Superfund Research Program
Effects Related Biomarkers of Toxic Exposures
Project Leader: Terrance J. Kavanagh
Grant Number: P42ES004696
Funding Period: 1995 - 2006
During the past year, project investigators have made progress in two areas. The first is in characterizing GLCL overexpressing transgenic mice. These mice are based on the GeneSwitch system in which administration of mifepristone results in transactivation of target genes (in this case GLClc or GLCLr) by a chimeric modified progesterone receptor. Researchers now have evidence of inducible and controllable expression in two GLCLc (catalytic subunit) founder lines, and four GLCLr (regulatory subunit) founder lines. The GLCLc lines express GLClc transgene mRNA in the liver, embryonic yolk sac and eye upon induction with mifepristone. The researchers also have evidence that GLCLr transgene mRNA is expressed in liver. Some of these lines have been back-crossed onto C57Bl/6 for 5 generations and are now ready to test for their sensitivity to MeHg-induced oxidative stress. Progress has also been made in the characterization of the GAG trinucleotide GLCLc polymorphism in the 5'UTR of the mRNA for this gene, with respect to risk for developing idiopathic pulmonary fibrosis (IPF). There is an under-representation of the 9 GAG repeat allele in IPF patients, and a suggestion of an over-representation of the 8 GAG repeat allele, compared to controls. These data were recently presented at the Society of Toxicology meeting in Philadelphia.