Skip to main content
SpringerLink
Log in

The Urine Proteome as a Radiation Biodosimeter

  • Chapter
  • First Online:
Book cover Radiation Proteomics

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 990))

Abstract

The global rise in terrorism has increased the risk of radiological events aimed at creating chaos and destabilization, although they may cause relatively limited number of immediate casualties. We have proposed that a self-administered test would be valuable for initial triage following terrorist use of nuclear/radiological devices. The urine proteome may be a useful source of the biomarkers required for developing such a test. We have developed and extensively used a rat model to study the acute and late effect of total body (TBI) and partial body irradiation on critical organ systems. This model has proven valuable for correlating the structural and functional effects of radiation with molecular changes. Results show that nephron segments differ with regard to their sensitivity and response to ionizing radiation. The urine proteome was analyzed using LC-MS/MS at 24 h after TBI or local kidney irradiation using a 10 Gy single dose of X rays. LC-MS/MS data were analyzed and grouped under Gene Ontology categories Cellular Localization, Molecular Function and Biological Process. We observed a decrease in urine protein/creatinine ratio that corroborated with decreased spectral counts for urinary albumin and other major serum proteins. Interestingly, TBI caused greater decline in urinary albumin than local kidney irradiation. Analysis of acute-phase response proteins and markers of acute kidney injury showed increased urinary levels of cystatin superfamily proteins and alpha-1-acid glycoprotein. Among proteases and protease inhibitors, levels of Kallikrein 1-related peptidase b24, precursor and products of chymotrypsin-like activity, were noticeably increased. Among the amino acids that are susceptible to oxidation by free radicals, oxidized histidine levels were increased following irradiation. Our results suggest that proteomic analysis of early changes in urinary proteins will identify biomarkers for developing a self-administered test for radiation biodosimetry.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. National Research Council (2009) Assessing medical preparedness to respond to a terrorist nuclear event: workshop report. The National Academy Press, Washington, DC

    Google Scholar 

  2. Sarin R (2011) Chernobyl, Fukushima, and beyond: a health safety perspective. J Cancer Res Ther 7(2):109–111

    Article  PubMed  Google Scholar 

  3. National Council on Radiation Protection and Measurements (2001) Management of terrorist events involving radioactive material. NCRP report no. 138, Bethesda

    Google Scholar 

  4. Swartz HM, Flood AB, Gougelet RM, Rea ME, Nicolalde RJ, Williams BB (2010) A critical assessment of biodosimetry methods for large-scale incidents. Health Phys 98(2):95–108

    Article  PubMed  CAS  Google Scholar 

  5. Lenarczyk M, Cohen EP, Fish BL, Irving AA, Sharma M, Driscoll CD et al (2009) Chronic oxidative stress as a mechanism for radiation nephropathy. Radiat Res 171(2):164–172

    Article  PubMed  CAS  Google Scholar 

  6. Moulder JE, Cohen EP, Fish BL (2011) Captopril and losartan for mitigation of renal injury caused by single-dose total body irradiation. Radiat Res 175(1):29–36

    Article  PubMed  CAS  Google Scholar 

  7. Baker JE, Fish BL, Su J, Haworth ST, Strande JL, Komorowski RA et al (2009) 10 Gy total body irradiation increases risk of coronary sclerosis, degeneration of heart structure and function in a rat model. Int J Radiat Biol 85(12):1089–1100

    Article  PubMed  CAS  Google Scholar 

  8. Moulder JE, Fish BL, Holcenberg JS, Sun GX (1990) Hepatic function and drug pharmacokinetics after total body irradiation plus bone marrow transplant. Int J Radiat Oncol Biol Phys 19:1389–1396

    Article  PubMed  CAS  Google Scholar 

  9. Rosenthal RA, Fish B, Hill RP, Huffman KD, Lazarova Z, Mahmoud J et al (2011) Salen Mn complexes mitigate radiation injury in normal tissues. Anti-Cancer Agents Med Chem 11(4):359–371

    Article  CAS  Google Scholar 

  10. McCarthy ET, Sharma R, Sharma M (2005) Protective effect of 20-hydroxy-eicosatetraenoic acid (20-HETE) on glomerular protein permeability barrier. Kidney Int 67(1):152–156

    Article  PubMed  CAS  Google Scholar 

  11. Dahly-Vernon AJ, Sharma M, McCarthy ET, Savin VJ, Ledbetter SR, Roman RJ (2005) Transforming growth factor-β, 20-HETE interaction, and glomerular injury in Dahl Salt-Sensitive rats. Hypetension 45:1–6

