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RNA expression in the early characterization of hepatotoxicants in Wistar rats by high-density DNA microarrays
S J Bulera1, S M Eddy, E Ferguson
1Drug Safety Evaluation and Molecular Biology, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. steven.bulera@pfizer.com
Abstract:
High-density microarrays are useful tools to study gene expression for the purpose of characterizing functional tissue changes in response to the action of drugs and chemicals. To test whether high-density expression data can identify mechanisms of toxicity and to identify an unknown sample through its RNA expression pattern, groups of male Wistar rats were administered 6 hepatotoxicants. The compounds chosen for this study were microcystin-LR (MLR), phenobarbital (PB), lipopolysaccharide (LPS), carbon tetrachloride (CT), thioacetamide (THA), and cyproterone acetate (CPA). These hepatotoxicants are known to induce adverse liver effects through different mechanisms. Liver mRNA was isolated and used to generate biotinylated cRNA for hybridization to a custom 1,600-rat gene DNA microarray. Treatment correlation matrices analyzed hybridization data from a hepatotoxicant-blinded sample, with gene expression coefficients (GEC) evaluated by means of hierarchical cluster analysis and visual representation as dendrograms. The experimental liver toxicity from the different treatments was confirmed by means of concurrent histopathology, liver enzymes, and bilirubin assays. This toxico genomic analysis identified multiple genes and groups of genes that were affected by the hepatotoxicants on study, indicating that high-density microarray expression data are useful to identify groups of genes involved in toxicity. In addition, the mRNA expression profile of an unidentified sample can be accurately identified when compared with the expression profiles resident in the data set. This study supports the use of gene expression-profiling technology to determine or to predict toxic liver effects.
Insights
High-density microarrays effectively identify toxicity mechanisms and unknown samples by analyzing gene expression patterns. This toxicogenomic approach aids in predicting and determining toxic liver effects from chemical exposures.
Area of Science:
- Toxicology
- Genomics
- Molecular Biology
Background:
- High-density microarrays are valuable for studying gene expression changes in response to drugs and chemicals.
- Understanding functional tissue changes is crucial for assessing chemical safety and toxicity.
Purpose of the Study:
- To evaluate the utility of high-density expression data in identifying toxicity mechanisms.
- To determine if RNA expression patterns can accurately identify unknown toxicant-exposed samples.
Main Methods:
- Male Wistar rats were exposed to six known hepatotoxicants (MLR, PB, LPS, CT, THA, CPA).
- Liver mRNA was isolated, converted to cRNA, and hybridized to a custom 1,600-gene rat microarray.
- Gene expression data were analyzed using correlation matrices, hierarchical clustering, and dendrograms; toxicity was confirmed by histopathology and biochemical assays.
Main Results:
- Toxicogenomic analysis revealed multiple genes and gene groups affected by the different hepatotoxicants.
- High-density microarray data successfully identified specific gene expression profiles associated with distinct toxicity mechanisms.
- The mRNA expression profile of an unknown sample was accurately identified by comparison with the established dataset.
Conclusions:
- High-density gene expression profiling is a powerful tool for identifying genes and pathways involved in chemical toxicity.
- This technology can accurately identify unknown samples based on their RNA expression signatures.
- Gene expression profiling supports the prediction and determination of toxic liver effects.
