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Toxicogenomics and systems toxicology: aims and prospects

Key Points

  • Toxicology is the science of poisons. The global biological responses that result from toxicant-induced molecular perturbations are kinetic and dynamic phenomena that depend on the dose of the toxicant and the period of exposure to it.

  • By contrast, toxicogenomics combines genetics, the analysis of genome-scale mRNA expression (transcriptomics), cell and tissue-wide protein expression (proteomics), metabolite profiling (metabolomics and metabonomics), and bioinformatics with conventional toxicology to understand the role of gene–environment interactions in disease.

  • Gene, protein and metabolite-expression profiles can be thought of as 'snapshots' of a currently poorly mapped molecular landscape. The ultimate aim of toxicogenomics is to fully map this landscape and to realize a systems toxicology.

  • Systems toxicology is the description of all the toxicological interactions within a living system. Like systems biology, systems toxicology attempts to define the behaviour and relationships of all of the components of a biological system on the premise that global-molecular data can be integrated and modelled computationally.

  • The science of systems toxicology must capture data from experiments in molecular expression and toxicology and convert them into knowledge about the toxicological responses of cells and organisms under stress. This will be accomplished through the development of knowledgebases that support the integration of data from multiple domains, as well as through computational modelling.

  • Toxicogenomics experiments have succeeded in defining several molecular signatures of exposure to drugs and chemicals and expression patterns corresponding to various histopathologies and diseases; however, much more remains to be done to delineate the toxicity response of many target organs and to predict disease outcomes following exposures to toxicants.

Abstract

Toxicogenomics combines transcript, protein and metabolite profiling with conventional toxicology to investigate the interaction between genes and environmental stress in disease causation. The patterns of altered molecular expression that are caused by specific exposures or disease outcomes have revealed how several toxicants act and cause disease. Despite these success stories, the field faces noteworthy challenges in discriminating the molecular basis of toxicity. We argue that toxicology is gradually evolving into a systems toxicology that will eventually allow us to describe all the toxicological interactions that occur within a living system under stress and use our knowledge of toxicogenomic responses in one species to predict the modes-of-action of similar agents in other species.

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Figure 1: The role of genetic susceptibility and computational models on the continuum from exposure to disease outcome.
Figure 2: A framework for systems toxicology.
Figure 3: Bioinformatics challenges and biological complexity.
Figure 4: Conceptual framework for the development of the Chemical Effects in Biological Systems (CEBS) knowledgebase.

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Acknowledgements

We are indebted to B. Alex Merrick, Richard S. Paules and Raymond W. Tennant for their consultation and assistance with this manuscript, and to Kenneth Olden, Samuel Wilson, Lutz Birnbaumer and the staff of the National Center for Toxicogenomics for their continuing support and involvement with this work.

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Correspondence to Michael D. Waters.

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DATABASES

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FURTHER INFORMATION

Chemical Effects in Biological Systems

CEBS Development Forum

Clinical Data Interchange Standards Consortium

EMBL-European Bioinformatics Institute

'From OMICS to systems biology' poster

ILSI Health and Environmental Services Institute

MGED Reporting Structure for Biological Investigations (RSBI)

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Glossary

NECROSIS

The localized death of living cells.

MODE-OF-ACTION

The sequence of events from the absorption of a compound into an organism to a toxic outcome or death.

PROTEIN CHIP

A genomic set of proteins that are arrayed on a solid surface without denaturation.

NUCLEAR MAGNETIC RESONANCE

An analytical chemistry technique that is used to study molecular structure and dynamics; it explores spectral differences that are caused by the differential alignment of atomic spins in the presence of a strong magnetic field.

TRANSCRIPTOMICS

Techniques that measure the full complement of activated genes, mRNAs or transcripts in a particular tissue at a particular time, typically through the use of cDNA or oligonucleotide microarrays.

PROTEOMICS

A collection of techniques used to measure the structural and functional properties of proteins through the use of 2-dimensional gel electrophoresis or liquid chromatography; typically followed by protein identification using some form of mass spectrometry.

METABONOMICS

Techniques that detect changes in the concentration of low-molecular-weight metabolites present in a cell or organism at a given time (the metabonome) by using nuclear magnetic resonance or mass spectrometry coupled to gas or liquid chromatography.

KNOWLEDGEBASE

An archival and computational system that uses data, information and knowledge captured from experts to carry out tasks that create new information and new understanding.

SYSTEMS TOXICOLOGY

The study of the perturbation of biological systems by chemicals and stressors, monitoring changes in molecular expression and conventional toxicological parameters, and iteratively integrating response data to describe the functioning organism.

SYSTEMS BIOLOGY

The integrated study of biological systems (cells, tissues, organs or entire organisms) at the molecular level. It involves perturbing systems, monitoring molecular expression, integrating response data and modelling the molecular structure and network function of the system.

BIOMARKER

A pharmacological or physiological measurement that is used to predict a toxic event in an animal.

TOXICOINFORMATICS

The description of a toxicological stress and the annotation of the dose-dependent molecular responses that are elicited over time.

INFORMATION SCIENCE

The systematic study and analysis of the sources, development, collection, organization, dissemination, evaluation, use and management of information in all its forms, including the media (formal and informal) and technology used in its communication.

METABOLOMICS

The directed use of quantitative analytical methods for analysing the entire metabolic content of a cell or organism at a given time (the metabolome).

FUNCTIONAL GENOMICS

The development and application of global (genome-wide or system-wide) experimental approaches to assess gene function by making use of information and reagents provided by physical mapping and sequencing of genomes.

TANDEM MASS SPECTROMETRY

The use of two mass spectrometers in series to detect and identify substances on the basis of mass and charge.

SYNOVIOCYTES

Cells believed to be responsible for the production of synovial-fluid components in joints, for absorption from the joint cavity, and for blood/synovial fluid exchanges.

CHONDROCYTES

Cartilage cells that produce the structural components of cartilage.

LEAD COMPOUNDS

Chemicals or drugs that show promise for commercialization.

LONGITUDINAL DATA MINING

The process of locating previously unknown patterns and relationships within data that result from multiple observations of a population of genes, animals or patients.

PRINCIPAL-COMPONENT ANALYSIS

A statistical method that seeks to reduce the dimensionality of a data set by projecting the data onto new axes that align with the variability in the data.

NUTRIGENOMICS

The study of the nutritional environment and related cellular or genetic processes at the level of the genome.

PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELLING

Involves deriving a set of mathematical (differential) equations that are structured to provide a time course for a chemical's mass–balance disposition (wherein all inputs, outputs and changes in total mass of the chemical are accounted for) in preselected anatomical compartments.

PHARMACODYNAMIC MODELLING

Involves the development of a mathematical description of a toxicological or disease outcome after therapy.

TARGET TISSUE

The tissue or tissues that are damaged as a result of exposure to a toxicant or stressor.

REAL-TIME PCR

A process that allows the amount of PCR product to be quantified during each cycle of a PCR reaction. The product concentration, as a function of cycle number, provides a good estimation of the relative quantity of the mRNA being tested.

PARSING

The process of determining the syntactic structure of a sentence or string of symbols in a language.

RNA INTERFERENCE

An ancient natural antiviral mechanism that directs silencing of gene expression in a sequence-specific manner and can be exploited artificially to inhibit the expression of any gene of interest.

BIOLOGICALLY-BASED DOSE-RESPONSE MODELLING

The science of establishing dose-response models based on underlying biological processes.

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Waters, M., Fostel, J. Toxicogenomics and systems toxicology: aims and prospects. Nat Rev Genet 5, 936–948 (2004). https://doi.org/10.1038/nrg1493

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