Long-term dioxin exposure promotes systemic endothelial damage and diastolic cardiac dysfunction in mice

Abstract

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic and persistent organic pollutant that bioaccumulates in the body through the food chain. The toxicity of TCDD is mediated by the activation of aryl hydrocarbon receptor (AHR), a transcription factor regulating detoxification enzyme expression. Although human exposure to TCDD has been shown to be associated with increased risk of cardiovascular disease and deaths, the impact of TCDD exposure on the heart at cellular and molecular levels remains poorly understood. To assess the cardiac and vascular stress response to long-term TCDD exposure in mice. Height-week-old C57BL/6N male mice were exposed for 12 months to low-dose TCDD (4 μg/kg, once per week) or vehicle by oral gavage. One-year TCDD exposure did not affect body weight or arterial pressure in mice, but cardiac mass index was increased. Echocardiographic analysis showed that long-term TCDD exposure led to diastolic LV dysfunction with preserved ejection fraction. Diastolic LV dysfunction was confirmed by PV loop analysis showing an increased diastolic stiffness with preserved systolic contractility in TCDD-exposed mice. Using permeabilized cardiac myofibers, we showed that chronic TCDD administration alters cardiac mitochondrial energetics and increases ROS production. Confocal imaging and q-PCR analysis revealed that AHR is expressed in the mouse heart, especially in endothelial cells that respond better than cardiomyocytes to TCDD exposure. Cardiac MRI showed decreased LV perfusion in TCDD-exposed mice. This was associated with a loss of endothelium-mediated relaxation responses to acetylcholine and to flow in mesenteric arteries of TCDD-exposed mice. In parallel, en face microscopy revealed profound disruptions of endothelial adherens junctions in the aorta of mice after TCDD exposure. These data demonstrate severe cardiac and systemic endothelial dysfunction upon TCDD exposure. This endothelial dysfunction was associated with a metabolic adaptation of endothelial cells, as assessed by the enhanced mitochondrial oxidative phosphorylation in TCDD-exposed primary muscle endothelial cells. Long-term exposure to TCDD promotes endothelial dysfunction and diastolic LV impairment, possibly through an increased oxidative stress and disrupted mitochondrial bioenergetics in both endothelial cells and cardiomyocytes.