    Article  Google Scholar 

  12. Sharma R, Sharma M, Reddy S, Savin VJ, Nagaria AM, Wiegmann TB (2006) Chronically increased intrarenal angiotensin II causes nephropathy in an animal model of type 2 diabetes. Front Biosci 1(11):968–976

    Article  Google Scholar 

  13. Sharma M, Sharma R, Reddy SR, McCarthy ET, Savin VJ (2002) Proteinuria after injection of human focal segmental glomerulosclerosis factor. Transplantation 73:366–372

    Article  PubMed  Google Scholar 

  14. Sharma M, Sharma R, McCarthy ET, Savin VJ (2004) The FSGS permeability factor: biochemical characteristics and biological effects. Exp Biol Med 229:85–98

    CAS  Google Scholar 

  15. Sharma M, Sharma R, Ge XL, Fish BL, McCarthy ET, Savin VJ, Cohen EP, Moulder JE (2001) Early detection of radiation-induced glomerular injury by albumin permeability assay. Radiat Res 155:474–480

    Article  PubMed  CAS  Google Scholar 

  16. Sharma M, Halligan BD, Wakim BT, Savin VJ, Cohen EP, Moulder JE (2008) The urine proteome as a biomarker of radiation injury. Proteomics Clin Appl 2(7):1065–1086

    Article  PubMed  CAS  Google Scholar 

  17. Yammani RR, Sharma M, Seetharam S, Moulder JE, Seetharam B (2002) Loss of albumin and megalin binding to renal cubilin results in albuminuria in rats exposed to total body irradiation. Am J Physiol Regul Integr Comp Physiol 283(2):R339–R346

    PubMed  CAS  Google Scholar 

  18. Rose BD (1987) Pathophysiology of renal disease. McGraw-Hill Professional, New York, pp 366–368

    Google Scholar 

  19. Prasanna PGS, Blakely WF, Bertho JM, Chute JP, Cohen EP, Goans RE et al (2010) Synopsis of partial-body radiation diagnostic biomarkers and medical management of radiation injury workshop. Radiat Res 173(2):245–253

    Article  PubMed  CAS  Google Scholar 

  20. Savin VJ, McCarthy ET, Sharma M (2012) Permeability factors in nephrotic syndrome and focal segmental glomerulosclerosis. Kidney Res Clin Pract 31:205–213

    Google Scholar 

  21. Rojas-Palma C, Liland A, Jerstad AN, Etherington G, del Rosario Pérez M, Rahola T et al (2009) TMT HANDBOOK—triage, monitoring and treatment—handbook for management of the public in the event of malevolent use of radiation. Norwegian Radiation Protection Agency, Østerås

    Google Scholar 

  22. Swartz HM, Williams BB, Nicolade RJ, Demidenko E, Flood AB (2011) Overview of biodosimetry for management of unplanned exposures to ionizing radiation. Radiat Meas 46:742–748

    Article  CAS  Google Scholar 

  23. Demidenko E, Williams BB, Swartz HM (2009) Radiation dose prediction using data on time to emesis in the case of nuclear terrorism. Radiat Res 171(3):310–319

    Article  PubMed  CAS  Google Scholar 

  24. IAEA (2001) Cytogenetic analysis for radiation dose assessment: a manual. Technical report 405, IAEA, Vienna

    Google Scholar 

  25. ISO (2004) Radiation protection—performance criteria for service laboratories performing biological dosimetry by cytogenetics. ISO 19238:2004, International Organization for Standardization, Geneva

    Google Scholar 

  26. Garty G, Karam A, Brenner DJ (2011) Infrastructure to support ultra high throughput biodosimetry screening after a radiological event. Int J Radiat Biol 87:754–765

    Article  PubMed  CAS  Google Scholar 

  27. IAEA (2002) Use of electron paramagnetic resonance dosimetry with tooth enamel for retrospective dose assessment. TECDOC-1331, IAEA. Vienna

    Google Scholar 

  28. Swartz HM, Burke G, Coey M, Demidenko E, Dong R, Grinberg O, Hilton J, Iwasaki A, Lesniewski P, Schauer DA (2007) In vivo EPR for dosimetry. Radiat Meas 42:1075–1084

    Article  PubMed  CAS  Google Scholar 

  29. Trompier F, Kornak L, Calas C, Romanyukha A, Leblanc B, Mitchell CA, Swartz HM, Clairand I (2007) Protocol for emergency EPR dosimetry in fingernails. Radiat Meas 42:1085–1088

