Exploring the mechanisms underlying effects of oxygenated polycyclic aromatic hydrocarbons exposure on inflammatory bowel disease

Oxygenated polycyclic aromatic hydrocarbons (OPAHs), emerging contaminants in the environment, demonstrate heightened toxicity versus their parent compounds, creating substantial health hazards. Inflammatory bowel disease (IBD) encompasses chronic conditions marked by severe inflammation in the digestive tract. Environmental factors contribute to the development of both types of IBD. However, the toxicological mechanisms underlying OPAHs-induced IBD remain poorly understood. This investigation methodically examined the potential connection between OPAHs and IBD, identifying key genes involved in OPAHs-induced IBD. Using a network toxicology approach, 324 overlapping genes were identified between disease targets and five representative OPAHs effectors. These genes were further refined to 15 potential targets through analysis with STRING and Cytoscape. GO and KEGG pathway enrichment analyses indicated these targets primarily participate in oxidative stress responses, cell death, chemical stress reactions, inflammatory processes, and immune pathways. Subsequent analysis with machine learning algorithms highlighted three core targets: AKT1, ALB, and APP. Immune landscape analysis and single-cell RNA sequencing demonstrated strong associations between these hub genes and immune cell infiltration and immune responses. Molecular docking revealed high binding affinities between OPAHs and these hub proteins. In vitro experiments confirmed that OPAHs significantly elevated reactive oxygen species levels and induced intestinal epithelial barrier dysfunction. This study elucidates the molecular mechanisms through which OPAHs influence IBD development, offering valuable insights into the health risks posed by environmental pollutants and identifying potential targets for therapeutic development. • Integrated computational toxicology and experiments to explore the impact of OPAHs on IBD. • Identified AKT1/ALB/APP as core targets in OPAHs-induced IBD. • Uncovered oxidative stress and immune activation for OPAHs-induced IBD. • OPAHs triggered ROS production and induced gut barrier dysfunction. • Developed a novel paradigm for health risk assessments of environmental contaminants.