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.
| Rufer, Echoleah S; Hacker, Timothy A; Flentke, George R et al. (2010) Altered cardiac function and ventricular septal defect in avian embryos exposed to low-dose trichloroethylene. Toxicol Sci 113:444-52 |
| Drake, Victoria J; Koprowski, Stacy L; Lough, John et al. (2006) Trichloroethylene exposure during cardiac valvuloseptal morphogenesis alters cushion formation and cardiac hemodynamics in the avian embryo. Environ Health Perspect 114:842-7 |
| Drake, Victoria J; Koprowski, Stacy L; Lough, John W et al. (2006) Gastrulating chick embryo as a model for evaluating teratogenicity: a comparison of three approaches. Birth Defects Res A Clin Mol Teratol 76:66-71 |
| Drake, Victoria J; Koprowski, Stacy L; Hu, Norman et al. (2006) Cardiogenic effects of trichloroethylene and trichloroacetic acid following exposure during heart specification of avian development. Toxicol Sci 94:153-62 |
