Abstract: Toxicogenomic profiling is a molecular approach to capture the global, transcriptomic response of a biological system caused by perturbations resulted from chemical exposure. Coupled with advanced bioinformatic techniques, it allows for the elucidation of the molecular mechanisms of chemical toxicity, as well as the identification of novel biomarkers predictive for chemical exposure. In an effort to investigate if gene expression changes in whole blood can serve as novel biomarkers indicative of organ-specific malfunction resulted from chemical exposure, we have initiated a transcriptomic profiling study using chemicals with different target organ toxicity in a rat model. The first three compounds chosen were alpha-naphthylisothiocyanate (ANIT, 0.1 - 100 mg/kg), chlorpyrifos (CPF, 0.5 - 50 mg/kg) and 2-bromoethylamine (BEA, 1.0 - 250 mg/kg), which are model hepatotoxin, neurotoxin and nephrotoxin, respectively. Gene expression profiles of blood samples isolated from control and chemical-treated rats were determined using DNA microarrays (Affymetrix GeneChip, RAE23OA). The expression levels of 584, 303 and 441 genes were significantly altered after chemical treatments as determined by t-test, ANOVA and SAM (significance analysis of microarray), respectively. Close examination of these gene lists revealed that there are a total of 1075 unique genes that collectively comprised these lists. Of these unique genes, 213 were identified by two methods, while 40 genes were common in all three methods. Using a dataset of the expression profiles of these 40 genes as input data in hierarchical clustering and principal component analysis demonstrated that these are useful discriminators for separating animal groups treated with different chemicals. This result strongly supports the premise that whole blood is a suitable surrogate tissue for monitoring gene expression changes for detection of organ-specific toxicity.
| Limitations: |
 APPROVED FOR PUBLIC RELEASE |
| Pages: |
16 |
| Report Date: |
FEB 2006 |
| Contract Number: |
F3361500C6060 |
| Report Number: |
A518754 |
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