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.
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