Susceptibility to Trichloroetylene

本研究项目的总体目标是确定三氯乙烯（TCE）及其代谢物三氯乙酸（TCAA）和二氯乙酸（DCAA）在发育心脏中的作用机制。我们的假设是，母体摄入特定毒物的饮用水在环境相关的剂量产生改变胚胎表达的基因的正常心脏发育的关键。特别是，我们将探讨这些卤代烃可能会破坏特定的生化过程，这是至关重要的正常胚胎分化，包括蛋氨酸补救途径和酪氨酸 新陈代谢.此外，我们将测试的假设，是可能的，以防止或改善由这些有毒物质在心血管系统中的饮食干预与叶酸引起的疾病的发生。为了解决这些问题，我们提出以下具体目标：1。在转基因（CYP 2 E1无效）和正常小鼠模型中鉴定由于母体TCE暴露而改变的心脏基因表达; 2.在正常和GSTz缺失小鼠中鉴定由于母体暴露于TCAA和DCAA而改变的心脏基因表达;和3.评估饮食引起的叶酸缺乏和补充对母亲暴露于TCE和TCAA诱导的基因表达改变的影响。我们之前的研究 他们记录了TCE和TCAA改变许多基因表达的能力，包括一些参与关键发育过程的基因，如胚胎心脏瓣膜和隔膜的形成，以及参与调节钙浓度的基因。在目前的研究中，我们将利用这些信息来确定被TCE和TCAA破坏的分子途径，并试图通过膳食补充叶酸来逆转或最大限度地减少其对发育的负面影响。这些研究的结果将是非常重要的潜在影响，在接触人群的预防策略的设计。

The overall goal of this research project is to identify the mechanism(s) of action of trichloroethylene (TCE) and its metabolites trichloroacetic acid (TCAA) and dichloroacetic acid (DCAA) in the developing heart. Our hypothesis is that maternal ingestion of specific toxicants in drinking water at environmentally relevant doses produces altered embryonic expression of genes critical to normal heart development. In particular, we will explore the possibility that these halogenated hydrocarbons may disrupt specific biochemical processes that are essential for the normal embryonic differentiation including a methionine salvage pathway and tyrosine metabolism. In addition, we will test the hypothesis that is possible to prevent or ameliorate the occurrence of disorders induced by these toxicants in the cardiovascular system by dietary intervention with folic acid. In order to address these issues, we propose the following Specific Aims: 1. Identify altered cardiac gene expression due to maternal TCE exposure in genetically modified (CYP2E1 null) and normal mouse model; 2. Identify altered cardiac gene expression due to maternal exposure to TCAA and DCAA in normal and GSTz null mice; and 3. Assess the effects of folic acid deficiency and supplementation, created by diet, on alteration of gene expression induced by maternal exposure to TCE and TCAA. Our previous research has documented the ability of TCE and TCAA to alter the expression of numerous genes, including some involved in crucial developmental processes such as the formation of valves and septa in the embryonic heart, and genes involved in regulating calcium concentrations. In the current study we will use this information to identify the molecular pathways that are disrupted by TCE and TCAA and try to reverse or minimize their negative effects on development by dietary supplementation with folic acid. The outcome of these studies will be highly significant in light of the potential implications for the design of preventive strategies in exposed populations.