Molecular Analysis of Toxicant-Mediated Teratogenesis

Background
The specific effects of trichloroethylene (TCE) and arsenic (As) exposure on the developmental pathways of embryos are still unknown.

Goal
To assess whether specific developmental toxicants (e.g. trichloroethylene (TCE) and (As) arsenic) perturb one or more developmental pathways leading to morphologic alterations resulting in specific birth defects.

Objectives
1. Identify the distribution and timing of gene expression for four specific clones that were selected by screens for differential expression after exposure to teratogenic doses of TCE.

2. Evaluate the sensitivity of altered marker expression in embryos exposed to varying levels of toxicants in maternal drinking water. The goal is to determine minimum exposure levels that result in altered gene expression and use the most sensitive markers for risk assessment.

3. Clone the promoter region of the markers identified in Objective 1.

4. Test the potential relationship between TCE exposure and the NMDA (N-Methyl-D-Aspartate) glutamate receptor and/or NFATc pathways as a mechanism of TCE teratogenicity.

5. Identify and characterize markers of As exposure in developing embryos.

Significant Findings
1. TCE exposure in vitro blocks required cell invasion in the heart.

2. Approximately 80 genes in rat embryo hearts were altered by exposure to 110 ppm TCE.

3. Two genes (p137, serca 2) selected at 110 ppm were tested and found to be sensitive to 100 ppb TCE.

4. Identified alterations in extracellular matrix genes in the lung following in utero exposure to 500 ppb arsenite.

Publications

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