Multi-omics integrative analysis of the mechanisms linking environmental pollutant exposure to bladder cancer pathogenesis

Bladder cancer (BCa), the most prevalent malignancy of the urinary system, is strongly associated with environmental factors including smoking and industrial chemical exposure. Although previous studies have explored the relationship between various environmental pollutants and BCa mechanisms, there is still a need for an in-depth analysis of the specific effects and particular roles of these pollutants. This study investigates the molecular mechanisms linking environmental pollutant exposure to bladder carcinogenesis through a multi-omics integrative analysis that systematically elucidates the environment-gene interaction network. By integrating transcriptomic data from multiple BCa cohorts with the Comparative Toxicogenomics Database (CTD) gene-chemical-disease network, we identified 168 environment-responsive differentially expressed genes (DEGs). Subsequent Mendelian Randomization (MR), Summary-data-based MR (SMR), and colocalization analyses revealed three causal hub genes (CTSK, GSTM5, and PAFAH1B3; PP4 > 0.70) and associated them with 34 high-risk environmental pollutants. Molecular docking demonstrated strong binding affinities between these hub genes and more than ten pollutants, with bisphenol A, sodium arsenite, and tetrachlorodibenzodioxin (TCDD) differentially regulating distinct targets: significantly suppressing tumor-suppressor genes CTSK (OR = 0.91, p = 0.004) and GSTM5 (OR = 0.77, p < 0.001) while upregulating the oncogenic factor PAFAH1B3 (OR = 2.11, p < 0.001). Single-cell RNA sequencing (scRNA-seq) analysis and Human Protein Atlas (HPA) database validation confirmed tissue-specific expression patterns of these hub genes in bladder tissues. Our findings establish a comprehensive evidence chain connecting "environmental pollutant exposure - gene interaction - bladder carcinogenesis," providing novel biomarkers and preventive targets for molecular subtyping and precision prevention of environmentally associated BCa.