Susceptibility to Trichloroethylene (TCE) and Chlorinated Acids in Heart Development

Figure shows GPI-p137 and fibrillin-2 Immunostaining. Distribution of p137 protein expression in stage 16-17 chicken embryos showing epithelial and cardiac staining. A-G: Bright field images of immunostained sections. B-G:Immunostained sections. Areas positive for p137 include: B, cardiac myocardium and endocardium, D: View of cardiac cushion showing double layer of endocardium and overlying extracellular matrix (ecm) and myocardium; F: Heart tube showing p137 localization in the ecm and fibrillin-2 in the endocardium; H: Cardiac cushions showing transformed mesenchymal cells associated to p137 staining in the ecm surrounding the invading mesenchymal cells (arrows). Lu, lumen of the hear tube; myo, myocardial layer; asterisk (*), ecm of the heart tube. All sections were post-stained with DAPI to identify nuclei. Proposed mechanisms for TCE interaction with the methylation pathway and the NMDA receptor.

Background
Our previous research has documented the ability of trichloroethylene (TCE) and trichloroacetic acid (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.

Goal
To identify the mechanism(s) of action of trichloroethylene (TCE) and its metabolites trichloroacetic acid (TCAA) and dichloroacetic acid (DCAA) in the developing heart.

Objectives
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.

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.

Contact
Ornella Selmin
selmin@email.arizona.edu
(520) 626-6087