Chronic Benzene Exposure Aggravates Pressure Overload-Induced Cardiac Dysfunction

• Published in: Toxicological sciences Vol. 185; no. 1; pp. 64 - 76
• Main Authors: Zelko, Igor N, Dassanayaka, Sujith, Malovichko, Marina V, Howard, Caitlin M, Garrett, Lauren F, Uchida, Shizuka, Brittian, Kenneth R, Conklin, Daniel J, Jones, Steven P, Srivastava, Sanjay
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 28.12.2021
• Subjects: Animals; Benzene - toxicity; Endothelial Cells - metabolism; Environmental Toxicology; Heart Failure; Male; Mice; Mice, Inbred C57BL; Ventricular Remodeling - physiology; heart failure; endothelial cells; RNA-seq; adhesion molecules; neutrophils; benzene
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfab125

Abstract Benzene is a ubiquitous environmental pollutant abundant in household products, petrochemicals, and cigarette smoke. Benzene is a well-known carcinogen in humans and experimental animals; however, little is known about the cardiovascular toxicity of benzene. Recent population-based studies indicate that benzene exposure is associated with an increased risk for heart failure. Nonetheless, it is unclear whether benzene exposure is sufficient to induce and/or exacerbate heart failure. We examined the effects of benzene (50 ppm, 6 h/day, 5 days/week, and 6 weeks) or high-efficiency particulate absorbing-filtered air exposure on transverse aortic constriction (TAC)-induced pressure overload in male C57BL/6J mice. Our data show that benzene exposure had no effect on cardiac function in the Sham group; however, it significantly compromised cardiac function as depicted by a significant decrease in fractional shortening and ejection fraction, as compared with TAC/Air-exposed mice. RNA-seq analysis of the cardiac tissue from the TAC/benzene-exposed mice showed a significant increase in several genes associated with adhesion molecules, cell-cell adhesion, inflammation, and stress response. In particular, neutrophils were implicated in our unbiased analyses. Indeed, immunofluorescence studies showed that TAC/benzene exposure promotes infiltration of CD11b+/S100A8+/myeloperoxidase+-positive neutrophils in the hearts by 3-fold. In vitro, the benzene metabolites, hydroquinone, and catechol, induced the expression of P-selectin in cardiac microvascular endothelial cells by 5-fold and increased the adhesion of neutrophils to these endothelial cells by 1.5- to 2.0-fold. Benzene metabolite-induced adhesion of neutrophils to the endothelial cells was attenuated by anti-P-selectin antibody. Together, these data suggest that benzene exacerbates heart failure by promoting endothelial activation and neutrophil recruitment.