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Genomic interrogation of mechanism(s) underlying cellular responses to toxicants
Rupesh P Amin1, Hisham K Hamadeh, Pierre R Bushel
1National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, Mail Drop F1-05, Research Triangle Park, NC 27709, USA.
Abstract:
Assessment of the impact of xenobiotic exposure on human health and disease progression is complex. Knowledge of mode(s) of action, including mechanism(s) contributing to toxicity and disease progression, is valuable for evaluating compounds. Toxicogenomics, the subdiscipline which merges genomics with toxicology, holds the promise to contributing significantly toward the goal of elucidating mechanism(s) by studying genome-wide effects of xenobiotics. Global gene expression profiling, revolutionized by microarray technology and a crucial aspect of a toxicogenomic study, allows measuring transcriptional modulation of thousands of genes following exposure to a xenobiotic. We use our results from previous studies on compounds representing two different classes of xenobiotics (barbiturate and peroxisome proliferator) to discuss the application of computational approaches for analyzing microarray data to elucidate mechanism(s) underlying cellular responses to toxicants. In particular, our laboratory demonstrated that chemical-specific patterns of gene expression can be revealed using cDNA microarrays. Transcript profiling provides discrimination between classes of toxicants, as well as, genome-wide insight into mechanism(s) of toxicity and disease progression. Ultimately, the expectation is that novel approaches for predicting xenobiotic toxicity in humans will emerge from such information.
Insights
Toxicogenomics uses genome-wide gene expression profiling to understand how xenobiotics affect human health. This approach reveals toxicant mechanisms, aiding in predicting chemical toxicity.
Area of Science:
- Toxicology
- Genomics
- Computational Biology
Background:
- Assessing xenobiotic impact on human health is complex.
- Understanding mechanisms of toxicity and disease progression is crucial for compound evaluation.
- Toxicogenomics merges genomics and toxicology to study genome-wide xenobiotic effects.
Purpose of the Study:
- To discuss computational approaches for analyzing microarray data in toxicogenomics.
- To elucidate mechanisms underlying cellular responses to toxicants.
- To demonstrate the application of transcript profiling in understanding xenobiotic action.
Main Methods:
- Utilizing cDNA microarrays for global gene expression profiling.
- Analyzing microarray data with computational approaches.
- Comparing gene expression patterns from different classes of xenobiotics (barbiturate and peroxisome proliferator).
Main Results:
- Chemical-specific gene expression patterns were identified using cDNA microarrays.
- Transcript profiling effectively discriminated between different classes of toxicants.
- Genome-wide insights into toxicity and disease progression mechanisms were obtained.
Conclusions:
- Transcript profiling is a valuable tool in toxicogenomics for elucidating xenobiotic mechanisms.
- Computational analysis of microarray data provides genome-wide insight into toxicant responses.
- This research paves the way for novel approaches to predict human xenobiotic toxicity.