{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T23:48:39Z","timestamp":1768520919526,"version":"3.49.0"},"posted":{"date-parts":[[2025,2,2]]},"group-title":"Pharmacology and Toxicology","reference-count":5,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,2]],"date-time":"2025-02-02T00:00:00Z","timestamp":1738454400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,2]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n Benzene is a ubiquitous environmental pollutant generated by a variety of natural and anthropological sources. It is a known carcinogen and hematopoietic toxin; however, little is known about benzene\u2019s potential atherogenicity.<\/jats:p>\n <\/jats:sec>\n \n Hypothesis<\/jats:title>\n Inhaled benzene induces atherogenesis by increasing vascular inflammation in LDL receptor Knockout (LDLR-KO) mice.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Male LDLR-KO mice were exposed to HEPA-filtered air or benzene (1 ppm, 6h\/day, 5days\/week) for 24 weeks. For the last 12 weeks of exposure, the mice were maintained on a western diet. The single nuclei RNA sequencing (snRNAseq) of aortae was performed at Novogene. For\n in vitro<\/jats:italic>\n experiments, splenic na\u00efve T cells were exposed to 1 \u00b5M of hydroquinone (HQ) for 24 hours, and intracellular ROR-gamma levels were measured by flow cytometry.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Benzene inhalation increased the aortic valve lesion area by more than 25% (P<0.05) in LDLR-KO mice. Using snRNAseq, eleven major cell types were detected, including T cells and vascular smooth muscle cells (VSMC). Benzene increased the number of T cells by 2.5-fold, proliferating T-cells by 5.8-fold, and VSMC by 1.6-fold, suggesting increased cellularity and reduced plaque stability. In addition, benzene upregulated Th17 polarization marker\n Rorc<\/jats:italic>\n and negative regulators of apoptosis\n Rag1<\/jats:italic>\n and\n Bcl11b<\/jats:italic>\n while significantly attenuating the expression of proliferation inhibitor\n Ms4a4b<\/jats:italic>\n in T cells. In VSMC, benzene downregulated extracellular matrix organization genes and upregulated platelet degranulation pathways. Polarization of T cells into Th17 was confirmed by HQ-dependent upregulation of ROR-gamma\n in vitro<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n Our data suggest that inhaled benzene exposure compromises plaque cellularity and stability by facilitating T-cell proliferation and polarization, which coincides with the degradation of smooth muscle extracellular matrix and platelet activation.<\/jats:p>\n <\/jats:sec>","DOI":"10.1101\/2025.01.29.635519","type":"posted-content","created":{"date-parts":[[2025,2,2]],"date-time":"2025-02-02T23:10:21Z","timestamp":1738537821000},"source":"Crossref","is-referenced-by-count":1,"title":["Chronic Inhaled Benzene Exposure Exacerbates Atherosclerosis in LDL Receptor-Null Mice"],"prefix":"10.64898","author":[{"given":"Igor N.","family":"Zelko","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina V.","family":"Malovichko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha A.","family":"McFall","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Breandon S.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel J.","family":"Conklin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjay","family":"Srivastava","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025020410051148000_2025.01.29.635519v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-020-0371-2"},{"key":"2025020410051148000_2025.01.29.635519v1.2","unstructured":"PHS USDoHaHS. Agency for Toxic Substances and Disease Registry (ATSDR): Toxicological profile for benzene. 2007:1\u2013438."},{"key":"2025020410051148000_2025.01.29.635519v1.3","doi-asserted-by":"publisher","DOI":"10.1006\/enrs.1998.3845"},{"key":"2025020410051148000_2025.01.29.635519v1.4","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.120.316903"},{"key":"2025020410051148000_2025.01.29.635519v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03493-5"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.01.29.635519","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T07:58:24Z","timestamp":1768463904000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.01.29.635519"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,2]]},"references-count":5,"URL":"https:\/\/doi.org\/10.1101\/2025.01.29.635519","relation":{},"subject":[],"published":{"date-parts":[[2025,2,2]]},"subtype":"preprint"}}