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From Drug Identification to Systems Toxicology

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P5 Medicine and Justice

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Abstract

Biomedical sciences are at the edge of an extraordinary transformation in the conduct of toxicological evaluations using modern biomolecular analysis techniques to elucidate mechanisms of toxicity. To this transformation have contributed the increasing power and availability of molecular measurement tools, the possibility of probing biological networks inside organisms, organs, tissues, and cells, the affordability of high-throughput characterization tools, and the availability of potent bioinformatic tools. The classical toxicant-by-toxicant approach, that has been applied to solve clinical and forensic toxicology challenges for decades, has now turned to a multidisciplinary approach. The application of the newest biomolecular measurements to the field of toxicology led to the emergence of new sub-disciplines, such as toxicogenetics, toxicoproteomics, and systems toxicology. The leading approaches are briefly reviewed, with a special focus on technological advances, the omics era, systems toxicology and the toxome.

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References

  1. Waters MD, Fostel JM (2004) Toxicogenomics and systems toxicology: aims and prospects. Nat Rev Genet 5:936–948

    Article  CAS  PubMed  Google Scholar 

  2. Amala S (2010) Toxicogenomics. J Bioinform Seq Anal 2(4):42–46

    Google Scholar 

  3. Chen M, Zhang M, Borlak J, Tong W (2012) A decade of toxicogenomic research and its contribution to toxicological science. Toxicol Sci 130(2):217–228

    Article  CAS  PubMed  Google Scholar 

  4. Norris JL, Caprioli RM (2013) Imaging mass spectrometry: a new tool for pathology in a molecular age. Proteomics Clin Appl 7:733–738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Deutskens F, Yang J, Caprioli RM (2011) High spatial resolution imaging mass spectrometry and classical histology on a single tissue section. J Mass Spectrom 46(6):568–571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Rashed MS, Bucknall MP, Little D, Awad A, Jacob M, Alamoudi M, Alwattar M, Ozand PT (1997) Screening blood spots for inborn errors of metabolism by electrospray tandem mass spectrometry with a microplate batch process and a computer algorithm for automated flagging of abnormal profiles. Clin Chem 43(7):1129–1141

    CAS  PubMed  Google Scholar 

  7. Sauer S, Kliem M (2010) Mass spectrometry tools for the classification and identification of bacteria. Nat Rev Microbiol 8(1):74–82. doi:10.1038/nrmicro2243

    Article  CAS  PubMed  Google Scholar 

  8. Meng QH (2013) Mass spectrometry applications in clinical diagnostics. J Clin Exp Pathol, S6

    Google Scholar 

  9. Andresen H, Augustin C, Streichert T (2013) Toxicogenetics–cytochrome P450 microarray analysis in forensic cases focusing on morphine/codeine and diazepam. Int J Legal Med 127(2):395–404

    Article  CAS  PubMed  Google Scholar 

  10. Wang Y, Jurgen B, Weida T (2013) Toxicogenomics–a drug development perspective. In: Yao Y, Jallal B, Ranade K (eds) Genomic biomarkers for pharmaceutical development. Elsevier Inc, Amsterdam, pp 127–155

    Google Scholar 

  11. Kerksick Chad M et al (2015) How can bioinformatics and toxicogenomics assist the next generation of research on physical exercise and athletic performance. J Strength Conditioning Res 29:270–278

    Article  Google Scholar 

  12. Stamer UM, Stüber F, Muders T, Musshoff F (2008) Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. Anesth Analg 107:926–929

    Article  PubMed  Google Scholar 

  13. Levo A, Koski A, Ojanperä I, Vuori E, Sajantila A (2003) Post-mortem SNP analysis of CYP2D6 gene reveals correlation between genotype and opioid drug (tramadol) metabolite ratios in blood. Forensic Sci Int 135:9–15

    Article  CAS  PubMed  Google Scholar 

  14. Madadi P, Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder JS, Teitelbaum R, Karaskov T, Aleksa K (2007) Safety of codeine during breastfeeding: fatal morphine poisoning in the breastfed neonate of a mother prescribed codeine. Can Fam Physician 53:33–35

    PubMed  PubMed Central  Google Scholar 

  15. Musshoff F, Stamer UM, Madea B (2010) Pharmacogenetics and forensic toxicology. Forensic Sci Int 203(1–3):53–62

    Article  CAS  PubMed  Google Scholar 

  16. Morris MK, Chi A, Melas IN, Alexopoulos LG (2014) Phosphoproteomics in drug discovery. Drug Discov Today 19:425–432

    Article  CAS  PubMed  Google Scholar 

  17. Bausch-Fluck D, Hofmann A, Wollscheid B (2012) Cell surface capturing technologies for the surfaceome discovery of hepatocytes. Methods Mol Biol 909:1–16

