Systems toxicology: applications of toxicogenomics, transcriptomics, proteomics and metabolomics in toxicology

Toxicogenomics can facilitate the identification and characterization of toxicity, as illustrated in this review. Toxicogenomics, the application of the functional genomics technologies (transcriptomics, proteomics and metabolomics) in toxicology enables the study of adverse effects of xenobiotic substances in relation to structure and activity of the genome. The advantages and limitations of the different technologies are evaluated, and the prospects for integration of the technologies into a systems biology or systems toxicology approach are discussed. Applications of toxicogenomics in various laboratories around the world show that the crucial steps and sequence of events at the molecular level can be studied to provide detailed insights into mechanisms of toxic action. Toxicogenomics allowed for more sensitive and earlier detection of adverse effects in (animal) toxicity studies. Furthermore, the effects of exposure to mixtures could be studied in more detail. This review argues that in the (near) future, human health risk assessment will truly benefit from toxicogenomics (systems toxicology).

[1]  R. Stierum,et al.  Toxicogenomics concepts and applications to study hepatic effects of food additives and chemicals. , 2005, Toxicology and applied pharmacology.

[2]  R. Stierum,et al.  Toxicogenomic analysis of gene expression changes in rat liver after a 28-day oral benzene exposure. , 2005, Mutation research.

[3]  Ben van Ommen,et al.  Profiles of Metabolites and Gene Expression in Rats with Chemically Induced Hepatic Necrosis , 2005, Toxicologic pathology.

[4]  John Quackenbush,et al.  Corrigendum: Multiple-laboratory comparison of microarray platforms , 2005, Nature Methods.

[5]  John Quackenbush,et al.  Multiple-laboratory comparison of microarray platforms , 2005, Nature Methods.

[6]  A. Kong,et al.  Toxicogenomics of resveratrol in rat liver. , 2005, Life sciences.

[7]  Gérard Steinmetz,et al.  Transcriptomic and proteomic responses of human renal HEK293 cells to uranium toxicity , 2005, Proteomics.

[8]  Genomic and proteomic profiling for biomarkers and signature profiles of toxicity. , 2004 .

[9]  Michael D. Waters,et al.  Toxicogenomics and systems toxicology: aims and prospects , 2004, Nature Reviews Genetics.

[10]  Katie Chan,et al.  Human and animal hepatocytes in vitro with extrapolation in vivo. , 2004, Chemico-biological interactions.

[11]  Gordon Vansant,et al.  Gene expression profiling of rat livers reveals indicators of potential adverse effects. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[12]  S. De Flora,et al.  Proteomic analysis as related to transcriptome data in the lung of chromium(VI)-treated rats. , 2004, International journal of oncology.

[13]  Ben van Ommen,et al.  Bromobenzene-induced hepatotoxicity at the transcriptome level. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[14]  Angela J Harris,et al.  Comparison of basal gene expression profiles and effects of hepatocarcinogens on gene expression in cultured primary human hepatocytes and HepG2 cells. , 2004, Mutation research.

[15]  Janine Ezendam,et al.  Toxicogenomics of subchronic hexachlorobenzene exposure in Brown Norway rats. , 2004, Environmental health perspectives.

[16]  S. Bijlsma,et al.  A combination of proteomics, principal component analysis and transcriptomics is a powerful tool for the identification of biomarkers for macrophage maturation in the U937 cell line , 2004, Proteomics.

[17]  Eunil Lee,et al.  Proteomic analysis of plasma proteins of workers exposed to benzene. , 2004, Mutation research.

[18]  William Pennie,et al.  Toxicogenomics in risk assessment: an overview of an HESI collaborative research program. , 2004, Environmental health perspectives.

[19]  S. Krawetz,et al.  Surrogate tissue analysis: monitoring toxicant exposure and health status of inaccessible tissues through the analysis of accessible tissues and cells. , 2004, Toxicology and applied pharmacology.

[20]  D. Baunsgaard,et al.  Combination of ‘omics’ data to investigate the mechanism(s) of hydrazine-induced hepatotoxicity in Rats and to identify potential biomarkers , 2004, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[21]  B Alex Merrick,et al.  Genomic and proteomic profiling for biomarkers and signature profiles of toxicity. , 2004, Current opinion in molecular therapeutics.

[22]  Barbara A Wetmore,et al.  Toxicoproteomics: proteomics applied to toxicology and pathology. , 2004, Toxicologic pathology.

[23]  H. Jaeschke Are cultured liver cells the right tool to investigate mechanisms of liver disease or hepatotoxicity? , 2003, Hepatology.

[24]  Thierry Arnould,et al.  Use of a low-density microarray for studying gene expression patterns induced by hepatotoxicants on primary cultures of rat hepatocytes. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[25]  B. Jessen,et al.  Assessment of hepatocytes and liver slices as in vitro test systems to predict in vivo gene expression. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[26]  G. Orphanides,et al.  Toxicogenetics: applications and opportunities. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[27]  Sorin Drăghici,et al.  Data Analysis Tools for DNA Microarrays , 2003 .

