Fetal Dioxin Exposure and Adult Heart Disease

描述（由申请人提供）：人类成年后职业性接触TCDD和相关化学物质与心脏病死亡风险增加有关;然而，目前尚不清楚胎儿接触非致畸水平的TCDD是否也会增加成年后患心脏病的风险。心肌重塑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，而高剂量则会导致明显的心肌病。我们的研究表明，胎儿TCDD暴露以剂量相关的方式增加与心肌重塑和纤维化相关的基因表达;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反应。因此，我们建议测试的假设，胎儿TCDD暴露永久性地破坏心脏细胞外基质（ECM）的调节，通过芳烃受体（AhR）介导的机制，并增加心脏功能障碍和失败的风险在成年期。在目标1中，我们将确定剂量相关的程度，在子宫内TCDD暴露改变胎儿ECM基因，以及这些基因表达的变化是否需要AhR使用AhR裸小鼠。在目标2中，我们将阐明在子宫内和哺乳期暴露于分级剂量的TCDD是否（1）导致成年期心功能障碍和ECM调节的永久性变化，以及（2）在存在第二个风险因素的情况下增加心力衰竭的易感性。我们将分析成年小鼠，暴露于子宫内/哺乳期TCDD，在心血管形态和功能的变化，使用超声心动图和血压遥测，并在心脏ECM表达的持续变化，使用实时RT-PCR，酶谱和蛋白质印迹。在这些评估之后，这些动物的子集将长期暴露于抑制剂量的心力衰竭风险因子血管紧张素II（Ang II），并分析心血管形态、功能和ECM表达的变化。研究胎儿TCDD暴露对心血管形态和功能的长期影响，将阐明TCDD暴露是否有助于在成年期的心血管疾病的风险在生命早期。

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.