{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:49:25Z","timestamp":1785408565790,"version":"3.56.0"},"reference-count":38,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,4,5]],"date-time":"2026-04-05T00:00:00Z","timestamp":1775347200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010178","name":"Indiana University Bloomington","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100010178","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/02k40bc56","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Sex differences in lung cancer incidence and outcomes are well recognized, yet the relative contributions of sex chromosomes and gonadal sex remain incompletely defined. We aimed to disentangle chromosomal complement and hormonal sex in urethane-induced lung tumorigenesis using the Four Core Genotypes mouse model. Methods: Mice (6\u20138 weeks old) with independently varied chromosomal complement (XX vs. XY) and gonadal sex received urethane (1 g\/kg body weight) weekly for 10 weeks and were evaluated after a 20-week latency period. Tumor multiplicity, tumor area, normalized tumor burden, and Ki-67 proliferation indices were quantified histologically. Hepatic Cyp2e1 expression was measured to assess carcinogen bioactivation. Tumor mutations were analyzed by Sanger sequencing. RAS Q61R immunoreactivity and ERK phosphorylation were evaluated to assess oncogenic signaling. Bronchoalveolar lavage fluid cellularity was analyzed. Survival was monitored. Statistical analyses tested the main effects of chromosomal complement, gonadal sex, and their interaction. Results: Tumor multiplicity (p = 0.0729), tumor area (p = 0.5302), normalized tumor burden (p = 0.5316), and Ki-67 indices (p = 0.6551) did not differ among genotypes. Hepatic Cyp2e1 expression was comparable across groups (genotype p = 0.076; treatment p = 0.445). Sanger sequencing confirmed canonical Kras Q61R mutations. Anti-RAS (Q61R) immunohistochemistry revealed a significant genotype effect on mutant RAS expression (F(3,23) = 3.48, p = 0.032), with the highest H-scores observed in XYF mice compared with male gonadal genotypes; ERK phosphorylation did not differ. Bronchoalveolar lavage fluid analysis revealed increased lymphocytes after urethane exposure without genotype-dependent effects. Survival differed significantly, with XX females demonstrating prolonged survival relative to XY males. Conclusions: Sex influenced survival independently of tumor burden, indicating that sex-associated differences in lung cancer outcomes are likely driven by systemic or microenvironmental factors rather than tumor-intrinsic growth mechanisms.<\/jats:p>","DOI":"10.3390\/cancers18071172","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T00:19:32Z","timestamp":1775434772000},"page":"1172","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dissecting Sex Chromosome and Hormonal Contributions to Urethane-Induced Lung Tumorigenesis Using the Four Core Genotypes Mouse Model"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2110-4218","authenticated-orcid":false,"given":"Maksat","family":"Babayev","sequence":"first","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health-Bloomington, Indiana University, Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar A.","family":"Borges-Sosa","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health-Bloomington, Indiana University, Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9045-4457","authenticated-orcid":false,"given":"Carolyn D.","family":"Ekpruke","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health-Bloomington, Indiana University, Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Parker","sequence":"additional","affiliation":[{"name":"Biostatistics Consulting Center, Department of Epidemiology and Biostatistics, School of Public Health-Bloomington, Indiana University, Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3377-9324","authenticated-orcid":false,"given":"Dustin","family":"Rousselle","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health-Bloomington, Indiana University, Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyidia","family":"Dinwiddie","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health-Bloomington, Indiana University, Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Alford","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health-Bloomington, Indiana University, Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shikha","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Forensic Science, Henry C. Lee College of Criminal Justice and Forensic Sciences, University of New Haven, West Haven, CT 06516, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Praveen","family":"Chirumamilla","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health-Bloomington, Indiana University, Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle C.","family":"Boulos","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health-Bloomington, Indiana University, Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aakash","family":"Parekh","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health-Bloomington, Indiana University, Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew L.","family":"Retzner","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health-Bloomington, Indiana University, Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5797-3458","authenticated-orcid":false,"given":"Catherine R.","family":"Sears","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Section, Department of Medicine, Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA"},{"name":"Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"},{"name":"Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E.","family":"Klaunig","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health-Bloomington, Indiana University, Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Commodore","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health-Bloomington, Indiana University, Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7083-8915","authenticated-orcid":false,"given":"Patricia","family":"Silveyra","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health-Bloomington, Indiana University, Bloomington, IN 47405, USA"},{"name":"Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,5]]},"reference":[{"key":"ref_1","first-page":"10","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel","year":"2025","journal-title":"CA Cancer J. 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