Metabolomics in toxicology and preclinical research.

Metabolomics, the comprehensive analysis of metabolites in a biological system, provides detailed information about the biochemical/physiological status of a biological system, and about the changes caused by chemicals. Metabolomics analysis is used in many fields, ranging from the analysis of the physiological status of genetically modified organisms in safety science to the evaluation of human health conditions. In toxicology, metabolomics is the -omics discipline that is most closely related to classical knowledge of disturbed biochemical pathways. It allows rapid identification of the potential targets of a hazardous compound. It can give information on target organs and often can help to improve our understanding regarding the mode-of-action of a given compound. Such insights aid the discovery of biomarkers that either indicate pathophysiological conditions or help the monitoring of the efficacy of drug therapies. The first toxicological applications of metabolomics were for mechanistic research, but different ways to use the technology in a regulatory context are being explored. Ideally, further progress in that direction will position the metabolomics approach to address the challenges of toxicology of the 21st century. To address these issues, scientists from academia, industry, and regulatory bodies came together in a workshop to discuss the current status of applied metabolomics and its potential in the safety assessment of compounds. We report here on the conclusions of three working groups addressing questions regarding 1) metabolomics for in vitro studies 2) the appropriate use of metabolomics in systems toxicology, and 3) use of metabolomics in a regulatory context.

[1]  H. Volk,et al.  T cell stimulus-induced crosstalk between lymphocytes and liver macrophages results in augmented cytokine release. , 1996, Experimental cell research.

[2]  Florian Gantner,et al.  Phagocytosis of Nonapoptotic Cells Dying by Caspase- Independent Mechanisms1 , 2000, The Journal of Immunology.

[3]  Marcel Leist,et al.  Metabolic Depletion of Atp by Fructose Inversely Controls Cd95- and Tumor Necrosis Factor Receptor 1–Mediated Hepatic Apoptosis , 2000, The Journal of experimental medicine.

[4]  M Ingelman-Sundberg,et al.  Genetic variability in susceptibility and response to toxicants. , 2001, Toxicology letters.

[5]  Michael Balls,et al.  ECVAM Good Cell Culture Practice Task Force Report 1 , 2002, Alternatives to laboratory animals : ATLA.

[6]  Henrik Antti,et al.  Contemporary issues in toxicology the role of metabonomics in toxicology and its evaluation by the COMET project. , 2003, Toxicology and applied pharmacology.

[7]  Elaine Holmes,et al.  Metabonomics: systems biology in pharmaceutical research and development. , 2004, Current opinion in molecular therapeutics.

[8]  Jeppe Falsig,et al.  Specific Modulation of Astrocyte Inflammation by Inhibition of Mixed Lineage Kinases with CEP-13471 , 2004, The Journal of Immunology.

[9]  Michael Balls,et al.  Guidance on Good Cell Culture Practice , 2005, Alternatives to laboratory animals : ATLA.

[10]  J. Lindon,et al.  Pharmaco-metabonomic phenotyping and personalized drug treatment , 2006, Nature.

[11]  Philip G Hewitt,et al.  Acute hepatotoxicity: a predictive model based on focused illumina microarrays. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[12]  Michael Balls,et al.  Guidance on Good Cell Culture Practice , 2007 .

[13]  Elaine Holmes,et al.  Prediction and classification of drug toxicity using probabilistic modeling of temporal metabolic data: the consortium on metabonomic toxicology screening approach. , 2007, Journal of proteome research.

[14]  S. Stürzenbaum,et al.  'Systems toxicology' approach identifies coordinated metabolic responses to copper in a terrestrial non-model invertebrate, the earthworm Lumbricus rubellus , 2008, BMC Biology.

[15]  B. van Ravenzwaay,et al.  The use of metabolomics for the discovery of new biomarkers of effect. , 2007, Toxicology letters.

[16]  Thomas Hartung,et al.  Food for thought... on cell culture. , 2007, ALTEX.

[17]  Marta Cascante,et al.  Metabolomics and fluxomics approaches. , 2008, Essays in biochemistry.

[18]  M. Leist,et al.  Food for thought... on the real success of 3R approaches. , 2008, ALTEX.

[19]  Thomas Hartung,et al.  The dawning of a new age of toxicology. , 2008, ALTEX.

[20]  Thomas Hartung,et al.  Food for thought ... on the evolution of toxicology and the phasing out of animal testing. , 2008, ALTEX.

[21]  Steven K. Gibb Toxicity testing in the 21st century: a vision and a strategy. , 2008, Reproductive toxicology.

[22]  Thomas Hartung,et al.  Food for thought... on evidence-based toxicology. , 2009, ALTEX.

[23]  E. Heinzle,et al.  Effects of drugs in subtoxic concentrations on the metabolic fluxes in human hepatoma cell line Hep G2. , 2009, Toxicology and applied pharmacology.

[24]  Donald G Robertson,et al.  Mechanistic aspects and novel biomarkers of responder and non-responder phenotypes in galactosamine-induced hepatitis. , 2009, Journal of proteome research.

