Susceptibility to Trichloroetylene (TCE) and Chlorinated Acid

本研究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(S)。我们的假设是，母亲摄入与环境相关的剂量的饮用水中的特定毒物会改变对正常心脏发育至关重要的基因的胚胎表达。特别是，我们将探索这些卤代烃可能会扰乱正常胚胎分化所必需的特定生化过程，包括蛋氨酸挽救途径和酪氨酸。 新陈代谢。此外，我们还将检验通过叶酸饮食干预来预防或改善这些毒物在心血管系统中引起的疾病的发生的假设。为了解决这些问题，我们提出了以下具体目标：1.在转基因小鼠模型和正常小鼠模型中确定母体TCE暴露引起的心脏基因表达变化；2.在正常和GSTZ空白鼠中确定母体暴露TCAA和DCAA引起的心脏基因表达变化；3.评估叶酸缺乏和饮食补充对母体暴露TCE和TCAA引起的基因表达变化的影响。我们之前的研究已经 据文献记载，TCE和TCAA能够改变许多基因的表达，包括一些参与胚胎心脏瓣膜和隔膜形成等关键发育过程的基因，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TCE和TCAA破坏的分子途径，并试图通过饮食补充叶酸来逆转或减少它们对发育的负面影响。鉴于这些研究对制定暴露人群预防策略的潜在影响，这些研究的结果将具有重要意义。

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.