Fetal Dioxin Exposure and Adult Heart Disease

描述（由申请人提供）：人类在成年期职业暴露于TCDD和相关化学品与心脏病死亡风险增加有关；然而，胎儿暴露于非致畸水平的TCDD是否也会增加成年后患心脏病的风险尚不清楚。心肌重构和纤维化是大多数慢性心血管疾病发病率和死亡率的主要决定因素。低剂量的TCDD已被证明会增加成年动物的心肌纤维化，而高剂量则会引起明显的心肌病。我们的研究表明，胎儿暴露于TCDD会以剂量相关的方式增加与心肌重构和纤维化相关的基因的表达；然而，尚不清楚这些基因表达的变化是否会导致心血管功能的永久性不良影响。因此，我们提出验证胎儿暴露于TCDD通过芳烃受体（AhR）介导的机制永久性地破坏心脏细胞外基质（ECM）调节，并增加成年期心功能障碍和心力衰竭的风险的假设。在目的1中，我们将通过使用AhR缺失的小鼠来确定子宫内TCDD暴露改变胎儿ECM基因的剂量相关性，以及这些基因表达的变化是否需要AhR。在目的2中，我们将阐明是否在子宫内和哺乳期暴露于分级剂量的TCDD(1)会导致成年期心功能障碍和ECM调节的永久性改变，以及(2)在存在第二个风险因素的情况下增加对心力衰竭的易感性。我们将使用超声心动图和血压遥测技术分析暴露于子宫/哺乳期TCDD的成年小鼠心血管形态和功能的变化，并使用实时RT-PCR、酶谱分析和Western blots分析心脏ECM表达的持续变化。根据这些评估，这些动物的一个子集将长期暴露于心脏衰竭风险因子血管紧张素II （Ang II）的抑制剂量，并分析心血管形态、功能和ECM表达的变化。研究胎儿接触TCDD对心血管形态和功能的长期影响，将阐明生命早期接触TCDD是否会增加成年后心血管疾病的风险。

DESCRIPTION (provided by applicant): 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.