A brief overview to systems biology in toxicology: The journey from in to vivo, in-vitro and –omics

Abstract Toxicology aims to comprehend and envisage the adverse outcomes of chemicals and xenobiotics on the biological system. Predicting toxicity on the biological system is a complex and immense process. In-vivo, in-vitro, pre-, clinical and –omics level experimental approaches have been utilized to describe the toxicological impact of these chemicals and this has generated a vast wealth of data. Hence, there now exist a need for a system that can interrelate and provide accurate and robust extrapolation of these data across various systems. Therefore, it is essential to re-shift our notion from empirical, animal-based testing to a mechanistic understanding. Systems biology is one such system that can extrapolate and interrelate these vast biological system data. Systems biology is a computational and mathematical modelling approach developed to understand interrelationships between networks of biological systems. The use of systems biology to answer toxicology-related questions is termed as systems toxicology. In this review we will look at the standard and classical toxicology experimentations and how we can use mechanistic data (systems biology) to answer toxicology-related questions using systems toxicology and what are the future opportunities in systems toxicology. The advancement of systems toxicology heralds new dawn of technologies that will aid in our quest to better comprehend and envisage the adverse outcomes of chemicals and xenobiotics on the biological system.

[1]  S. Rappaport Implications of the exposome for exposure science , 2011, Journal of Exposure Science and Environmental Epidemiology.

[2]  Yvonne Will,et al.  Toxicology Strategies for Drug Discovery: Present and Future. , 2016, Chemical research in toxicology.

[3]  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.

[4]  F. Crick,et al.  Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid , 1953, Nature.

[5]  Shu-juan Guo,et al.  Protein microarrays for systems biology , 2011, Acta biochimica et biophysica Sinica.

[6]  Weihua Li,et al.  Insights into mechanisms and severity of drug-induced liver injury via computational systems toxicology approach. , 2019, Toxicology letters.

[7]  Manuel C. Peitsch,et al.  Systems Toxicology Approach to Unravel Early Indicators of Squamous Cell Carcinoma Rate in Rat Nasal Epithelium Induced by Formaldehyde Exposure , 2019, PACBB.

[8]  W. Blackstock,et al.  Proteomics: quantitative and physical mapping of cellular proteins. , 1999, Trends in biotechnology.

[9]  Eytan Ruppin,et al.  Predicting selective drug targets in cancer through metabolic networks , 2011, Molecular Systems Biology.

[10]  Karen M Polizzi What is synthetic biology? , 2013, Methods in molecular biology.

[11]  K. Mooney,et al.  Systems Biology and Synthetic Biology: A New Epoch for Toxicology Research , 2015 .

[12]  Mathieu Vinken,et al.  The adverse outcome pathway concept: a pragmatic tool in toxicology. , 2013, Toxicology.

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

[14]  Ian D. Wilson,et al.  Metabolic Phenotyping in Health and Disease , 2008, Cell.

[15]  N. Anderson,et al.  Proteome and proteomics: New technologies, new concepts, and new words , 1998, Electrophoresis.

[16]  C. Wild,et al.  The exposome: from concept to utility. , 2012, International journal of epidemiology.

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

[18]  Kevin R Hayes,et al.  Advances in toxicogenomics. , 2005, Chemical research in toxicology.

[19]  M. Peitsch,et al.  Evaluation of the Tobacco Heating System 2.2. Part 1: Description of the system and the scientific assessment program. , 2016, Regulatory toxicology and pharmacology : RTP.

[20]  Dean P. Jones,et al.  The nature of nurture: refining the definition of the exposome. , 2014, Toxicological sciences : an official journal of the Society of Toxicology.

[21]  Olivier Taboureau,et al.  The use of systems biology in chemical risk assessment , 2019, Current Opinion in Toxicology.

[22]  A. Nasi,et al.  Proteomic approaches to study structure, functions and toxicity of legume seeds lectins. Perspectives for the assessment of food quality and safety. , 2009, Journal of proteomics.

[23]  Elaine Holmes,et al.  The Consortium for Metabonomic Toxicology (COMET): aims, activities and achievements. , 2005, Pharmacogenomics.

[24]  K. Haynes Synthetic biology: Building genetic containment. , 2016, Nature chemical biology.

[25]  Merle G Paule,et al.  Systems biology approaches for toxicology , 2007, Journal of applied toxicology : JAT.

[26]  Manuel C. Peitsch,et al.  Systems Toxicology: From Basic Research to Risk Assessment , 2014, Chemical research in toxicology.

[27]  J. Lindon,et al.  Metabonomics: a platform for studying drug toxicity and gene function , 2002, Nature Reviews Drug Discovery.

[28]  Yogeshwer Shukla,et al.  Toxicoproteomics: New paradigms in toxicology research , 2010, Toxicology mechanisms and methods.

