Halogenated aromatic hydrocarbons are persistent environmental pollutants that pose potential risks to human health. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most potent of these chemicals and, thus, serves as a prototype for studying their toxicity. Numerous studies have shown that reproductive and developmental toxicity represents some of the most sensitive adverse effects of TCDD and related chemicals. This is of concern because humans accumulate TCDD and related chemicals from the diet over their lifetime, women can transfer a proportion of their accumulated body burden to their children in utero and via lactation, and current human body burdens approach or exceed those fetal concentrations associated with developmental toxicity in laboratory animals. Using a chick embryo model, we have demonstrated that early developmental TCDD exposure induces dilated cardiomyopathy that progresses to a phenotype consistent with congestive heart failure. This phenotype includes a decreased ability of the heart to respond to beta-adrenergic receptor (beta-AR) stimulation. Congestive heart failure is known to be associated with a desensitization and downregulation of beta-AR due to chronic exposure to elevated catecholamines and to hypoxia. In this AREA grant proposal, we will test the hypothesis that developmental TCDD-induced heart failure results from a disruption of cardiac beta1-adrenergic receptor (beta1-AR) signaling by (1) determining the sensitivity and temporal relationship of the decreased beta1-AR responsiveness and the cardiomyopathy observed in the chick embryos; and (2) determining whether developmental TCDD exposure alters beta 1-AR mRNA expression, protein density or affinity, or phosphorylation state in the chick embryo heart. If alterations in beta 1-AR signaling are found to be sensitive effects that correlate temporally with the cardiotoxicity observed in the chick embryo, future studies will investigate whether TCDD and its receptor, the aryl hydrocarbon receptor (AhR), regulate beta 1-AR gene expression directly or indirectly as a result of elevated catecholamine concentrations and/or cardiac hypoxia.
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| Sommer, Rebecca J; Hume, Adam J; Ciak, Jessica M et al. (2005) Early developmental 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure decreases chick embryo heart chronotropic response to isoproterenol but not to agents affecting signals downstream of the beta-adrenergic receptor. Toxicol Sci 83:363-71 |
