Cellular and Molecular Basis for TRI Cardiotoxicity

三氯乙烯（TRI）是饮用水中最常见的十大环境污染物之一。流行病学数据揭示了母亲TRI暴露与后代先天性心脏畸形风险增加之间的相关性。 动物模型显示TRI暴露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的心脏致畸性的基础，特别是在细胞和分子水平上，几乎一无所知。 这使得难以评估风险暴露和设计适当的干预战略。 最近的研究表明，TRI破坏了发育中的心室壁中的瓣膜间隔形成和早期成熟事件。 该建议结合了体外和卵内实验，使用鸡胚模型与体内实验，使用小鼠模型来测试TRI是心脏致畸剂的假设，因为它破坏了心脏发育的早期阶段的心源性事件。目的1使用形态学和分子标准检查TRI-exposed心前组织和永久心脏，从发育的最早阶段开始，目的是识别TRI-sensitive事件和暴露风险窗口。 AIM 2使用鸡和小鼠模型来检验TRI代谢有助于其致畸性并因此调节TRI暴露风险的假设。 AIM 3是否分子标记物的改变，在响应TRI应用这样做的方式，反映TRI的致畸潜力，并询问这些分子反应是否可能解释随后的畸形。 在这项工作结束时，我们将对TRI如何在细胞和分子水平上破坏心脏发生有深入的了解，从而确定可用于评估TRI暴露风险的分子标记物。

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.