What is toxicogenomics?

A new sub discipline in toxicology has emerged: “toxicogenomics".

In itself, toxicogenomics represents an effort surpassing the boundaries of toxicology and many other traditional disciplines, because new profiling techniques enable the examination of many variables at once. For instance. by using DNA microarray technologies, the variation in expression of over 10,000 genes as a result of exposure to chemicals in target tissue or cells can be monitored and this enables the identification of the mode of action on the transcription level. Identification of those genes, which are representatives of a certain mode of action, refines and simplifies the analyses. Transcriptomics using microarrays can be combined with similarly powerful techniques such as proteomics (2D electrophoresis/MS, SELDI-TOFF/MS or protein arrays) and metabolomics (LC-MS, GC-MS, NMR), thereby monitoring translational and posttranslational events as well.Toxicogenomics provides the opportunity to reduce the uncertainty of extrapolating from laboratory animal models to the human, e.g. by developing “bridging effect markers". A bridging effect marker would be a set of key genes in a gene expression fingerprint for a given exposure to a particular toxicant which is highly similar between a laboratory animal model and man (or human cells) as indicated below:

After extensive and proper validation (for instance, by comparison with effects in conventional assays), such a set of key genes could be eventually assessed solely in human cells thereby providing a screen for chemical safety assessment, even without applying animal testing any longer. Such predictive gene expression fingerprints would also be of high economic value because dedicated screening devices for chemical testing may be derived from them, while furthermore; current chemical risk assessment procedures may improve in quality and in speed. These toxicogenomics-based predictive screens for toxicity testing as a non-animal model may also serve multiple additional purposes:

  • Gene/protein/metabolite expression profiles derived from short-term animal studies, may predict (toxicity) effects in long-term studies and thus enable shorter animal studies.
  • By applying these profiling technologies, early-warning effect markers may be identified enabling the monitoring of early adverse effects of chemical compounds, possibly also at lower dose levels (e.g. below pathological thresholds) which may lead to improved extrapolations in the low dose range.
  • Dedicated screens can be used to select the most appropriate animal model prior to the conduct of toxicity studies, thereby reducing the use of laboratory animals in chemical testing.
  • Screens for toxicity testing can be developed for predicting effects of real-life chemical mixtures (as most commercial products are a combination of chemicals, and humans are rarely exposed to single chemicals).

It is the goal of the Netherlands Toxicogenomics Centre to provide the scientific basis for developing these predictive screens for various endpoints of toxicity which can ultimately be applied in chemical safety procedures as alternatives to current rodent testing models. This approach will provide detailed understanding of the mode of action of toxicants and by linking this information to the parameters studied in routine toxicity tests (phenotypic anchoring), ultimately this will lead to the use of specific in vitro systems that predict specific in vivo toxicity.

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