0.1–0.5 mg·L−1) of PS-NH2 also enhanced transformation, with stronger effects than PS-COOH at equal doses, whereas high concentrations (1–20 mg·L−1) inhibited it. Mechanistically, PS-COOH (0.1–20 mg·L−1) and low PS-NH2 induced intracellular reactive oxygen species (ROS), increased cell membrane permeability, elevated the protein-to-polysaccharide ratio in extracellular polymeric substances (EPS), and promoted biofilm formation, thereby facilitating transformation. High PS-NH2 concentrations caused excessive ROS leading to cell lysis and formed aggregates with plasmids larger than membrane pores, blocking uptake. These findings provide a theoretical basis for assessing the combined environmental health risks of NPs and ARGs.
Cardiovascular Toxicity Induced by Micro/Nano-Plastics and Its Mechanisms
Micro/nano-plastics (MNPs) are emerging contaminants widely detected in human circulatory systems, including blood, heart, and vascular endothelium, raising concerns about cardiovascular health risks. This systematic review analyzed 61 peer-reviewed studies (2008–2024) to elucidate the cardiotoxic effects and molecular mechanisms of MNPs. Evidence indicates that MNPs exposure elevates risks of atherosclerosis, thrombosis, and arrhythmias through oxidative stress, inflammatory cascades, endothelial dysfunction, and metabolic dysregulation. Notably, co-exposure with persistent organic pollutants (POPs) or heavy metals may produce synergistic or antagonistic effects. Current research relies predominantly on animal and cell models, with critical gaps in low-dose, long-term exposure data and epidemiological evidence. Future studies should optimize experimental designs, integrate metabolomics and epigenetics, and explore transgenerational effects and combined toxicity mechanisms to inform pollution control policies and mitigate cardiovascular risks.
Body Burden of Polybrominated Diphenyl Ethers and Joint Effects on Thyroid Function in a Physical Examination Population in Shenzhen
This study characterized the body burden of polybrominated diphenyl ethers (PBDEs) in a physical examination population in Shenzhen and evaluated its impact on thyroid function. Serum samples from 368 residents were analyzed for eight PBDE congeners using atmospheric pressure gas chromatography-tandem mass spectrometry (APGC-MS/MS). The median concentration of ∑8PBDEs was 10.2 ng·g⁻¹ lipid weight (lw), ranging from 0.13 to 2089.4 ng·g⁻¹ lw, with BDE-209 predominating (59.7% of total). Multiple linear regression revealed that a 1.7-fold increase in serum BDE-153 was associated with a 0.4% increase in free triiodothyronine (FT3) (P<0.05), while a 1.7-fold increase in BDE-183 was associated with a 0.9% decrease in total triiodothyronine (T3) and a 0.7% decrease in FT3 (P<0.05). Bayesian kernel machine regression (BKMR) indicated a negative correlation between mixed PBDE exposure and thyroid-stimulating hormone (TSH) at high exposure levels. Weighted quantile sum (WQS) regression showed that mixed exposure was associated with decreased T3 levels and T3/FT3 ratio, with BDE-153 and BDE-183 as the primary contributors. These findings suggest that PBDE exposure may adversely affect thyroid function and disrupt thyroid hormone homeostasis, with BDE-183 and BDE-153 playing key roles. This study provides a scientific basis for PBDE health risk assessment and thyroid protection.
Mechanisms of Natural Organic Matter in Regulating Microplastic Aggregation and Transport in Soil-Groundwater Systems: A Review
Microplastics (MPs) are persistent emerging contaminants ubiquitously distributed in soil-groundwater environments, where their aggregation and transport critically govern pollutant fate and ecological risks. Natural organic matter (NOM), a complex assemblage of organic compounds, interacts with MPs and porous media via hydrogen bonding, π-π interactions, hydrophobic effects, and electrostatic binding, thereby modulating MP surface properties and environmental behavior. This review systematically synthesizes the mechanisms by which NOM influences MP aggregation and transport, with emphasis on the distinct roles of humic substances, proteins, and extracellular polymeric substances (EPS), and their synergistic modulation with solution chemistry (pH, ionic strength, ion type). Additionally, NOM accelerates MP aging and alters surface characteristics, consequently impacting transport capacity. Current research limitations are identified, and future directions are proposed to inform MP pollution risk assessment and management strategies. Key findings indicate that NOM generally enhances MP stability and mobility at low ionic strengths, while high ionic strengths may induce aggregation depending on NOM type and ion valence. Humic substances predominantly increase electrostatic repulsion, whereas proteins and EPS can bridge particles, promoting aggregation. Aging processes, accelerated by NOM photochemical activity, increase surface oxygen functionality and hydrophilicity, further altering transport. The review underscores the need for systematic studies under environmentally relevant conditions to predict MP fate accurately.
Neurotoxicity of Carboxyl-Modified Polystyrene Microplastics on Zebrafish at Early Developmental Stage
Carboxyl-modified polystyrene microplastics (PS-COOH) are negatively charged particles formed by surface oxidation and functional group modification of polystyrene microplastics (PS), widely used in biomedical and analytical chemistry. However, studies on their neurotoxic effects on aquatic organisms are scarce. This study employed zebrafish (Danio rerio) as a model organism, exposing embryos to environmentally relevant concentrations (0.1, 1, 10, 100 μg·L−1) of PS and PS-COOH. Neurotoxic effects were assessed by measuring tail coiling frequency at 24 hpf and swimming velocity under alternating light/dark cycles at 120 hpf. Results demonstrated that both PS and PS-COOH induced neurotoxicity, with PS-COOH significantly reducing tail coiling frequency and average swimming speed compared to PS (P<0.05). Exposure to 10 μg·L−1 PS-COOH disrupted neurotransmitter homeostasis, altering levels of acetylcholine (ACh), serotonin (5-HT), and γ-aminobutyric acid (GABA). Transgenic zebrafish Tg(huc:EGFP) fluorescence assays revealed that PS-COOH (0.1–100 μg·L−1) caused damage to central neurons. These findings indicate that PS-COOH exposure impairs cholinergic, serotonergic, and GABAergic neurotransmission, induces neuronal damage, and exerts neurotoxic effects on zebrafish larvae. This study provides a theoretical basis for assessing the ecological and health risks of modified microplastics.