    Article  PubMed  CAS  Google Scholar 

  30. Godfrey-Smith DI, Pass B (1997) A new method for retrospective radiation dosimetry: optically stimulated luminescence in dental enamel. Health Phys 72:744–749

    Article  PubMed  CAS  Google Scholar 

  31. Blakely WF, Prasanna PG, Grace MB, Miller AC (2001) Radiation exposure assessment using cytological and molecular biomarkers. Radiat Prot Dosimetry 97(1):17–23

    Article  PubMed  CAS  Google Scholar 

  32. Meadows SK, Dressman HK, Muramoto GG, Himburg H, Salter A, Wei Z, Ginsburg G, Chao NJ, Nevins JR, Chute JP (2008) Gene expression signatures of radiation response are specific, durable and accurate in mice and humans. PLoS One 3:e1912

    Article  PubMed  Google Scholar 

  33. Kabacik S, Mackay A, Tamber N, Manning G, Finnon P, Paillier F, Ashworth A, Bouffler S, Badie C (2011) Gene expression following ionising radiation: identification of biomarkers for dose estimation and prediction of individual response. Int J Radiat Biol 87(2):115–129

    Article  PubMed  CAS  Google Scholar 

  34. Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120:15–20

    Article  PubMed  CAS  Google Scholar 

  35. Marsit CJ, Eddy K, Kelsey KT (2006) MicroRNA responses to cellular stress. Cancer Res 66:10843–10848

    Article  PubMed  CAS  Google Scholar 

  36. Cha HJ, Seong KM, Bae S, Jung JH, Kim CS, Yang KH, Jin YW, An S (2009) Identification of specific microRNAs responding to low and high dose gamma-irradiation in the human lymphoblast line IM9. Oncol Rep 22(4):863–868

    PubMed  CAS  Google Scholar 

  37. Coy SL, Cheema AK, Tyburski JB, Laiakis EC, Collins SP, Fornace A Jr (2011) Radiation metabolomics and its potential in biodosimetry. Int J Radiat Biol 87(8):802–823

    Article  PubMed  CAS  Google Scholar 

  38. Chen C, Brenner DJ, Brown TR (2011) Identification of urinary biomarkers from X-irradiated mice using NMR spectroscopy. Radiat Res 175(5):622–630

    Article  PubMed  CAS  Google Scholar 

  39. Johnson CH, Patterson AD, Krausz KW, Lanz C, Kang DW, Luecke H, Gonzalez FJ, Idle JR (2011) Radiation metabolomics. 4. UPLC-ESI-QTOFMS-Based metabolomics for urinary biomarker discovery in gamma-irradiated rats. Radiat Res 175(4):473–484

    Article  PubMed  CAS  Google Scholar 

  40. Kortz L, Helmschrodt C, Ceglarek U (2011) Fast liquid chromatography combined with mass spectrometry for the analysis of metabolites and proteins in human body fluids. Anal Bioanal Chem 399:2635–2644

    Article  PubMed  CAS  Google Scholar 

  41. Zerefos PG, Aivaliotis M, Baumann M, Vlahou A (2012) Analysis of the urine proteome via a combination of multi‐dimensional approaches. Proteomics—European Consortium. doi:10.1002/pmic.201100212

  42. Thongboonkerd V (2007) Practical points in urinary proteomics. J Proteome Res 6(10):3881–3890

    Article  PubMed  CAS  Google Scholar 

  43. Apweiler R, Aslanidis C, Deufel T, Gerstner A et al (2009) Approaching clinical proteomics: current state and future fields of application in fluid proteomics. Clin Chem Lab Med 47(6):724–744

    Article  PubMed  CAS  Google Scholar 

  44. Court M, Selevsek N, Matondo M, Allory Y, Garin J, Masselon CD, Domon B (2011) Toward a standardized urine proteome analysis methodology. Proteomics 11(6):1160–1171

    Article  PubMed  CAS  Google Scholar 

  45. Mirza SP, Olivier M (2008) Methods and approaches for the comprehensive characterization and quantification of cellular proteomes using mass spectrometry. Physiol Genomics 33:3–11

    Article  PubMed  CAS  Google Scholar 

  46. Calligaris D, Villard C, Lafitte D (2011) Advances in top-down proteomics for disease biomarker discovery. J Proteomics 74(7):920–934

    Article  PubMed  CAS  Google Scholar 

  47. Halligan BD, Greene AS (2011) Visualize: a free and open source multifunction tool for proteomics data analysis. Proteomics 11(6):1058–1063

