{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T14:01:54Z","timestamp":1774274514153,"version":"3.50.1"},"reference-count":65,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T00:00:00Z","timestamp":1774137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002850","name":"Fondecyt-ANID","doi-asserted-by":"publisher","award":["1221033"],"award-info":[{"award-number":["1221033"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002850","name":"Fondecyt-ANID","doi-asserted-by":"publisher","award":["1220353"],"award-info":[{"award-number":["1220353"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002850","name":"Fondecyt-ANID","doi-asserted-by":"publisher","award":["1231773"],"award-info":[{"award-number":["1231773"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002850","name":"Fondecyt-ANID","doi-asserted-by":"publisher","award":["1231275"],"award-info":[{"award-number":["1231275"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002850","name":"Fondecyt-ANID","doi-asserted-by":"publisher","award":["1230102"],"award-info":[{"award-number":["1230102"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002850","name":"Fondecyt-ANID","doi-asserted-by":"publisher","award":["1231537"],"award-info":[{"award-number":["1231537"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Chronic exposure to benzo[a]pyrene (BaP), a Group 1 IARC carcinogen, is a major driver of lung carcinogenesis; however, how sustained subcytotoxic exposure reprograms bronchial epithelium toward preneoplastic states remains poorly defined. Here, we subjected BEAS-2B human bronchial epithelial cells to 12 weeks of continuous BaP at environmentally relevant concentrations (0.1 and 1.0 \u00b5M) and interrogated the resulting phenotypes using an integrated multi-scale framework encompassing functional toxicology, RT-qPCR, RNA-seq, phospho-kinase\/NF-\u03baB arrays, and organotypic air\u2013liquid interface (ALI) cultures. Cells maintained metabolic competence throughout, evidenced by sustained CYP1A1 and CYP1B1 induction at both acute (4 h) and chronic (12-week) timepoints, while accumulating genotoxic stress as demonstrated by dose-dependent nuclear \u03b3-H2AX foci formation and ATM phosphorylation (Ser1981). RNA-seq revealed a dose-dependent transcriptional shift: 0.1 \u00b5M BaP yielded 119 differentially expressed genes (DEGs; |log2FC| \u2265 1, FDR &lt; 0.05), whereas 1.0 \u00b5M generated 255 DEGs. Downregulated transcripts were enriched for extracellular matrix and cell-adhesion programs (COL14A1, ADAMTS2, CSMD3, CADM3), while upregulated genes encompassed inflammatory, calcium-signaling, and vesicle-trafficking modules (NFATC4, CSF2RA, SYT1, PCLO). Phospho-kinase\/NF-\u03baB arrays confirmed a p53\/NF-\u03baB signaling nexus, with concurrent activation of MAPK\/ERK (Thr202\/Tyr204) and PI3K\/Akt (Ser473) pathways. Despite persistent genotoxic stress, cells did not acquire anchorage-independent growth and remained non-tumorigenic in vivo. Critically, ALI organotypic cultures derived from BaP-exposed cells exhibited histological dysplasia, nuclear pleomorphism, and disrupted apical-basal polarity. These findings mechanistically link chronic BaP exposure to an initiation-like preneoplastic state and establish a validated 2D\/3D multi-omics platform for PAH-driven lung carcinogenesis research.<\/jats:p>","DOI":"10.3390\/cells15060566","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:07:06Z","timestamp":1774271226000},"page":"566","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modeling Chronic BaP Exposure in Bronchial Epithelial Cells Reveals Multi-Scale Drivers of Early Preneoplastic Reprogramming"],"prefix":"10.3390","volume":"15","author":[{"given":"Cristian","family":"Andrade-Madrigal","sequence":"first","affiliation":[{"name":"Laboratory of Oncovirology, Departamento de Ciencias Biom\u00e9dicas, Facultad de Medicina, Universidad de Tarapac\u00e1, Arica 1000000, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cecilia","family":"Rojas-Fuentes","sequence":"additional","affiliation":[{"name":"Laboratorio de Virolog\u00eda Molecular y Celular, N\u00facleo Interdisciplinario de Microbiolog\u00eda, Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile"},{"name":"Instituto Milenio en Inmunolog\u00eda e Inmunoterapia, Santiago 8380453, Chile"},{"name":"Center for HIV\/AIDS Integral Research (CHAIR), Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"D\u00edaz-Mijares","sequence":"additional","affiliation":[{"name":"Laboratorio de Virolog\u00eda Molecular y Celular, N\u00facleo Interdisciplinario de Microbiolog\u00eda, Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile"},{"name":"Instituto Milenio en Inmunolog\u00eda e Inmunoterapia, Santiago 8380453, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3542-296X","authenticated-orcid":false,"given":"Gloria M.","family":"Calaf","sequence":"additional","affiliation":[{"name":"Instituto de Alta Investigaci\u00f3n, Universidad de Tarapac\u00e1, Arica 1000000, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4342-8069","authenticated-orcid":false,"given":"Pablo M.","family":"Santoro","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Faculty of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Portugal 61, Santiago 8330023, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandro H.","family":"Corval\u00e1n","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Faculty of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Portugal 61, Santiago 8330023, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisca J.","family":"Medina","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Cl\u00ednicas, Facultad de Ciencias Veterinarias y Pecuarias, Universidad de Chile, Santiago 8320000, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0019-2404","authenticated-orcid":false,"given":"Cristian G.","family":"Torres","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Cl\u00ednicas, Facultad de Ciencias Veterinarias y Pecuarias, Universidad de Chile, Santiago 8320000, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paula","family":"Romero-Vicencio","sequence":"additional","affiliation":[{"name":"Laboratorio de Transformaci\u00f3n Celular, N\u00facleo Interdisciplinario de Biolog\u00eda y Gen\u00e9tica (NiBG), Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile, Av. Independencia 1027, Santiago 8380453, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1678-2708","authenticated-orcid":false,"given":"Julio C.","family":"Tapia","sequence":"additional","affiliation":[{"name":"Laboratorio de Transformaci\u00f3n Celular, N\u00facleo Interdisciplinario de Biolog\u00eda y Gen\u00e9tica (NiBG), Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile, Av. Independencia 1027, Santiago 8380453, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2289-6667","authenticated-orcid":false,"given":"M\u00f3nica L.","family":"Acevedo","sequence":"additional","affiliation":[{"name":"Laboratorio de Virolog\u00eda Molecular y Celular, N\u00facleo Interdisciplinario de Microbiolog\u00eda, Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile"},{"name":"Instituto Milenio en Inmunolog\u00eda e Inmunoterapia, Santiago 8380453, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0945-2970","authenticated-orcid":false,"given":"Ricardo","family":"Soto-Rifo","sequence":"additional","affiliation":[{"name":"Laboratorio de Virolog\u00eda Molecular y Celular, N\u00facleo Interdisciplinario de Microbiolog\u00eda, Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile"},{"name":"Instituto Milenio en Inmunolog\u00eda e Inmunoterapia, Santiago 8380453, Chile"},{"name":"Center for HIV\/AIDS Integral Research (CHAIR), Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1900-0273","authenticated-orcid":false,"given":"Enrique","family":"Boccardo","sequence":"additional","affiliation":[{"name":"Laboratory of Oncovirology, Department of Microbiology, Instituto de Ci\u00eancias Biom\u00e9dicas, Universidade de S\u00e3o Paulo, Sao Paulo 05508-900, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco","family":"Aguayo","sequence":"additional","affiliation":[{"name":"Laboratory of Oncovirology, Departamento de Ciencias Biom\u00e9dicas, Facultad de Medicina, Universidad de Tarapac\u00e1, Arica 1000000, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,22]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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