Superfund Research Program
Effects Related Biomarkers of Toxic Exposures
Project Leader: Terrance J. Kavanagh
Grant Number: P42ES004696
Funding Period: 1995 - 2006
Oxidative stress plays an important role in a number of diseases, including cardiovascular disease, pulmonary fibrosis, diabetes, Parkinson's disease, and Alzheimer’s disease. Because the antioxidant glutathione has been shown to be altered in a number of these diseases, Dr. Kavanagh and his research team has been examining the role of the rate-limiting enzyme in glutathione synthesis, glutamate-cysteine ligase (GCLC), in their pathophysiology. They have investigated the role of a GAG trinucleotide repeat polymorphism in GCLC in a number of diseases including cystic fibrosis, Type 1 diabetes mellitus (T1DM) and Parkinson's disease (PD). In CF and T1DM, they have found associations between the numbers of repeats and the severity of disease or the age of onset. In a collaboration with the project investigators’ colleagues in UW Pulmonary Medicine and at the University of British Columbia, the investigators have extended their original observations made in a Seattle cohort of CF patients, and have found that this association still holds.
In parallel with the human translational research, project investigators have developed a transgenic mouse model to investigate the functional effects of genetic variants in terms of chemical detoxification. Using homologous recombination and embryonic stem cell technology, the investigators generated transgenic mice, which are null for the Gclm gene. These mice have been used to assess the effects of oxidative stress from acetaminophen exposure. They are highly sensitive to these exposures. Testing of additional compounds, including nethylmercury, which is especially toxic for children’s nervous system, is ongoing. These studies involve characterization of mechanisms by which GCLC gene alterations influence methylmercury toxicity to specific cells in mouse brain. The findings could ultimately have important implications for understanding the underlying basis of neurodevelopmental dysfunction due to methylmercury exposure in humans, and could inform prevention and treatment strategies.