EFFECTS OF DIOXIN ON CORONARY ANGIOGENESIS

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The developing fetus is more sensitive to 2,3,7,8-tetrachloriodibenzo-p-dioxin (TCDD) toxicity than adults with fetal concentration as low as 40 ng\kg, while highly exposed humans exceed this concentration by 2-175 times. There is uncertainty in predicting the risk posed by TCDD to human development, because adverse developmental effects observed in laboratory species differ and because the mechanism(s) by which TCDD causes developmental toxicity have not been elucidated. TCDD binds the aryl hydrocarbon receptor (AhR) and dimerizes with the AhR nuclear translocator (ARNT). ARNT also can dimerize with hypoxia-inducible factor 1a and mediate responses to hypoxia, including angiogenesis induced by vascular endothelial growth factor (VEGF). TCDD may cause developmental toxicity by sequestering ARNT and inhibiting hypoxia-induced angiogenesis, in a tissue specific manner. If TCDD inhibits hypoxia induced angiogenesis embryonic development will be at risk, because localized hypoxia stimulates normal tissue angiogenesis in the developing embryo. Using the chick embryo as a model, we will test the hypothesis that TCDD inhibits coronary angiogenesis by inhibiting hypoxia-induced VEGF expression. In the chick embryo, TCDD reduces cardiac VEGF mRNA, prevents ventricular wall thickening, and induces dilated cardiomyopathy, all consistent with and inhibition of coronary angiogenesis. The aims of this research are to elucidate 1.) The timing and location of hypoxia-induced VEGF expression in the embryo heart, identifying the window of development when the embryo heart is most susceptible to TCDD, 2.) The time-course and dose response for TCDD inhibition of cardiac VEGF mRNA, and 3.) The cellular and morphological consequences of reduced cardiac VEGF expression, including flk-1 receptor expression, coronary angiogenesis, and ventricle wall proliferation. The research will help to elucidate a fundamental mechanism underlying TCDD-induced developmental toxicity, which can then be extrapolated to mammalian and human development.