    Article  PubMed  CAS  Google Scholar 

  48. Wu B, Guan Z, Zhao H (2006) Parametric and nonparametric FDR estimation revisited. Biometrics 62:735–744

    Article  PubMed  Google Scholar 

  49. Ashburner M, Ball CA, Blake JA, Botstein D et al (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25:25–29

    Article  PubMed  CAS  Google Scholar 

  50. Harris MA, Clark J, Ireland A, Lomax J et al (2004) The Gene Ontology (GO) database and informatics resource. Nucleic Acids Res 32(Database issue):D258–D261

    Google Scholar 

  51. Pan S, Aebersold R, Chen R, Rush J, Goodlett DR, McIntosh MW, Zhang J, Brentnall TA (2009) Mass spectrometry based targeted protein quantification: methods and applications. J Proteome Res 8(2):787–797

    Article  PubMed  CAS  Google Scholar 

  52. Brewis IA, Brennan P (2010) Proteomics technologies for the global identification and quantification of proteins. Adv Protein Chem Struct Biol 80:1–44

    Article  PubMed  CAS  Google Scholar 

  53. Deutsch EW, Mendoza L, Shteynberg D, Farrah T, Lam H, Tasman N, Sun Z, Nilsson E, Pratt B, Prazen B, Eng JK, Martin DB, Nesvizhskii AI, Aebersold R (2010) A guided tour of the Trans-Proteomic Pipeline. Proteomics 10(6):1150–1159

    Article  PubMed  CAS  Google Scholar 

  54. Cohen EP, Fish BL, Sharma M, Li XA, Moulder JE (2007) The role of the angiotensin II type-2 receptor in radiation nephropathy. Transl Res 150:106–115

    Article  PubMed  CAS  Google Scholar 

  55. Sharma M, Halligan BD, Wakim BT, Savin VJ et al (2010) The urine proteome for radiation biodosimetry: effect of total body versus local kidney irradiation. Health Phys 98(2):186–195

    Article  PubMed  CAS  Google Scholar 

  56. Sharma M, McCarthy ET, Sharma R, Fish BL et al (2006) Arachidonic acid metabolites mediate the radiation-induced increase in glomerular albumin permeability. Exp Biol Med (Maywood) 231:99–106

    CAS  Google Scholar 

  57. Konvalinka A, Scholey JW, Diamandis EP (2011) Searching for new biomarkers of renal diseases through proteomics. Clin Chem. doi:10.1373/clinchem.2011.165969

  58. Coca SG, Singanamala S, Parikh CR (2011) Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int. doi:10.1038/ki.2011.379

  59. Bonventre JV (2007) Diagnosis of acute kidney injury: from classic parameters to new biomarkers. Contrib Nephrol 156:213–219

    Article  PubMed  Google Scholar 

  60. Honore PM, Joannes-Boyau O, Boer W (2007) The early biomarker of acute kidney injury: in search of the Holy Grail. Intensive Care Med 33:1866–1868

    Article  PubMed  CAS  Google Scholar 

  61. Devarajan P (2008) Proteomics for the investigation of acute kidney injury. Contrib Nephrol 160:1–16

    Article  PubMed  CAS  Google Scholar 

  62. Kalousova M, Zima T, Tesar V, Dusilova-Sulkova S, Skrha J (2005) Advanced glycoxidation end products in chronic diseases-clinical chemistry and genetic background. Mutat Res 579:37–46

    Article  PubMed  CAS  Google Scholar 

  63. Narita T, Sasaki H, Hosoba M, Miura T et al (2004) Parallel increase in urinary excretion rates of immunoglobulin G, ceruloplasmin, transferrin, and orosomucoid in normoalbuminuric type 2 diabetic patients. Diabetes Care 27:1176–1181

    Article  PubMed  CAS  Google Scholar 

  64. Horvath AJ, Forsyth SL, Coughlin PB (2004) Expression patterns of murine antichymotrypsin-like genes reflect evolutionary divergence at the Serpina3 locus. J Mol Evol 59:488–497

    Article  PubMed  CAS  Google Scholar 

  65. Suzuki Y, Yoshida K, Honda E, Sinohara H (1991) Molecular cloning and sequence analysis of cDNAs coding for guinea pig alpha 1-antiproteinases S and F and contrapsin. J Biol Chem 266:928–932

    PubMed  CAS  Google Scholar 

  66. Burkle A (2001) Poly(APD-ribosyl)ation, a DNA damage-driven protein modification and regulator of genomic instability. Cancer Lett 163:1–5

