Chronic dioxin exposure aggravates endothelial damage and left ventricular diastolic dysfunction only in male obese mice - 21/05/25
, Raphaël Courcoux 1, Marie Quétin 1, Christelle Dubois 1, Frédéric Relaix 1, Paul Mulder 2, Mathias Mericskay 3, Marianne Gervais 1
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Résumé |
Introduction |
Although human and animal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to be associated with cardiovascular diseases and death, the impact of long-term TCDD exposure on the heart remains poorly understood, especially in vulnerable populations. In male healthy mice, we have shown that TCDD exposure led to an early and progressive onset of endothelial damage and left ventricular (LV) diastolic dysfunction while preserving systolic function. However, it remains unclear whether chronic low-dose TCDD exposure accelerates the development and progression of cardiomyopathy in obese subjects. Additionally, there are few published studies investigating whether TCDD exposure leads to sex-specific metabolic cardiovascular outcomes in obese mice.
Objective |
Our goal was to investigate the cardiovascular toxicity of prolonged exposure to TCDD in the context of obesity and to uncover potential sexual dimorphism.
Method |
Six-month-old male and female C57BL6N mice were fed with normal diet or high fat diet (60 kcal% fat) and simultaneously exposed to vehicle or low-dose TCDD (4μg/kg, once per week, oral gavage) for 30 weeks.
Results |
During the follow up, TCDD exposure had no impact on weight gain in obese mice, whatever the gender. After 30 weeks, HFD increased fat mass and glucose intolerance in both gender. TCDD exposure did not affect body fat or glucose tolerance in lean and obese mice of either sex. Echocardiography analysis showed that HFD induced LV systolic and diastolic dysfunctions only in male mice. Chronic TCDD exposure exacerbated LV diastolic dysfunction in male obese mice, while female mice were preserved. The worsening of diastolic dysfunction in obese male mice exposed to TCDD is associated with an increase in heart weight and cardiomyocyte size, without an increase in cardiac fibrosis. In both gender, AHR was expressed in obese heart, especially in cardiac endothelial cells that responded strongly to TCDD exposure by increasing CYP1A1 expression, whatever the diet. Using in vivo flow-mediated dilatation analysis, we showed that HFD did not affect endothelium-dependent arterial relaxation in both gender, whether chronic TCDD exposure led to strong endothelial dysfunction only in male obese mice, while female mice were protected.
Conclusion |
In obese mice, prolonged low-dose TCDD exposure aggravated endothelial damage and LV diastolic dysfunction only in males.
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Vol 118 - N° 6-7S1
P. S205 - juin 2025 Retour au numéro
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