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Ah receptor expression in cardiomyocytes protects adult female mice from heart dysfunction induced by TCDD exposure

Author:
Kurita, Hisaka, Carreira, Vinicius S., Fan, Yunxia, Jiang, Min, Naticchioni, Mindi, Koch, Sheryl, Rubinstein, Jack, Puga, Alvaro
Source:
Toxicology 2016 v.355-356 pp. 9-20
ISSN:
0300-483X
Subject:
adults, blood pressure, body weight, calcium signaling, cardiomyocytes, epidemiological studies, females, fibrosis, gene expression, genes, heart diseases, humans, hypertrophy, knockout mutants, males, mice, myosin, sexual dimorphism, tetrachlorodibenzo-p-dioxin, toxicity
Abstract:
Epidemiological studies in humans and experimental work in rodents suggest that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent environmental toxicant, is associated with incidence of heart disease. Although TCDD toxicity depends by and large on the aryl hydrocarbon receptor (AHR), the role of the cardiac AHR in TCDD induced cardiovascular disease is not well defined. To determine whether the Ahr gene mediates disruption of heart function by TCDD, we generated a cardiomyocyte-specific Ahr knockout mouse by crossing Ahrᶠˣ/ᶠˣ mice with βMhc:cre/+ mice, in which expression of Cre recombinase is driven by the promoter of the βMhc (myosin heavy chain-beta) gene. Starting at three months of age, mice with cardiomyocyte-specific Ahr ablation were exposed to 1μg/kg/week of TCDD or control vehicle by oral gavage for an additional three months. Relative to unexposed controls, TCDD-exposure induced cardiomyocyte Ahr-independent changes in males but not females, including a significant increase in body weight, blood pressure, and cardiac hypertrophy and a decrease in cardiac ejection fraction. TCDD exposure also induced cardiomyocyte Ahr-dependent changes in fibrosis and calcium signaling gene expression in both males and females. TCDD exposure appears to cause sexually dimorphic effects on heart function and induce fibrosis and changes in calcium signaling in both males and females through activation of the cardiomyocyte-specific Ahr.
Agid:
6077498