[25]  H. Kamp,et al.  Influence of strain and sex on the metabolic profile of rats in repeated dose toxicological studies. , 2009, Toxicology letters.

[26]  T. Hartung Toxicology for the twenty-first century , 2009, Nature.

[27]  Marcel Leist,et al.  The suitability of BV2 cells as alternative model system for primary microglia cultures or for animal experiments examining brain inflammation. , 2009, ALTEX.

[28]  W. Cho An omics perspective on cancer research , 2010 .

[29]  Hennicke Kamp,et al.  The Use of Metabolomics in Cancer Research , 2010 .

[30]  Marcel Leist,et al.  Food for thought ... considerations and guidelines for basic test method descriptions in toxicology. , 2010, ALTEX.

[31]  Melvin E Andersen,et al.  A mechanistic redefinition of adverse effects - a key step in the toxicity testing paradigm shift. , 2010, ALTEX.

[32]  Krishna Prasad,et al.  Renal biomarker qualification submission: a dialog between the FDA-EMEA and Predictive Safety Testing Consortium , 2010, Nature Biotechnology.

[33]  J. Graham,et al.  Standardization and omics science: technical and social dimensions are inseparable and demand symmetrical study. , 2010, Omics : a journal of integrative biology.

[34]  J. Bailar,et al.  Toxicity Testing in the 21st Century: A Vision and a Strategy , 2010, Journal of toxicology and environmental health. Part B, Critical reviews.

[35]  A. Henn,et al.  Reduced Immunoproteasome Formation and Accumulation of Immunoproteasomal Precursors in the Brains of Lymphocytic Choriomeningitis Virus-Infected Mice , 2010, The Journal of Immunology.

[36]  Robert Landsiedel,et al.  Linking energy metabolism to dysfunctions in mitochondrial respiration--a metabolomics in vitro approach. , 2011, Toxicology letters.

[37]  E. Heinzle,et al.  Metabolic flux analysis gives an insight on verapamil induced changes in central metabolism of HL-1 cells. , 2011, Journal of biotechnology.

[38]  Harvey J Clewell,et al.  Can case study approaches speed implementation of the NRC report: "toxicity testing in the 21st century: a vision and a strategy?". , 2011, ALTEX.

[39]  Melvin E. Andersen,et al.  Toxicity Testing in the 21st Century: Defining New Risk Assessment Approaches Based on Perturbation of Intracellular Toxicity Pathways , 2011, PloS one.

[40]  P. Fraser,et al.  Metabolomics: a second-generation platform for crop and food analysis. , 2011, Bioanalysis.

[41]  Henner Hollert,et al.  Endocrine disruptor screening: regulatory perspectives and needs , 2011 .

[42]  D J Dix,et al.  Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics. , 2011, Toxicology and applied pharmacology.

[43]  Elmar Heinzle,et al.  Metabolic profiling using HPLC allows classification of drugs according to their mechanisms of action in HL-1 cardiomyocytes. , 2011, Toxicology and applied pharmacology.

[44]  Erwin van Vliet,et al.  Current standing and future prospects for the technologies proposed to transform toxicity testing in the 21st century. , 2011, ALTEX.

[45]  Arjen Lommen,et al.  An untargeted multi-technique metabolomics approach to studying intracellular metabolites of HepG2 cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin , 2011, BMC Genomics.

[46]  Eric Leclerc,et al.  The Current Status of Alternatives to Animal Testing and Predictive Toxicology Methods Using Liver Microfluidic Biochips , 2011, Annals of Biomedical Engineering.

[47]  Timothy M. D. Ebbels,et al.  Consensus-Phenotype Integration of Transcriptomic and Metabolomic Data Implies a Role for Metabolism in the Chemosensitivity of Tumour Cells , 2011, PLoS Comput. Biol..

[48]  Marcel Leist,et al.  TLR2 Hypersensitivity of Astrocytes as Functional Consequence of Previous Inflammatory Episodes , 2011, The Journal of Immunology.

[49]  Gyun Min Lee,et al.  CHO cells in biotechnology for production of recombinant proteins: current state and further potential , 2012, Applied Microbiology and Biotechnology.

[50]  Thomas Hartung,et al.  Food for Thought ... on mapping the human toxome. , 2011, ALTEX.

[51]  Andreas Luch,et al.  Application of laser postionization secondary neutral mass spectrometry/time-of-flight secondary ion mass spectrometry in nanotoxicology: visualization of nanosilver in human macrophages and cellular responses. , 2011, ACS nano.

[52]  P. Hewitt,et al.  Biomarkers for Drug-Induced Renal Damage and Nephrotoxicity—An Overview for Applied Toxicology , 2011, The AAPS Journal.

[53]  Harvey J Clewell,et al.  Quantitative in vitro to in vivo extrapolation of cell-based toxicity assay results , 2012, Critical reviews in toxicology.

