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Analysis of baseline gene expression levels from toxicogenomics study control animals to identify sources of variation and predict responses to chemicals
Citation:
CORTON, C. Analysis of baseline gene expression levels from toxicogenomics study control animals to identify sources of variation and predict responses to chemicals. Presented at European Environmental Mutagen Society (EEMS), Oslo, NORWAY, September 16 - 18, 2010.
Impact/Purpose:
A dataset of control animal microarray expression data was assembled by a working group of the Health and Environmental Sciences Institute's Technical Committee on the Application of Genomics in Mechanism Based Risk Assessment in order to provide a public resource for assessments of variability in baseline gene expression.
Description:
The use of gene expression profiling to predict chemical mode of action would be enhanced by better characterization of variance due to individual, environmental, and technical factors. Meta-analysis of microarray data from untreated or vehicle-treated animals within the control arm of toxicogenomics studies has yielded useful information on baseline fluctuations in gene expression. A dataset of control animal microarray expression data was assembled by a working group of the Health and Environmental Sciences Institute's Technical Committee on the Application of Genomics in Mechanism Based Risk Assessment in order to provide a public resource for assessments of variability in baseline gene expression. Data from over 500 Affymetrix microarrays from control rat liver and kidney were collected from 16 different institutions. Thirty-five biological and technical factors were obtained for each animal, describing a wide range of study characteristics, and a subset were evaluated in detail for their contribution to total variability using multivariate statistical and graphical techniques. The study factors that emerged as key sources of variability included gender, organ section, strain, and fasting state. These and other study factors were identified as key descriptors that should be included in the minimal information about a toxicogenomics study needed for interpretation of results by an independent source. Genes that are the most and least variable, gender-selective, or altered by fasting were identified and functionally categorized. Baseline gene expression in the livers of control animals as a function of life stage (fetal, neonatal, adult and old age) has been characterized and with information about gene-chemical relationships from the Comparative Toxicogenomics Database is being used to predict differences in chemical responses as a function of life stage, gender and disease state. Better characterization of gene expression variability in control animals will aid in the design of toxicogenomics studies and in the interpretation of their results. Additionally, gene expression differences between biological states could be used to predict chemical toxicity. (This abstract does not necessarily reflect US EPA policy).