    Article  PubMed  CAS  Google Scholar 

  67. Lakin ND, Jackson SP (1999) Regulation of p53 in response to DNA damage. Oncogene 18:7644–7655

    Article  PubMed  CAS  Google Scholar 

  68. Kriengsinyos W, Rafii M, Wykes LJ, Ball RO, Pencharz PB (2002) Long-term effects of histidine depletion on whole-body protein metabolism in healthy adults. J Nutr 132:3340–3348

    PubMed  CAS  Google Scholar 

  69. Uchida K, Kawakishi S (1993) 2-Oxo-histidine as a novel biological marker for oxidatively modified proteins. FEBS Lett 332:208–210

    Article  PubMed  CAS  Google Scholar 

  70. Moulder JE (2002) Report on an interagency workshop on the radiobiology of nuclear terrorism. Radiat Res 158(1):118–124

    Article  PubMed  CAS  Google Scholar 

  71. Moulder JE, Medhora M (2011) Advances in mitigation of injuries from radiological terrorism or nuclear accidents. Defence Sci J 61(2):99–104

    Google Scholar 

  72. Pellmar TC, Rockwell S (2005) Priority list of research areas for radiological nuclear threat countermeasures. Radiat Res 163(1):115–123

    Article  PubMed  CAS  Google Scholar 

  73. Brown SL, Kolozsvary A, Liu J, Jenrow KA, Ryu S, Kim JH (2010) Antioxidant diet supplementation starting 24 hours after exposure reduces radiation lethality. Radiat Res 173(4):462–468

    Article  PubMed  CAS  Google Scholar 

  74. MacVittie TJ, Farese AM, Jackson W (2005) Defining the full therapeutic potential of recombinant growth factors in the post radiation-accident environment: the effect of supportive care plus administration of G-CSF. Health Phys 89(5):546–555

    Article  PubMed  CAS  Google Scholar 

  75. Epperly MW, Wang H, Jones JA, Dixon T, Montesinos CA, Greenberger JS (2011) Antioxidant-chemoprevention diet ameliorates late effects of total-body irradiation and supplements radioprotection by MnSOD-plasmid liposome administration. Radiat Res 175(6):759–765

    Article  PubMed  CAS  Google Scholar 

  76. Ghosh SN, Zhang R, Fish BL, Semenenko VA, Li XA, Moulder JE et al (2009) Renin-angiotensin system suppression mitigates experimental radiation pneumonitis. Int J Radiat Oncol Biol Phys 75(5):1528–1536

    Article  PubMed  CAS  Google Scholar 

  77. Jenrow KA, Brown SL, Liu J, Kolozsvary A, Kim JH (2010) Ramipril mitigates radiation-induced impairment of neurogenesis in the rat dentate gyrus. Radiat Oncol 5(1):Article 6

    Google Scholar 

  78. Cohen EP, Bedi M, Irving AA, Jacobs ER, Tomic R, Klein JP et al (2012) Mitigation of late renal and pulmonary injury after hematopoietic stem cell transplantation. Int J Radiat Oncol Biol Phys 83(1):292–296

    Google Scholar 

  79. Moulder JE, Robbins MEC, Cohen EP, Hopewell JW, Ward WF (1998) Pharmacologic modification of radiation-induced late normal tissue injury. Cancer Treat Res 93:129–151

    Article  PubMed  CAS  Google Scholar 

  80. Bertho JM, Roy L, Souidi M, Benderitter M, Gueguen Y, Lataillade JJ et al (2008) New biological indicators to evaluate and monitor radiation-induced damage: an accident case report. Radiat Res 169(5):543–550

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Veterans Administration Medical Center, F2-120, Nephrology, Research Service, 4801 E. Linwood Blvd., Kansas City, MO, 64128-2226, USA

    Mukut Sharma

  2. Department of Radiation Oncology, Medical College of Wisconsin, Radiation Biology, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA

    John E. Moulder

Authors
  1. Mukut Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John E. Moulder
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mukut Sharma .

Editor information

Editors and Affiliations

  1. Radiation and Nuclear Safety Authority, STUK, Laippatie 4, Helsinki, 00880, Finland

    Dariusz Leszczynski

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Sharma, M., Moulder, J.E. (2013). The Urine Proteome as a Radiation Biodosimeter. In: Leszczynski, D. (eds) Radiation Proteomics. Advances in Experimental Medicine and Biology, vol 990. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5896-4_5

Download citation

Publish with us

Policies and ethics

Search

Navigation