Cellular and Molecular Basis for TRI Cardiotoxicity

三氯乙烯是饮用水中十种最常见的环境污染物之一。流行病学数据显示，母亲暴露于TRI与子代患先天性心脏畸形风险增加之间存在相关性。动物模型显示，三次接触会导致类似心脏缺陷的高风险。然而，尽管TRI对发育中的心血管系统有明显的选择性作用，但对TRI心脏致畸的基础几乎一无所知，特别是在细胞和分子水平上。这使得评估风险敞口和设计适当的干预策略变得困难。最近的研究表明，Tri可破坏发育中的室壁的瓣膜间隔形成和早熟事件。这一建议将使用鸡胚胎模型的体外和体外实验与使用小鼠模型的体内实验相结合，以验证TRI是心脏畸形物的假设，因为它在心脏发育的早期阶段扰乱了心源性事件。目的1从发育的最早阶段开始，使用形态和分子标准来检查三次暴露的心脏前组织和确定的心脏，目的是识别三敏感事件和暴露风险的窗口。目的2利用鸡和小鼠两种模型来验证这样的假设：TRI的代谢有助于其致畸，从而调节TRI暴露的风险。目的探讨因应用TRI而改变的分子标记是否以反映TRI致畸潜能的方式改变，并询问这些分子反应是否可解释随后的畸形。在这项工作的结论中，我们将对TRI如何在细胞和分子水平上扰乱心脏发生有一个更深入的理解，从而识别出可用于评估三次暴露风险的分子标志物。

Trichloroethylene (TRI) is one of the ten most common environmental contaminants in drinking water. Epidemiological data reveal a correlation between maternal TRI exposure and increased risk for congenital heart malformations in offspring. Animal models show hat TRI exposure causes a high risk of similar heart defects. However, despite this apparently selective effect of TRI on the developing cardiovascular system, next to nothing is known about the basis for TRI's cardiac teratogenicity, particularly at the cellular and molecular levels. This makes it difficult to evaluate risk exposure and design appropriate intervention strategies. It has recently been shown that TRI disrupts valvuloseptal formation and early maturational events in the developing ventricular wall. This proposal combines in vitro and in ovo experiments using the chick embryo model with in vivo experiments using the mouse model to test the hypothesis that TRI is a cardiac teratogen because it disrupts cardiogenic events during the early stages of heart development. AIM 1 uses morphological and molecular criteria to examine TRI-exposed precardiac tissues and definitive hearts, beginning at the earliest stages of development, with the goal of identifying TRI-sensitive events and windows of exposure risk. AIM 2 uses both chick and mouse models to test the hypothesis that metabolism of TRI contributes to its teratogenicity and thus modulates TRI exposure risk. AIM3 whether molecular markers that are altered in response to TRI application do so in a fashion that reflects TRI's teratogenic potential, and asks whether these molecule responses may account for subsequent dysmorphology. At the conclusion of this, work we will have an advanced understanding of how TRI disrupts cardiogenesis at the cellular and molecular level, thereby having identified molecular markers that can be used to assess TRI-exposure risk.