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We investigated the effects of inhaled benzene on pulmonary mechanics and surfactant homeostasis in diabetic mice with varying glycemic severity. Mildly hyperglycemic KK and severely hyperglycemic, insulin-resistant KK-Ay mice were exposed to filtered air or 50\u2009ppm benzene (6\u2009h\/d, 5\u2009d\/wk) for 2\u2009wk. Pulmonary function was assessed by the forced-oscillation technique, and bronchoalveolar lavage fluid was analyzed for surfactant proteins and lipid composition by lipidomics; whole-lung transcriptomes were profiled by RNA sequencing. Benzene increased respiratory system resistance and Newtonian resistance in KK-Ay mice without altering tissue elastance or compliance in either strain. Methacholine challenge revealed exaggerated bronchoconstriction in benzene-exposed KK-Ay mice, with significant increases in Rn and tissue damping absent in benzene-exposed KK controls. Surfactant protein B was reduced by benzene in both strains, whereas SP-C was diminished in benzene-exposed KK-Ay mice compared with benzene-exposed KK controls. Lipidomic profiling demonstrated benzene-induced surfactant lipid remodeling characterized by elevated triradylglycerols, increased phosphatidylcholine-to-phosphatidylethanolamine ratio, and reduced phosphatidylserine, with specific lipid classes correlating with airway resistance. Transcriptomic analysis identified enrichment of neurotransmitter transport, ion-channel, and calcium-regulated exocytosis pathways, alongside upregulation of phase II detoxification enzymes. These findings demonstrate that in severe hyperglycemic KK-Ay mice, benzene induced airway hyperresponsiveness through convergent disruption of surfactant protein\/lipid homeostasis, identifying poorly controlled diabetes as a risk factor for benzene-related respiratory toxicity.<\/jats:p>","DOI":"10.1093\/toxsci\/kfag054","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T12:01:33Z","timestamp":1778760093000},"source":"Crossref","is-referenced-by-count":0,"title":["Benzene-induced pulmonary dysfunction in diabetic mice"],"prefix":"10.1093","volume":"209","author":[{"given":"Ahtesham","family":"Hussain","sequence":"first","affiliation":[{"name":"University of Louisville Superfund Research Center, University of Louisville , Louisville, KY 40202,","place":["United States"]},{"name":"Envirome Institute, University of Louisville , Louisville, KY 40202,","place":["United States"]},{"name":"Division of Environmental Medicine, Department of Medicine, University of Louisville , Louisville, KY 40202,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Srivastava","sequence":"additional","affiliation":[{"name":"University of Louisville Superfund Research Center, University of Louisville , Louisville, KY 40202,","place":["United States"]},{"name":"Envirome Institute, University of Louisville , Louisville, KY 40202,","place":["United States"]},{"name":"Division of Environmental Medicine, Department of Medicine, University of Louisville , Louisville, KY 40202,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3976-3884","authenticated-orcid":false,"given":"Igor N","family":"Zelko","sequence":"additional","affiliation":[{"name":"University of Louisville Superfund Research Center, University of Louisville , Louisville, KY 40202,","place":["United States"]},{"name":"Envirome Institute, University of Louisville , Louisville, KY 40202,","place":["United States"]},{"name":"Division of Environmental Medicine, Department of Medicine, University of Louisville , Louisville, KY 40202,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"2026052911065911000_kfag054-B1","doi-asserted-by":"crossref","first-page":"e0183602","DOI":"10.1371\/journal.pone.0183602","article-title":"Benzene exposure is associated with cardiovascular disease risk","volume":"12","author":"Abplanalp","year":"2017","journal-title":"PLoS One"},{"key":"2026052911065911000_kfag054-B2","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1093\/toxsci\/kfy252","article-title":"Benzene exposure induces insulin resistance in mice","volume":"167","author":"Abplanalp","year":"2019","journal-title":"Toxicol Sci"},{"key":"2026052911065911000_kfag054-B3","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1164\/rccm.201006-0937OC","article-title":"Chronic obstructive pulmonary disease and long-term exposure to traffic-related air pollution: a cohort study","volume":"183","author":"Andersen","year":"2011","journal-title":"Am J Respir Crit Care Med"},{"key":"2026052911065911000_kfag054-B4","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/0041-008X(86)90390-X","article-title":"Effects of benzene inhalation on lymphocyte subpopulations and immune response in mice","volume":"85","author":"Aoyama","year":"1986","journal-title":"Toxicol Appl Pharmacol"},{"key":"2026052911065911000_kfag054-B5","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: tool for the unification of biology. 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