REVIEWS TOXICOGENOMICS AND SYSTEMS TOXICOLOGY AIMS AND PROSPECTS Michael D Waters and Jennifer M Fostel 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 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 National Center for Toxicogenomics National Institute of Environmental Health Sciences PO Box 12233 MD F1 05 111 Alexander Drive Research Triangle Park North Carolina 27709 2233 USA Correspondence to M D W e mail waters2 niehs nih gov doi 10 1038 nrg1493 936 The ability to discern the mechanisms of toxicity that are related to health issues is an important challenge facing scientists public health decision makers and regulatory authorities whose aim is to protect humans and the environment from exposures to hazardous drugs chemicals and environmental stressors such as global warming or non ionizing radiation Also the problems of identifying environmental factors involved in the aetiology of human disease and of performing safety and risk assessments for drugs and chemicals have long been formidable issues Toxicology the study of poisons is focused on the substances and exposures that cause adverse effects in living organisms A vital part of this study is the empirical and contextual characterization of adverse effects at the level of the organism the tissue the cell and intracellular molecular systems Therefore studies in toxicology measure the effects of an agent on an organism s food consumption and digestion on its body and organ weight on microscopic histopathology and on cell viability immortalization NECROSIS and apoptosis1 The rapid accumulation of genomic sequence data and associated gene and protein annotation has catalysed the application of gene expression analysis to understanding the MODES OF ACTION of chemicals and other environmental stressors on biological systems DECEMBER 2004 VOLUME 5 FIG 1 These developments have facilitated the emergence of the field of toxicogenomics which aims to study the response of a whole genome to toxicants or environmental stressors2 13 The related field of toxicoproteomics14 16 is similarly defined with respect to the proteome the protein subset of the genome For example global technologies such as cDNA and oligonucleotide microarrays PROTEIN CHIPS and NUCLEAR MAGNETIC RESONANCE NMR based molecular profiling in corresponding order can simultaneously measure the expression of numerous genes proteins and metabolites therefore providing the potential to accelerate the discovery of toxicant pathways modes of action and specific chemical and drug targets So toxicogenomics combines toxicology with genetics global omics technologies BOX 1 and appropriate pharmacological and toxicological models FIG 1 to provide a comprehensive view of the function of the genetic and biochemical machinery of the cell This review explores the new field of toxicogenomics delineates some of its research approaches and success stories and describes the challenges it faces It discusses how integrating data that is derived from TRANSCRIPTOMICS PROTEOMICS and METABONOMICS studies can contribute to the development of a toxicogenomics KNOWLEDGEBASE FIG 2 BOX 1 and to the evolution of SYSTEMS TOXICOLOGY as it relates to molecular expression profiling In many www nature com reviews genetics 2004 Nature Publishing Group REVIEWS Dose 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 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 lowmolecular 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 Target tissue dose mod ode Dise ase S ys PBP BBD te m Rm sm odels dels K mo Exp osur em Internal dose els ls ode ls Disease aetiology Exposure TRANSCRIPTOMICS Genetic susceptibility Mode s of action Early biological effects Altered structure function Disease Figure 1 The role of genetic susceptibility and computational models on the continuum from exposure to disease outcome The sequence of events between initial exposure to a toxicant and final disease outcome are shown from left to right Note that genetic susceptibility red dot