[29]  How-Ran Guo,et al.  Arsenic trioxide induces programmed cell death through stimulation of ER stress and inhibition of the ubiquitin-proteasome system in human sarcoma cells. , 2015, Cancer letters.

[30]  E. Gillam,et al.  Prospects for Applying Synthetic Biology to Toxicology: Future Opportunities and Current Limitations for the Repurposing of Cytochrome P450 Systems. , 2017, Chemical research in toxicology.

[31]  P. James,et al.  Protein identification in the post-genome era: the rapid rise of proteomics , 1997, Quarterly Reviews of Biophysics.

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

[33]  Ozgur E. Akman,et al.  Nested sampling for parameter inference in systems biology: application to an exemplar circadian model , 2012, BMC Systems Biology.

[34]  Heather M. Wallace,et al.  Advancing human health risk assessment , 2019, EFSA journal. European Food Safety Authority.

[35]  Francois Pognan,et al.  Genomics, proteomics and metabonomics in toxicology: hopefully not 'fashionomics'. , 2004, Pharmacogenomics.

[36]  Nick Plant,et al.  An introduction to systems toxicology , 2015 .

[37]  F. Collins,et al.  Welcome to the genomic era. , 2003, The New England journal of medicine.

[38]  Y. Dragan,et al.  Quantitative Systems Toxicology Analysis of In Vitro Mechanistic Assays Reveals Importance of Bile Acid Accumulation and Mitochondrial Dysfunction in TAK-875-Induced Liver Injury , 2018, Toxicological sciences : an official journal of the Society of Toxicology.

[39]  Gary R. Mirams,et al.  Systems Toxicology: Real World Applications and Opportunities , 2017, Chemical research in toxicology.

[40]  Markus Schmidt,et al.  Synthetic toxicology: where engineering meets biology and toxicology. , 2011, Toxicological sciences : an official journal of the Society of Toxicology.

[41]  Rolf Altenburger,et al.  High‐throughput concentration–response analysis for omics datasets , 2015, Environmental toxicology and chemistry.

[42]  Paul T Anastas,et al.  Toward a comprehensive molecular design framework for reduced hazard. , 2010, Chemical reviews.

[43]  P. Bushel,et al.  The evolution of bioinformatics in toxicology: advancing toxicogenomics. , 2011, Toxicological sciences : an official journal of the Society of Toxicology.

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

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

[46]  M. Peitsch,et al.  A six-month systems toxicology inhalation/cessation study in ApoE-/- mice to investigate cardiovascular and respiratory exposure effects of modified risk tobacco products, CHTP 1.2 and THS 2.2, compared with conventional cigarettes. , 2019, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[47]  A. Hopkins Network pharmacology: the next paradigm in drug discovery. , 2008, Nature chemical biology.

[48]  Sharon Munn,et al.  Adverse outcome pathway (AOP) development I: strategies and principles. , 2014, Toxicological sciences : an official journal of the Society of Toxicology.

[49]  Daniel L Villeneuve,et al.  Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment , 2010, Environmental toxicology and chemistry.

[50]  A. Vinggaard,et al.  Applicability of computational systems biology in toxicology. , 2014, Basic & clinical pharmacology & toxicology.

[51]  D. Hochstrasser,et al.  From Proteins to Proteomes: Large Scale Protein Identification by Two-Dimensional Electrophoresis and Arnino Acid Analysis , 1996, Bio/Technology.

[52]  John M. Burke,et al.  Quantitative systems toxicology , 2017, Current opinion in toxicology.

[53]  J. Osorio Synthetic biology: Genetic kill switches — a matter of life or death , 2015, Nature reviews genetics.

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

[55]  Anders Wallqvist,et al.  Systems toxicology of chemically induced liver and kidney injuries: histopathology‐associated gene co‐expression modules , 2016, Journal of applied toxicology : JAT.

[56]  Claire D. McWhite,et al.  Sensitive detection of proteasomal activation using the Deg-On mammalian synthetic gene circuit , 2014, Nature Communications.

[57]  Gopal Pawar,et al.  In Silico Toxicology Data Resources to Support Read-Across and (Q)SAR , 2019, Front. Pharmacol..

[58]  Sharon Munn,et al.  Adverse outcome pathway development II: best practices. , 2014, Toxicological sciences : an official journal of the Society of Toxicology.

[59]  M. Fielden,et al.  The role of early in vivo toxicity testing in drug discovery toxicology , 2008 .

[60]  Narsis A Kiani,et al.  Systems Toxicology: Systematic Approach to Predict Toxicity. , 2016, Current pharmaceutical design.

[61]  S. Webb,et al.  A systems toxicology paracetamol overdose framework: accounting for high-risk individuals , 2019, Computational Toxicology.

[62]  Jerome T. Mettetal,et al.  A Systems Toxicology Approach for the Prediction of Kidney Toxicity and Its Mechanisms In Vitro. , 2019, Toxicological sciences : an official journal of the Society of Toxicology.