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ENVIRONMENTAL AND GENETIC INTERACTIONS IN HYPERTENSIVE RATS: OXIDATIVE STRESS AS A COMMON SUSCEPTABILITY ATTRIBUTE FOR NON-CANCER RISKS
Citation:
Kodavanti, U P., P. S. Gilmour, M. Schladweiler, J. E. Welch, S P. Darney, R C. MacPhail, PRS Kodavanti, B Veronesi, A M. Geller, W K. Boyes, W P. Watkinson, G. E. Hatch, J Gallagher, R. Sams, A J. Ghio, T. Illig, AND S. Kleeberger. ENVIRONMENTAL AND GENETIC INTERACTIONS IN HYPERTENSIVE RATS: OXIDATIVE STRESS AS A COMMON SUSCEPTABILITY ATTRIBUTE FOR NON-CANCER RISKS. Presented at EPA Science Forum, Washington, DC, June 1-3,2004.
Description:
Individuals compromised with preexisting conditions are likely to be more susceptible to environmental exposures, and the uncertainty factors employed to correct for this concern may not be adequate. Although diseases such as congestive heart failure, chronic pulmonary disease; atherosclerosis, Parkinson=s and Alzheimer=s diseases, and diabetes have diverse etiologies, they all appear to involve oxidative stress. The complex interactions between disease development and oxidative stress are not well understood, but may well be linked to genetic abnormalities. Animal models can be used to investigate the genetic mechanisms and the role of oxidative stress.
We propose to use a rat model exhibiting phenotypic predisposition to oxidative stress (associated with hypertension/cardiovascular disease) to understand genetic and environmental interactions. The research done under this project will use the Spontaneously Hypertensive (SH) rat as a model for oxidative stress relative to healthy and 1) compare the effects of known environmental chemicals that affect the pulmonary, cardiovascular, neuronal, ocular, and reproductive system; 2) the role for oxidative stress and genetic polymorphisms will be identified.
Scientists from 5 NHEERL divisions, NIEHS, GSF, Germany are collaborating on this project. In the first phase of the proposed research, a dose-response characterization will be done to determine relative susceptibility of SH versus healthy rats to various organ-specific toxicants (e.g., ozone, zinc, rotenone, acrylamide, carbamates, and organophosphates). The second and third phase will focus on mechanisms of oxidative stress, biomarkers and genetic polymorphisms. The high throughput data generated in these studies can potentially be used in computational toxicology in ORD. The genes for polymorphisms detection in rats will be selected based on historical evidence in humans and other animal species.
We have already shown that SH rats are more susceptible to inhaled pollutants, tobacco smoke and sulfur dioxide-induced pulmonary disease, and that dysfunctional compensatory glutathione increases in the lung appears to relate to injury at least with the toxic inhalants. A comparative systemic antioxidant and oxidative stress profile for SH and healthy rats is being established. The approaches to genetic polymorphisms analysis are being evaluated.
This proposal will determine the role of oxidative stress in increased susceptibility to a variety of toxic insults and organ systems, and promote a more accurate estimation of the uncertainty factor. In addition to providing potential new biomarkers for the toxicities of selected test compounds, and susceptibility/oxidative stress. This proposed project uses new technologies for 1) evaluating gene expression profile to understand pathology and 2) identifying potential gene polymorphisms to better define susceptibility.