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Here, we developed an interpretable chemotranscriptomic framework to attribute PM2.5-induced molecular perturbations to toxicity-relevant components. PM2.5 collected from urban roadside and coastal environments was separated into whole, extractable, and unextractable fractions, characterized by LC\/GC \u00d7 GC\u2013HRMS-based nontarget analysis and inductively coupled plasma mass spectrometry (ICP\u2013MS), and evaluated using cytotoxicity testing and transcriptomic profiling in human bronchial epithelial cells. Urban PM2.5 exhibited greater cytotoxic potency per unit mass than coastal PM2.5, with extractable fractions accounting for most cytotoxic and pathway-level responses. Transcriptomics revealed distinct site-specific modes of action: urban PM2.5 preferentially induced oxidative stress, xenobiotic metabolism, and cell cycle suppression, consistent with acute, nonapoptotic injury, whereas coastal PM2.5 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 \u223c95% of cumulative model contribution. Standard-confirmed contributors included plasticizer-related compounds, aromatic and heteroaromatic combustion products, and copper for urban PM2.5 and secondary\/aged organics and nickel for coastal PM2.5. These findings support mechanism-informed prioritization of hazardous PM2.5 components beyond mass-based assessment.<\/jats:p>","DOI":"10.1021\/acs.est.6c05482","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T11:55:56Z","timestamp":1784548556000},"page":"23840-23851","source":"Crossref","is-referenced-by-count":1,"title":["Attribution of PM2.5-Induced Transcriptomic\nPerturbation to Toxic Components"],"prefix":"10.1021","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9724-4628","authenticated-orcid":true,"given":"Shihao","family":"Wang","sequence":"first","affiliation":[{"name":"The Hong Kong Polytechnic University , , Hung Hom , , ,","place":["Kowloon, Hong Kong, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Li","sequence":"additional","affiliation":[{"name":"The Hong Kong Polytechnic University , , Hung Hom , , ,","place":["Kowloon, Hong Kong, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1855-4389","authenticated-orcid":true,"given":"Yong","family":"Han","sequence":"additional","affiliation":[{"name":"The Hong Kong Polytechnic University , , Hung Hom , , ,","place":["Kowloon, Hong Kong, China, 999077"]},{"name":"The Hong Kong Polytechnic University Shenzhen Research Institute , ,","place":["Shenzhen, China, 518057"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8784-7436","authenticated-orcid":true,"given":"Shulan","family":"Qiu","sequence":"additional","affiliation":[{"name":"The Hong Kong Polytechnic University , , Hung Hom , , ,","place":["Kowloon, Hong Kong, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhu","sequence":"additional","affiliation":[{"name":"The Hong Kong Polytechnic University , , Hung Hom , , ,","place":["Kowloon, Hong Kong, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyan","family":"Yu","sequence":"additional","affiliation":[{"name":"The Hong Kong Polytechnic University , , Hung Hom , , ,","place":["Kowloon, Hong Kong, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3943-6413","authenticated-orcid":true,"given":"Changchao","family":"Li","sequence":"additional","affiliation":[{"name":"The Hong Kong Polytechnic University , , Hung Hom , , ,","place":["Kowloon, Hong Kong, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xintong","family":"Liu","sequence":"additional","affiliation":[{"name":"The Hong Kong Polytechnic University , , Hung Hom , , ,","place":["Kowloon, Hong Kong, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4998-9791","authenticated-orcid":true,"given":"Weixiong","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Hong Kong Polytechnic University , , Hung Hom , , ,","place":["Kowloon, Hong Kong, China, 999077"]},{"name":"The Hong Kong Polytechnic University , , , ,","place":["Kowloon, Hong Kong, China, 999077"]},{"name":"The Hong Kong Polytechnic University , , , ,","place":["Kowloon, Hong Kong, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5220-7009","authenticated-orcid":true,"given":"Guangbo","family":"Qu","sequence":"additional","affiliation":[{"name":"Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , , ,","place":["Beijing, China, 100085"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[{"name":"City University of Hong Kong , , , ,","place":["Kowloon, Hong Kong, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7464-3437","authenticated-orcid":true,"given":"Kin Fai","family":"Ho","sequence":"additional","affiliation":[{"name":"The Chinese University of Hong Kong , , , ,","place":["Shatin, N.T., Hong Kong, China, 999077"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank J.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Imperial College London , , ,","place":["London, United Kingdom, W2 1PG"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5449-5836","authenticated-orcid":true,"given":"Chris K. 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Pollut."},{"issue":"5","key":"2026090307131049200_cit8","doi-asserted-by":"publisher","first-page":"2926","DOI":"10.1021\/acs.est.7b06376","article-title":"Development and application of a\nnovel bioassay system for dioxin\ndetermination and aryl hydrocarbon receptor activation evaluation\nin ambient-air samples","volume":"52","author":"Zhang","year":"2018","journal-title":"Environ. Sci. Technol."},{"issue":"24","key":"2026090307131049200_cit9","doi-asserted-by":"publisher","first-page":"10458","DOI":"10.1021\/acs.est.3c10012","article-title":"Multilevel screening\nstrategy to identify the hydrophobic organic components of ambient\nPM2.5 associated with hepatocellular steatosis","volume":"58","author":"Yan","year":"2024","journal-title":"Environ. Sci. 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Sci. Technol."},{"key":"2026090307131049200_cit16","unstructured":"World Health Organization.\n          .  WHO Guidelines for Indoor Air Quality: Selected\nPollutantsWorld Health Organization: Geneva; 2010."},{"key":"2026090307131049200_cit17","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1016\/j.envpol.2017.07.006","article-title":"Association\nof individual-level concentrations and human respiratory tract deposited\ndoses of fine particulate matter with alternation in blood pressure","volume":"230","author":"Yin","year":"2017","journal-title":"Environ. Pollut."},{"issue":"2","key":"2026090307131049200_cit18","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1152\/jappl.1986.60.2.532","article-title":"Estimation\nof volume\nof epithelial lining fluid recovered by lavage using urea as marker\nof dilution","volume":"60","author":"Rennard","year":"1986","journal-title":"J. Appl. 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