[28]  T. Zacharewski,et al.  Workshop overview: use of genomic data in risk assessment. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[29]  Silvio Albertini,et al.  Gene expression in two hepatic cell lines, cultured primary hepatocytes, and liver slices compared to the in vivo liver gene expression in rats: possible implications for toxicogenomics use of in vitro systems. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[30]  A. Andrew,et al.  Genomic and proteomic profiling of responses to toxic metals in human lung cells. , 2003, Environmental health perspectives.

[31]  Ben van Ommen,et al.  Toxicogenomics of bromobenzene hepatotoxicity: a combined transcriptomics and proteomics approach. , 2003, Biochemical pharmacology.

[32]  Thierry Lavé,et al.  Influence of isolation procedure, extracellular matrix and dexamethasone on the regulation of membrane transporters gene expression in rat hepatocytes. , 2002, Biochemical pharmacology.

[33]  J. Nicholson,et al.  NMR and pattern recognition studies on liver extracts and intact livers from rats treated with alpha-naphthylisothiocyanate. , 2002, Biochemical pharmacology.

[34]  K. Morgan Gene expression analysis reveals chemical-specific profiles. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[35]  Lee Bennett,et al.  Prediction of compound signature using high density gene expression profiling. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[36]  Richard S Paules,et al.  An overview of toxicogenomics. , 2002, Current issues in molecular biology.

[37]  M. Fielden,et al.  In Silico Approaches to Mechanistic and Predictive Toxicology: An Introduction to Bioinformatics for Toxicologists , 2002, Critical reviews in toxicology.

[38]  Marilyn J Aardema,et al.  Toxicology and genetic toxicology in the new era of "toxicogenomics": impact of "-omics" technologies. , 2002, Mutation research.

[39]  Robert P Tonge,et al.  Genomics and proteomics analysis of acetaminophen toxicity in mouse liver. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[40]  R. Aebersold,et al.  Quantitative profiling of differentiation-induced microsomal proteins using isotope-coded affinity tags and mass spectrometry , 2001, Nature Biotechnology.

[41]  R E Stoll,et al.  Assessment of cisplatin-induced nephrotoxicity by microarray technology. , 2001, Toxicological sciences : an official journal of the Society of Toxicology.

[42]  T. K. Baker,et al.  Temporal gene expression analysis of monolayer cultured rat hepatocytes. , 2001, Chemical research in toxicology.

[43]  R G Ulrich,et al.  Clustering of hepatotoxins based on mechanism of toxicity using gene expression profiles. , 2001, Toxicology and applied pharmacology.

[44]  P. Brown,et al.  Use of cDNA microarrays to analyze dioxin-induced changes in human liver gene expression. , 2001, Toxicology letters.

[45]  J. Emery,et al.  Unique gene expression patterns in liver and kidney associated with exposure to chemical toxicants. , 2001, The Journal of pharmacology and experimental therapeutics.

[46]  J. Reindel,et al.  RNA expression in the early characterization of hepatotoxicants in Wistar rats by high‐density DNA microarrays , 2001, Hepatology.

[47]  S. Ekström,et al.  Protein chips based on recombinant antibody fragments: a highly sensitive approach as detected by mass spectrometry. , 2001, BioTechniques.

[48]  D. Gerhold,et al.  Monitoring expression of genes involved in drug metabolism and toxicology using DNA microarrays. , 2001, Physiological genomics.

[49]  R G Ulrich,et al.  Microarray analysis of hepatotoxins in vitro reveals a correlation between gene expression profiles and mechanisms of toxicity. , 2001, Toxicology letters.

[50]  G. Orphanides,et al.  Application of genomics to the definition of the molecular basis for toxicity. , 2001, Toxicology letters.

[51]  J. Brady,et al.  Expression profiling of acetaminophen liver toxicity in mice using microarray technology. , 2001, Biochemical and biophysical research communications.

[52]  T R Zacharewski,et al.  Challenges and limitations of gene expression profiling in mechanistic and predictive toxicology. , 2001, Toxicological sciences : an official journal of the Society of Toxicology.

[53]  E Holmes,et al.  Metabonomic characterization of genetic variations in toxicological and metabolic responses using probabilistic neural networks. , 2001, Chemical research in toxicology.

[54]  A. Brazma,et al.  Gene expression data analysis. , 2001, FEBS letters.

[55]  P. Brown,et al.  Protein microarrays for highly parallel detection and quantitation of specific proteins and antibodies in complex solutions , 2001, Genome Biology.

[56]  R. Dunn,et al.  Toxicogenomics-based discrimination of toxic mechanism in HepG2 human hepatoma cells. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[57]  R. Somogyi,et al.  Gene Expression Microarray Data Analysis for Toxicology Profiling , 2000, Annals of the New York Academy of Sciences.

[58]  E. Winzeler,et al.  Genomics, gene expression and DNA arrays , 2000, Nature.

[59]  P Berndt,et al.  Two‐dimensional database of mouse liver proteins: Changes in hepatic protein levels following treatment with acetaminophen or its nontoxic regioisomer 3‐acetamidophenol , 2000, Electrophoresis.

