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Major PM2.5 components promote intracranial aneurysm via TP53: Insights from a comprehensive network analysis
Guanhui Li1, Keyu Yan1, Yuxiang Sun2
1Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050061, China.
Abstract:
In this study, we combined network toxicology with two-sample Mendelian randomization (MR) to investigate the potential mechanisms by which major components of PM2.5 influence the development of intracranial aneurysms (IAs). We first identified the target genes of six representative PM2.5 constituents (lead, cadmium, arsenic, benzo[a]pyrene, formaldehyde, and benzene) using the Comparative Toxicogenomics Database (CTD). We intersected these with a compiled list of intracranial aneurysm-related genes. This analysis highlighted TP53 as a key hub gene. MR analysis revealed a significant causal association between genetically predicted TP53 expression and aneurysm risk, suggesting that higher TP53 levels may be protective against intracranial aneurysm (odds ratio 0.850; 95 % CI: 0.734-0.985; P = 0.030). Subsequent molecular docking and dynamics simulations showed that PM2.5 components-especially benzo[a]pyrene-bind directly to the TP53 protein, potentially interfering with its function. Single-cell RNA sequencing and gene set enrichment analysis further indicated that high TP53 expression may protect vascular integrity and retard aneurysm progression by regulating pathways related to the cell cycle, apoptosis, inflammation, and oxidative stress. Moreover, protein expression and apoptosis assays in our cell-based experiments corroborated our findings. Together, these results form a chain of evidence linking PM2.5 exposure to intracranial aneurysm phenotypes via TP53. Our findings identify TP53 as the core mediator through which PM2.5 constituents promote intracranial aneurysm formation. This study provides new insight into how air pollution induces cerebrovascular disease and suggests potential molecular targets for intracranial aneurysm prevention and intervention.
Insights
Air pollution (PM2.5) may increase intracranial aneurysm (IA) risk by affecting the TP53 gene. Higher TP53 levels appear protective against IA development, offering potential intervention targets for cerebrovascular disease.
Area of Science:
- Environmental Toxicology
- Genetics
- Cardiovascular Research
Background:
- Particulate matter (PM2.5) exposure is linked to various health issues, including cerebrovascular diseases.
- Intracranial aneurysms (IAs) are a significant cause of subarachnoid hemorrhage.
- The precise mechanisms by which PM2.5 contributes to IA development remain unclear.
Purpose of the Study:
- To investigate the molecular mechanisms linking PM2.5 exposure to intracranial aneurysm (IA) development.
- To identify key genes and pathways involved in this association using network toxicology and Mendelian randomization (MR).
- To explore the role of the TP53 gene as a potential mediator.
Main Methods:
- Network toxicology approach to identify PM2.5 target genes from the Comparative Toxicogenomics Database (CTD).
- Intersection of PM2.5 target genes with IA-related genes to identify hub genes.
- Two-sample Mendelian randomization (MR) analysis to assess the causal effect of TP53 expression on IA risk.
- Molecular simulations and cell-based assays to validate findings.
Main Results:
- TP53 was identified as a key hub gene linking PM2.5 constituents to IA.
- Genetically predicted higher TP53 expression was causally associated with a reduced risk of IA (OR 0.850).
- PM2.5 components, particularly benzo[a]pyrene, were shown to bind to TP53, potentially altering its function.
- TP53 expression influences cell cycle, apoptosis, inflammation, and oxidative stress pathways, supporting vascular integrity.
Conclusions:
- PM2.5 exposure can promote intracranial aneurysm formation through the TP53 gene.
- TP53 acts as a central mediator, with higher expression offering protection against IA.
- This study provides novel insights into air pollution-induced cerebrovascular disease and identifies TP53 as a potential therapeutic target for IA prevention.
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