    CAS  PubMed  Google Scholar 

  18. Deininger L, Patel E, Clench MR, Sears V, Sammon C, Francese S (2016) Proteomics goes forensic: detection and mapping of blood signatures in fingermarks. Proteomics 16(11–12):1707–1717

    Article  CAS  PubMed  Google Scholar 

  19. Merrick BA, Witzmann FA (2009) The role of toxicoproteomics in assessing organ specific toxicity. EXS 99:367–400

    CAS  PubMed  PubMed Central  Google Scholar 

  20. George J, Singh R, Mahmood Z, Shukla Y (2010) Toxicoproteomics: new paradigms in toxicology research. Toxicol Mech Methods 20(7):415–423

    Article  CAS  PubMed  Google Scholar 

  21. Nagana Gowda GA, Raftery D (2013) biomarker discovery and translation in metabolomics. Curr Metabolomics 1(3):227–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fiehn O (2001) Combining genomics, metabolome analysis, and biochemical modeling to understand metabolic networks. Comp Funct Genomics 2:155–168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Athersuch TJ (2012) The role of metabolomics in characterizing the human exposome. Bioanalysis 4(18):2207–2212

    Article  CAS  PubMed  Google Scholar 

  24. Rappaport SM (2012) Biomarkers intersect with the exposome. Biomarkers 17(6):483–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Robertson DG (2005) Metabonomics in toxicology: a review. Toxicol Sci 85(2):809–822

    Article  CAS  PubMed  Google Scholar 

  26. Bouhifd M, Hartung T, Hogberg HT, Kleensang A, Zhao L (2013) Review: toxicometabolomics. J Appl Toxicol 33(12):1365–1383

    Article  CAS  PubMed  Google Scholar 

  27. Ramirez T, Daneshian M, Kamp H et al (2013) Metabolomics in toxicology and preclinical research. Altex 30(2):209–225

    Article  PubMed  PubMed Central  Google Scholar 

  28. Rappaport SM, Li H, Grigoryan H, Funk WE, Williams ER (2012) Adductomics: characterizing exposures to reactive electrophiles. Toxicol Lett 213(1):83–90

    Article  CAS  PubMed  Google Scholar 

  29. Pan Z, Raftery D (2007) Comparing and combining NMR spectroscopy and mass spectrometry in metabolomics. Anal Bioanal Chem 387:525–527

    Article  CAS  PubMed  Google Scholar 

  30. Dunn WB, Broadhurst DI, Atherton HJ, Goodacre R, Griffin JL (2011) Systems level studies of mammalian metabolomes: the roles of mass spectrometry and nuclear magnetic resonance spectroscopy. Chem Soc Rev 40(1):387–426

    Article  CAS  PubMed  Google Scholar 

  31. Robertson DG, Watkins PB, Reily MD (2011) Metabolomics in toxicology: preclinical and clinical applications. Toxicol Sci 120(Suppl 1):S146–S470

    Article  CAS  PubMed  Google Scholar 

  32. Castillo-Peinado LS, Luque de Castro MD (2016) Present and foreseeable future of metabolomics in forensic analysis. Anal Chim Acta 925:1–15

    Article  CAS  PubMed  Google Scholar 

  33. Shipkova D, Reily M (2010) PLC–MS in endogenous metabolite profiling and small-molecule biomarker discovery. In: Lee MS, Zhu M (eds) Mass spectrometry in drug metabolism and disposition: basic principles and applications. Wiley, Blackwell, Oxford, pp 685–722

    Google Scholar 

  34. Michalopoulos GK, DeFrances MC (1997) Liver regeneration. Science 276:60–66

    Article  CAS  PubMed  Google Scholar 

  35. Drasdo D, Hoehme S, Hengstler JG (2014) How predictive quantitative modelling of tissue organisation can inform liver disease pathogenesis. J Hepatol 61:951–956

    Article  PubMed  Google Scholar 

  36. Drasdo D, Bode J, Dahmen U, Dirsch O, Dooley S, Gebhardt R, Ghallab A, Godoy P, Häussinger D, Hammad S, Hoehme S, Holzhütter HG, Klingmüller U, Kuepfer L, Timmer J, Zerial M, Hengstler JG (2014) The virtual liver: state of the art and future perspectives. Arch Toxicol 88:2071–2075

    Article  CAS  PubMed  Google Scholar 

  37. Hoehme S, Brulport M, Bauer A et al (2010) Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration. Proc Natl Acad Sci U S A 107:10371–10376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ding BS, Cao Z, Lis R, Nolan DJ, Guo P, Simons M, Penfold ME, Shido K, Rabbany SY, Rafii S (2014) Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 505:97–102

