AH RECEPTOR AND CARDIAC ADRENERGIC SIGNALING - DESCRIPTION (provided by applicant): Based on expression data, the production of endogenous agonists in the mouse heart, and observations in knockout animals, it is becoming increasingly clear that the aryl hydrocarbon receptor (AhR) is important to normal development and function of the cardiovascular system. Exposure to the ubiquitous environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), potent agonist of the AhR, disrupts normal cardiovascular development and function. We hypothesize that this disruption results from a direct interaction of the AhR and beta-adrenergic receptor (B-AR) signaling systems. In this proposal we will investigate whether the cardiomyopathy observed in embryonic chicks exposed to TCDD is associated with a direct increase in B1-AR gene expression followed by a maladaptive decrease in B1-AR signaling. In support of this hypothesis, we have detected a 30% increase in cardiac B1-AR mRNA in embryonic day 10 chicks exposed to TCDD on day 0 and have observed a reduction in the ability of TCDD-exposed embryonic chicks and weanling mice to increase heart rate in response to isoproterenol, a B-AR agonist. The existence of four (4) putative dioxin response elements (DREs) in the 5' enhancer region of the human B1-AR gene raises the possibility that transcription of the gene may be directly regulated by the AhR. Currently, most of our experiments utilize a chick embryo model system, however, avian species may regulate the B1-AR gene differently than mammals by expressing a B1-AR splice variant. Experiments contained within this proposal will (1) determine whether the mouse also expresses the B1-AR splice variant; (2) test the hypothesis that the B1-AR gene is directly regulated by AhR; and (3) determine whether the decreased cardiac B1-AR responsiveness observed in TCDD-exposed chick and mouse heart is a direct effect of TCDD on cardiac myocytes. Completion of these studies will provide important mechanistic data on the cardiovascular toxicology of TCDD and provide insight into the normal role of the AhR in the developing heart.
