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TOXICITY PATHWAY ANALYSIS IN AGING BROWN NORWAY RAT BRAIN FOLLOWING ACUTE TOLUENE EXPOSURE
ROYLAND, J. E., PRASADA RAO S. KODAVANTI, AND R. C. MACPHAIL. TOXICITY PATHWAY ANALYSIS IN AGING BROWN NORWAY RAT BRAIN FOLLOWING ACUTE TOLUENE EXPOSURE. Presented at Molecular Genetics of Aging, Cold Springs, NY, September 28 - October 02, 2010.
The objective was to explore the toxicity pathways that contribute to the adverse effects of toluene exposure, and to determine if the response is age-dependent.
The influence of aging on susceptibility to environmental stressors is poorly understood. To investigate the contribution of different life stages on response to toxicants, we examined the effects of acute exposure by oral gavage of the volatile organic solvent toluene (0.00, 0.30, 0.65 or 1.0 g/kg) in the brains of male Brown Norway rats at 4, 12 and 24 months of age. Toluene is a known neurotoxicant with effects on cognition, motor activity and neurotransmitters in the central nervous system. The objective was to explore the toxicity pathways that contribute to the adverse effects of toluene exposure, and to determine if the response is age-dependent. In this study we examined gene expression in cerebellum, striatum, hippocampus and frontal cortex 4 hours post-dosing using a custom designed RT-PCR array containing 32 genes representing key toxicity pathways involving oxidative stress, energy metabolism, neuronal plasticity, immune and stress responses. Results showed that the effect of age exceeded that of toluene on number of genes affected (approx 1.5 times more with age). Numbers of up-and down-regulated genes were about the same due to age (e.g. 4 vs. 24 month controls), but, within a given age group (e.g. control vs. toluene at 4 mos), more were up-than down-regulated due to toluene exposure (approx. 70% up). However, when comparing age-related toluene effects (4 vs. 24 months treated) more genes were down-than up-regulated (approx. 65% down). These data indicate that life stage alone affects gene expression level and can also have an impact on genomic response to toxicant exposure. Affected genes were associated with stress-, growth-and survival-related pathways with degree and direction of change variable, depending upon condition tested. These ongoing studies contribute to defining a genomic model of toxicity pathways in the nervous system and their modification with aging. (This abstract does not necessarily reflect USEPA policy).