[60]  Hiroyuki Kaji,et al.  Profiling of Caenorhabditis elegans proteins using two‐dimensional gel electrophoresis and matrix assisted laser desorption/ionization‐time of flight‐mass spectrometry , 2000, Electrophoresis.

[61]  S. Weinberger,et al.  Recent advancements in surface‐enhanced laser desorption/ionization‐time of flight‐mass spectrometry , 2000, Electrophoresis.

[62]  W. Pennie,et al.  The principles and practice of toxigenomics: applications and opportunities. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[63]  A Buckpitt,et al.  Development of a toxicological gene array and quantitative assessment of this technology. , 2000, Archives of biochemistry and biophysics.

[64]  S. Steiner,et al.  Expression profiling in toxicology--potentials and limitations. , 2000, Toxicology letters.

[65]  Sten Orrenius,et al.  Molecular Mechanisms of Apoptosis Induced by Cytotoxic Chemicals , 2000, Critical reviews in toxicology.

[66]  D. Dix,et al.  DNA arrays: technology, options and toxicological applications , 2000, Xenobiotica; the fate of foreign compounds in biological systems.

[67]  J. Lindon,et al.  'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. , 1999, Xenobiotica; the fate of foreign compounds in biological systems.

[68]  J. Barrett,et al.  Application of complementary DNA microarray technology to carcinogen identification, toxicology, and drug safety evaluation. , 1999, Cancer research.

[69]  S. Gygi,et al.  Quantitative analysis of complex protein mixtures using isotope-coded affinity tags , 1999, Nature Biotechnology.

[70]  D J Dix,et al.  Application of DNA arrays to toxicology. , 1999, Environmental health perspectives.

[71]  J. Trent,et al.  Microarrays and toxicology: The advent of toxicogenomics , 1999, Molecular carcinogenesis.

[72]  P. Roepstorff,et al.  Mapping and identification of interferon gamma‐regulated HeLa cell proteins separated by immobilized pH gradient two‐dimensional gel electrophoresis , 1999, Electrophoresis.

[73]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[74]  Michael Ruogu Zhang,et al.  Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization. , 1998, Molecular biology of the cell.

[75]  E Holmes,et al.  Development of a model for classification of toxin‐induced lesions using 1H NMR spectroscopy of urine combined with pattern recognition , 1998, NMR in biomedicine.

[76]  E Holmes,et al.  Nuclear magnetic resonance spectroscopic and principal components analysis investigations into biochemical effects of three model hepatotoxins. , 1998, Chemical research in toxicology.

[77]  P. Brown,et al.  Exploring the metabolic and genetic control of gene expression on a genomic scale. , 1997, Science.

[78]  A. Podtelejnikov,et al.  Linking genome and proteome by mass spectrometry: large-scale identification of yeast proteins from two dimensional gels. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[79]  D. Lubman,et al.  Characterization of SDS--PAGE-separated proteins by matrix-assisted laser desorption/ionization mass spectrometry. , 1996, Analytical chemistry.

[80]  D. Lockhart,et al.  Expression monitoring by hybridization to high-density oligonucleotide arrays , 1996, Nature Biotechnology.

[81]  L. Penland,et al.  Use of a cDNA microarray to analyse gene expression patterns in human cancer , 1996, Nature Genetics.

[82]  Ronald W. Davis,et al.  Quantitative Monitoring of Gene Expression Patterns with a Complementary DNA Microarray , 1995, Science.

[83]  J. Stults Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). , 1995, Current opinion in structural biology.

[84]  Michael Balls,et al.  The three Rs: the way forward: the report and recommendations of ECVAM Workshop 11. , 1995, Alternatives to laboratory animals : ATLA.

[85]  P. Roepstorff,et al.  Identification of transformation sensitive proteins recorded in human two‐dimensional gel protein databases by mass spectrometric peptide mapping alone and in combination with microsequencing , 1994, Electrophoresis.

[86]  E Holmes,et al.  Mapping the biochemical trajectory of nephrotoxicity by pattern recognition of NMR urinanalysis , 1992, NMR in biomedicine.

[87]  E Holmes,et al.  Nuclear magnetic resonance spectroscopy and pattern recognition analysis of the biochemical processes associated with the progression of and recovery from nephrotoxic lesions in the rat induced by mercury(II) chloride and 2-bromoethanamine. , 1992, Molecular pharmacology.

[88]  J C Lindon,et al.  Application of pattern recognition methods to the analysis and classification of toxicological data derived from proton nuclear magnetic resonance spectroscopy of urine. , 1991, Molecular pharmacology.

[89]  R. Tompkins,et al.  Hepatocyte function and extracellular matrix geometry: long‐term culture in a sandwich configuration , 1989, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[90]  J. Nicholson,et al.  Proton NMR spectroscopy of bile for monitoring the excretion of endogenous and xenobiotic metabolites: application to para-aminophenol. , 1989, Journal of pharmaceutical and biomedical analysis.