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IMMORTALIZED MICROGLIAL CELLS AS A MODEL SYSTEM FOR OXIDATIVE STRESS: PESTICIDE-INDUCED GENOMIC GHANGES.
Citation:
Royland, J E., PRS Kodavanti, B Veronesi, M. Pooler, AND O. Makwana. IMMORTALIZED MICROGLIAL CELLS AS A MODEL SYSTEM FOR OXIDATIVE STRESS: PESTICIDE-INDUCED GENOMIC GHANGES. Presented at Society of Toxicology, New Orleans, LA, March 06 - 10, 2005.
Description:
In risk assessment there is a need to accelerate toxicological evaluation of vast numbers of chemicals. New programs focus on identifying common modes of action and on model systems for rapid screening. In this study we address both these issues. Oxidative stress is a good candidate as a mode of action for neurotoxicity testing. A role for reactive oxygen species has been well documented in both disease (e.g. Parkinson's disease, Alzheimer's disease, etc.) and toxicity (e.g. Paraquat) of the nervous system. Microglial cells are the major mediator of the brain's immune system. When activated in response to injury, they release an oxidative burst that is initially protective, but may become toxic in excess. We are investigating the use of immortalized murine microglial cells as a model test system for identifying chemicals that elicit the oxidative burst. Microglia were treated with the herbicide, Paraquat (1.0 ?M), or the insecticide, Rotenone (0.125 ?M), as prototypic compounds that generate reactive oxygen species (ROS). Hydrogen peroxide (0.002 mM) and lipopolysaccharide (25 ng/ml) are chemicals known to elicit oxidative stress in cell culture and were used as positive controls. Four hours after exposure, RNA was extracted for analysis on Affymetrix mouse genome 430 2.0 chips. Preliminary analysis showed similar numbers of up and down regulated genes across treatment groups with approximately equal distribution across ontology areas. The greatest proportions of genes identified were related to signal transduction (~41%), enzymes (~20%) or cell communication (~18%). Cluster analysis showed good correlation between samples from a given treatment group. However, only 5 genes were up regulated 2 or more fold by all 4 treatments and only 9 were down regulated. These data support oxidative stress as a mode of action where multiple pathways can contribute to a single outcome. (This abstract does not necessarily reflect US EPA policy).