(Taken from the Candidate's Abstract) Exposure to the environmental pollutant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been closely associated with increased mortality of humans from chronic ischemic heart disease. TCDD slows heart rate and attenuates responses to B-adrenergic receptor stimulation, but abnormally increases intracellular calcium concentration, enhances basal contractility, and produces arrhythmic after contractions. To elucidate the cellular and molecular mechanisms of these effects, this study proposes to investigate the alteration of cardiac action potentials and the underlying ion currents and to identify the functional changes of the single channel proteins produced by TCDD exposure. The study will be carried out using patch clamp technique in myocytes isolated from rat and guinea pig hearts.
The specific aims are: 1) to investigate the effects of acute exposure to TCDD on excitability of single cardiac myocytes; 2) to identify the ion channel proteins responsible for the cardiac toxicity of TCDD; and 3) to elucidate the molecular mechanism(s) of TCDD action on ion channel proteins. The following potential mechanisms of the toxic effects of TCDD on cardiac ion channel proteins will be evaluated: 1) induction of cytochrome P450 genes (e.g., CYPlAl and CYPlA2) by an aryl hydrocarbon receptor (AHR) signaling pathway and production of arachidonic acid metabolites; 2) alteration of protein kinase (e.g., PKC and PKA) activity; 3) production of reactive oxygen species (e.g., malondialdehyde and formaldehyde); and, 4) altered intracellular calcium concentration. The results of this study will provide us with new insight of the underlying cellular and molecular mechanism(s) for TCDD-produced cardiac toxicity. Because ion channel proteins are well characterized and their functions are finely regulated in diverse ways by hormonal signaling pathways, drugs, and mutations, there is the potential to treat TCDD- produced, as well as other cardiovascular diseases.
|Xie, An; Walker, Nigel J; Wang, Desuo (2006) Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) enhances triggered afterdepolarizations in rat ventricular myocytes. Cardiovasc Toxicol 6:99-110|