    Article  PubMed  Google Scholar 

  39. Ding BS, Nolan DJ, Butler JM, James D, Babazadeh AO, Rosenwaks Z, Mittal V, Kobayashi H, Shido K, Lyden D, Sato TN, Rabbany SY, Rafii S (2010) Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature 468:310–315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Madea B, Saukko P, Oliva A, Musshoff F (2010) Molecular pathology in forensic medicine–Introduction. Forensic Sci Int 203(1–3):3–14

    Article  CAS  PubMed  Google Scholar 

  41. Bouhifd M, Andersen ME, Baghdikian C, Boekelheide K, Crofton KM, Fornace AJ Jr, Kleensang A, Li H, Livi C, Maertens A, McMullen PD, Rosenberg M, Thomas R, Vantangoli M, Yager JD, Zhao L, Hartung T (2015) The human toxome project. Altex 32:112–124

    Article  PubMed  PubMed Central  Google Scholar 

  42. Nebert DW, Ingelman-Sundberg M (2016) What do animal experiments tell us that in vitro systems cannot? The Human Toxome Project. Regul Toxicol Pharmacol 75:1–4

    Article  PubMed  Google Scholar 

  43. Juberg DR, Borghoff SJ, Becker RA et al (2014) t4 workshop report–lessons learned, challenges, and opportunities: the U.S. Endocrine Disruptor Screening Program. ALTEX 31:63–78

    Article  PubMed  Google Scholar 

  44. Soto AM, Sonnenschein C, Chung KL, Fernandez MF, Olea N, Serrano FO (1995) The E-SCREEN assay as a tool to identify estrogens: an update on estrogenic environmental pollutants. Environ Health Perspect 103(Suppl 7):113–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Acevedo N, Davis B, Schaeberle CM, Sonnenschein C, Soto AM (2013) Perinatally administered bisphenol a as a potential mammary gland carcinogen in rats. Environ Health Perspect 121:1040–1046

    PubMed  PubMed Central  Google Scholar 

  46. Miller S, Kennedy D, Thomson J, Han F, Smith R, Ing N, Piedrahita J, Busbee D (2000) A rapid and sensitive reporter gene that uses green fluorescent protein expression to detect chemicals with estrogenic activity. Toxicol Sci 55:69–77

    Article  CAS  PubMed  Google Scholar 

  47. Bovee TF, Helsdingen RJ, Koks PD, Kuiper HA, Hoogenboom RL, Keijer J (2004) Development of a rapid yeast estrogen bioassay, based on the expression of green fluorescent protein. Gene 325:187–200

    Article  CAS  PubMed  Google Scholar 

  48. Huan J, Wang L, Xing L, Qin X, Feng L, Pan X, Zhu L (2014) Insights into significant pathways and gene interaction networks underlying breast cancer cell line MCF-7 treated with 17β-estradiol (E2). Gene 533:346–355

    Article  CAS  PubMed  Google Scholar 

  49. Kolle SN, Ramirez T, Kamp HG, Buesen R, Flick B, Strauss V, van Ravenzwaay B (2012) A testing strategy for the identification of mammalian, systemic endocrine disruptors with particular focus on steroids. Regul Toxicol Pharmacol 63:259–278

    Article  CAS  PubMed  Google Scholar 

  50. Notas G, Kampa M, Pelekanou V, Castanas E (2012) Interplay of estrogen receptors and GPR30 for the regulation of early membrane initiated transcriptional effects: a pharmacological approach. Steroids 77:943–950

    Article  CAS  PubMed  Google Scholar 

  51. Hartung T, McBride M (2011) Food for Thought … on mapping the human toxome. Altex 28(2):83–93

    Article  PubMed  Google Scholar 

  52. Bouhifd M, Hogberg HT, Kleensang A, Maertens A, Zhao L, Hartung T (2014) Mapping the human toxome by systems toxicology. Basic Clin Pharmacol Toxicol 115(1):24–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Richard AM (2006) Future of toxicology–predictive toxicology: An expanded view of “chemical toxicity”. Chem Res Toxicol 19(10):1257–1262

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Legal and Occupational Medicine, Toxicology and Public Health, University-Hospital of Padua, Via Falloppio 50, 35121, Padua, Italy

    Donata Favretto

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  1. Donata Favretto
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Correspondence to Donata Favretto .

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  1. Department of Legal and Occupational Medicine, Toxicology and Public Health, University-Hospital of Padova, Padova, Italy

    Santo Davide Ferrara

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Favretto, D. (2017). From Drug Identification to Systems Toxicology. In: Ferrara, S. (eds) P5 Medicine and Justice. Springer, Cham. https://doi.org/10.1007/978-3-319-67092-8_30

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