Attribution of PM 2.5 -Induced Transcriptomic Perturbation to Toxic Components

High Resolution Image Download MS PowerPoint Slide Ambient fine particulate matter (PM 2.5 ) is a chemically complex mixture whose health impacts are not fully captured by particle mass. Here, we developed an interpretable chemotranscriptomic framework to attribute PM 2.5 -induced molecular perturbations to toxicity-relevant components. PM 2.5 collected from urban roadside and coastal environments was separated into whole, extractable, and unextractable fractions, characterized by LC/GC × GC–HRMS-based nontarget analysis and inductively coupled plasma mass spectrometry (ICP–MS), and evaluated using cytotoxicity testing and transcriptomic profiling in human bronchial epithelial cells. Urban PM 2.5 exhibited greater cytotoxic potency per unit mass than coastal PM 2.5, with extractable fractions accounting for most cytotoxic and pathway-level responses. Transcriptomics revealed distinct site-specific modes of action: urban PM 2.5 preferentially induced oxidative stress, xenobiotic metabolism, and cell cycle suppression, consistent with acute, nonapoptotic injury, whereas coastal PM 2.5 elicited weaker cytotoxicity but stronger interferon-mediated immune and apoptosis-related signaling. Integrating chemical abundance with pathway activity using random forest regression, SHAP interpretation, and mechanistic corroboration reduced 5,033 detected features to 444 pathway-linked candidate drivers. Fewer than 5% of features explained ∼95% of cumulative model contribution. Standard-confirmed contributors included plasticizer-related compounds, aromatic and heteroaromatic combustion products, and copper for urban PM 2.5 and secondary/aged organics and nickel for coastal PM 2.5 . These findings support mechanism-informed prioritization of hazardous PM 2.5 components beyond mass-based assessment.