TY - JOUR T1 - Biomarkers of Cardiovascular Toxicity of Benzene Inhalation in Mice JF - bioRxiv DO - 10.1101/2021.08.31.458364 SP - 2021.08.31.458364 AU - Marina V. Malovichko AU - Wesley T. Abplanalp AU - Samantha A. McFall AU - Breandon S. Taylor AU - Nalinie S. Wickramasinghe AU - Israel D. Sithu AU - Igor N. Zelko AU - Shizuka Uchida AU - Saurin R. Sutaria AU - Michael H. Nantz AU - Aruni Bhatnagar AU - Daniel J. Conklin AU - Timothy E. O’Toole AU - Sanjay Srivastava Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/09/01/2021.08.31.458364.abstract N2 - Benzene is a ubiquitous environmental pollutant. Recent population-based studies suggest that benzene exposure is associated with an increased risk for cardiovascular disease. However, it is unclear whether benzene exposure is sufficient to induce cardiovascular toxicity. We examined the effects of benzene inhalation (50 ppm, 6 h/day, 5 days/week, 6 weeks) or HEPA-filtered air exposure on the biomarkers of cardiovascular toxicity in male C57BL/6J mice. Benzene inhalation significantly increased the biomarkers of endothelial activation and injury including endothelial microparticles, activated endothelial microparticles, endothelial progenitor cell microparticles, lung endothelial microparticles, and activated lung and endothelial microparticles while having no effect on circulating levels of endothelial adhesion molecules, endothelial selectins, and biomarkers of angiogenesis. To understand how benzene may induce endothelial injury, we exposed human aortic endothelial cells to benzene metabolites. Of metabolites tested, trans,trans-mucondialdehyde (10 μM, 18h) was most toxic. It induced caspases-3, −7 and −9 (intrinsic pathway) activation, and enhanced microparticle formation by 2.4-fold. Levels of plateletleukocyte aggregates, platelet macroparticles, and proportion of CD4+ and CD8+ T-cells were also significantly elevated in the blood of the benzene-exposed mice. We also found that benzene exposure increased the transcription of genes associated with endothelial cell and platelet activation in the liver; and induced inflammatory genes and suppressed cytochrome P450s in the lungs and the liver. Together, these data suggest that benzene exposure induces endothelial injury, enhances platelet activation and inflammatory processes; and circulatory levels of endothelial cell and platelet-derived microparticles and platelet-leukocyte aggregates are excellent biomarkers of cardiovascular toxicity of benzene.HighlightsInhaled benzene exposure increases the levels of blood endothelial microparticles.In vitro, benzene metabolite trans, trans-mucondialdehyde induces endothelial cell apoptosis and microparticles formation.Inhaled benzene exposure decreases the levels of hematopoietic progenitor cells in the bone marrow.Inhaled benzene exposure augments the circulating levels of platelet-leukocyte adducts.Competing Interest StatementThe authors have declared no competing interest. ER -