[54]  Roland Buesen,et al.  A testing strategy for the identification of mammalian, systemic endocrine disruptors with particular focus on steroids. , 2012, Regulatory toxicology and pharmacology : RTP.

[55]  Jan G Hengstler,et al.  Compound selection for in vitro modeling of developmental neurotoxicity. , 2012, Frontiers in bioscience.

[56]  H. Kamp,et al.  Metabolomics: a tool for early detection of toxicological effects and an opportunity for biology based grouping of chemicals-from QSAR to QBAR. , 2012, Mutation research.

[57]  G. Siuzdak,et al.  Innovation: Metabolomics: the apogee of the omics trilogy , 2012, Nature Reviews Molecular Cell Biology.

[58]  Chihae Yang,et al.  Novel technologies and an overall strategy to allow hazard assessment and risk prediction of chemicals, cosmetics, and drugs with animal-free methods. , 2012, ALTEX.

[59]  R. Breitling,et al.  Metabolomics methods for the synthetic biology of secondary metabolism , 2012, FEBS letters.

[60]  H. Kamp,et al.  Increased toxicity when fibrates and statins are administered in combination--a metabolomics approach with rats. , 2012, Toxicology letters.

[61]  H. Jungnickel,et al.  Monitoring oxidative stress biomarkers in the lipidome: is there a roadmap for "human inspection"? , 2012, Current molecular medicine.

[62]  Mardas Daneshian,et al.  Validation and quality control of replacement alternatives - Current status and future challenges , 2012 .

[63]  Hui Sun,et al.  Recent and potential developments of biofluid analyses in metabolomics. , 2012, Journal of proteomics.

[64]  H. Jungnickel,et al.  A personalized life: biomarker monitoring from cradle to grave. , 2012, Experientia supplementum.

[65]  Lyle D Burgoon,et al.  Comparative metabolomic and genomic analyses of TCDD-elicited metabolic disruption in mouse and rat liver. , 2012, Toxicological sciences : an official journal of the Society of Toxicology.

[66]  A. Henn,et al.  Characterization of mouse cell line IMA 2.1 as a potential model system to study astrocyte functions. , 2012, ALTEX.

[67]  F. Ausubel Metabolomics , 2012, Nature Biotechnology.

[68]  Ivan Rusyn,et al.  Predictive modeling of chemical hazard by integrating numerical descriptors of chemical structures and short-term toxicity assay data. , 2012, Toxicological sciences : an official journal of the Society of Toxicology.

[69]  A. Zhang,et al.  Serum metabolomics as a novel diagnostic approach for disease: a systematic review , 2012, Analytical and Bioanalytical Chemistry.

[70]  Elmar Heinzle,et al.  Isotope labeling experiments in metabolomics and fluxomics , 2012, Wiley interdisciplinary reviews. Systems biology and medicine.

[71]  R. Gerszten,et al.  Metabolomics and cardiovascular biomarker discovery. , 2012, Clinical chemistry.

[72]  Bas J Blaauboer,et al.  The use of biomarkers of toxicity for integrating in vitro hazard estimates into risk assessment for humans. , 2012, ALTEX.

[73]  Cécile Legallais,et al.  Metabolomics-on-a-chip and predictive systems toxicology in microfluidic bioartificial organs. , 2012, Analytical chemistry.

[74]  R. Woutersen,et al.  Toward in vitro biomarkers for developmental toxicity and their extrapolation to the in vivo situation , 2012, Expert opinion on drug metabolism & toxicology.

[75]  T. Knudsen,et al.  A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing. , 2012, ALTEX.

[76]  Shuzhao Li,et al.  Detailed Mitochondrial Phenotyping by High Resolution Metabolomics , 2012, PloS one.

[77]  Elmar Heinzle,et al.  Doxorubicin increases oxidative metabolism in HL-1 cardiomyocytes as shown by 13C metabolic flux analysis. , 2012, Toxicological sciences : an official journal of the Society of Toxicology.

[78]  C. Andrés-Lacueva,et al.  Nutrimetabolomic strategies to develop new biomarkers of intake and health effects. , 2012, Journal of agricultural and food chemistry.

[79]  Sebastian Hoffmann,et al.  Evidence-based toxicology for the 21st century: opportunities and challenges. , 2013, ALTEX.

[80]  Thomas Hartung,et al.  Review: Toxicometabolomics , 2013, Journal of applied toxicology : JAT.

[81]  D. Blacker Food for thought. , 2013, JAMA neurology.

[82]  H. Arlinghaus,et al.  TOF‐SIMS analysis of cell membrane changes in functional impaired human macrophages upon nanosilver treatment , 2013 .

[83]  Thomas Hartung,et al.  Perspectives on validation of high-throughput assays supporting 21st century toxicity testing. , 2013, ALTEX.

[84]  Liang Zhao,et al.  Mapping the human toxome by systems toxicology. , 2014, Basic & clinical pharmacology & toxicology.

[85]  Thomas B Knudsen,et al.  Systems Toxicology , 2015, International journal of toxicology.