Chronic inhalation of m-Xylene disrupts vascular homeostasis through endothelial injury and impaired vascular repair.

Xylenes are ubiquitous environmental chemicals associated with central nervous system toxicity; however, their effects on cardiovascular disease are poorly understood. We tested the hypothesis that chronic m-xylene inhalation disrupts vascular homeostasis by inducing endothelial toxicity. Male C57BL/6 J mice were exposed to HEPA-filtered air or m-xylene (50 ppm, 6 h/day, 5 days/week) for 12 weeks. Endothelial injury, platelet activation, immune remodeling, hepatic and pulmonary transcriptomic responses, and plasma metabolomic profiles were assessed using flow cytometry, RNA sequencing, and untargeted metabolomics. The data show that chronic m-xylene inhalation induced a coordinated vascular injury phenotype characterized by 2.4-3.6-fold increases in circulating endothelial extracellular vesicles (EVs), activated endothelial EVs, and endothelial progenitor cell-derived EVs, accompanied by a 60% reduction in circulating endothelial progenitor cells, ~25% increase in soluble ICAM-1, and ~ 50% higher plasma 8-isoprostaglandin F2α levels, indicating endothelial activation, impaired vascular repair, and systemic oxidative stress. m-Xylene exposure also increased platelet-lymphocytes and platelet-granulocyte aggregates by ~25% and platelet-derived EVs by 9-fold, demonstrating thrombo-inflammatory activation. Plasma metabolomics revealed extensive metabolic remodeling, including increased phase II xylene metabolites, bradykinin, cholic acid, and fructose (Log2 fold change >1.5). Transcriptomic analyses demonstrated adaptive hepatic induction of xenobiotic metabolism and antioxidant pathways together with pulmonary inflammatory and immune remodeling. These findings identify endothelial toxicity as an early and sensitive cardiovascular consequence of chronic xylene exposure, provide mechanistic support for epidemiological associations between BTEX exposure and CVD, and identify endothelial EVs, EPC depletion, platelet-derived EVs, and phase II xylene metabolites as promising biomarkers of m-xylene induced vascular injury.