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Title: Subclinical markers of cardiovascular toxicity of benzene inhalation in mice.

Authors: Malovichko, Marina V; Abplanalp, Wesley T; McFall, Samantha A; Taylor, Breandon S; Wickramasinghe, Nalinie S; Sithu, Israel D; Zelko, Igor N; Uchida, Shizuka; Hill, Bradford G; Sutaria, Saurin R; Nantz, Michael H; Bhatnagar, Aruni; Conklin, Daniel J; O'Toole, Timothy E; Srivastava, Sanjay

Published In Toxicol Appl Pharmacol, (2021 Nov 15)

Abstract: 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 by itself 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 the metabolites tested, trans,trans-mucondialdehyde (10 μM, 18h) was the most toxic. It induced caspases-3, -7 and -9 (intrinsic pathway) activation and enhanced microparticle formation by 2.4-fold. Levels of platelet-leukocyte aggregates, platelet macroparticles, and a 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.

PubMed ID: 34624356 Exiting the NIEHS site

MeSH Terms: Animals; Asymptomatic Diseases; Benzene/administration & dosage; Benzene/toxicity*; Biomarkers/blood; Blood Platelets/drug effects; Blood Platelets/metabolism; Blood Platelets/pathology; Cardiotoxicity; Cardiovascular Diseases/blood; Cardiovascular Diseases/chemically induced*; Cardiovascular Diseases/pathology; Cardiovascular System/drug effects*; Cardiovascular System/metabolism; Cardiovascular System/pathology; Cell-Derived Microparticles/drug effects; Cell-Derived Microparticles/metabolism; Cell-Derived Microparticles/pathology; Endothelial Cells/drug effects; Endothelial Cells/metabolism; Endothelial Cells/pathology; Hematopoietic Stem Cells/drug effects; Hematopoietic Stem Cells/metabolism; Hematopoietic Stem Cells/pathology; Inhalation Exposure; Leukocytes/drug effects; Leukocytes/metabolism; Leukocytes/pathology; Male; Mice, Inbred C57BL

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