Occupational exposure of humans to TCDD and related chemicals in adulthood has been linked to an increased risk of mortality from heart disease; however, it is unknown whether fetal exposure to non-teratogenic levels of TCDD also increases the risk of heart disease in adulthood. Myocardial remodeling and fibrosis are the primary determinants of morbidity and mortality from most chronic cardiovascular diseases. Low doses of TCDD have been shown to increase myocardial fibrosis in adult animals, while higher doses cause overt cardiomyopathy. Our research demonstrates that fetal TCDD exposure increases expression of genes associated with myocardial remodeling and fibrosis in a dose-related fashion; however, it is not known whether these changes in gene expression lead to permanent adverse effects in cardiovascular function. Thus, we proposed to test the hypothesis that fetal TCDD exposure permanently disrupts cardiac extracellular matrix (ECM) regulation via an aryl hydrocarbon receptor (AhR)-mediated mechanism and increases the risk of cardiac dysfunction and failure in adulthood.
In aim 1, we will determine the dose-related degree to which in utero TCDD exposure alters fetal ECM gene and whether these changes in gene expression require the AhR by use of AhR null mice.
In aim 2, we will elucidate whether exposure to graded doses of TCDD in utero and via lactation (1) causes cardiac dysfunction and permanent changes in ECM regulation in adulthood and (2) increases the susceptibility to heart failure in the presence of a second risk factor. We will analyze adult mice, exposed to in utero/lactational TCDD, for changes in cardiovascular morphology and function, using echocardiography and blood pressure telemetry, and for persistent changes in cardiac ECM expression, using real-time RT-PCR, zymography, and Western blots. Following these assessments, a subset of these animals will be exposed chronically to a suppressor dose of the heart failure risk factor, angiotensin II (Ang II), and analyzed for changes in cardiovascular morphology, function, and ECM expression. Studying long-term consequences of fetal TCDD exposure on cardiovascular morphology and function will elucidate whether TCDD exposure early in life contributes to the risk of cardiovascular disease in adulthood.
