Volume 2, Issue 3

Original research papers

Radiobiology

RADIATION DOSE-RATE EFFECTS ON SELECT BIOMARKERS IN A MOUSE TOTAL-BODY IRRADIATION MODEL

Sara R. Hegge, Gregory L. Kin

Pages: 158-163

DOI: 10.21175/RadJ.2017.03.033

Received: 24 MAY 2017, Received revised: 15 OCT 2017, Accepted: 20 OCT 2017, Published online: 23 DEC 2017

In the event of acute radiation exposure, absorbed dose may be unknown and biodosimetry tools are needed by first responders to properly triage patients. We evaluated two protein markers – FMS-related tyrosine kinase 3 ligand (Flt3L) and granulocyte colony-stimulating factor (G-CSF) – that are known to be elevated after an acute radiation exposure, as well as total white blood cell (WBC) count changes pre- and post-irradiation at different dose-rates. Female B6D2F1 mice were divided into one sham-irradiated control group and four total-body irradiated groups. Experimental groups received a total dose of 8 Gy of 60Co gamma photon irradiation at four dose-rates: 0.04, 0.15, 0.30, & 0.47 Gy min-1. Blood samples from mice were collected at 24 and 48 hours post-exposure for WBC and protein biomarkers (Flt3L and G-CSF). Flt3L values at all dose-rates except 0.15 were significantly elevated from controls but not each other. The G-CSF levels in mouse groups of 0.47 Gy min-1 and 0.04 Gy min-1 were significantly different from controls, and 0.15 Gy min-1 significantly differed from 0.47 Gy min-1. WBC changes from baseline showed that all experimental groups were significantly lower than controls, and additionally the 0.04 Gy min-1 group was significantly lower than the 0.30 Gy min-1 group. Though more research is needed, it would appear that at the fixed dose, dose-rates, and time points chosen herein may not be particularly strong or show predictable differences in the selected biomarker expression levels.
  1. S. A. Amundson et al., “Biological indicators for the identification of ionizing radiation exposure in humans,” Expert Rev Mol Diagn, vol. 1, no. 2, pp. 211 - 219, Jul. 2001.
    DOI: 10.1586/14737159.1.2.211
    PMid: 11901816
  2. N. I. Ossetrova and W.F. Blakely, “Multiple blood-proteins approach for early-response exposure assessment using an in vivo murine radiation model,” Int. J. Radiat. Biol., vol. 85. no. 10, pp. 837 - 850,Oct. 2009.
    DOI: 10.1080/09553000903154799
    PMid: 19863200
  3. N. I. Ossetrova et al., “Early-response biomarkers for assessment of radiation exposure in a mouse total-body irradiation model,” Health Phys., vol. 106, no. 6, pp. 772 - 786, Jun. 2014.
    DOI: 10.1097/HP.0000000000000094
    PMid: 24776912
  4. N. I. Ossetrova et al., “Acute Radiation Syndrome Severity Score System in Mouse Total-Body Irradiation Model,” Health Phys., vol. 111, no. 2, pp. 134 - 144, Aug. 2016.
    DOI: 10.1097/HP.0000000000000499
    PMid: 27356057
  5. N. I. Ossetrova et al., “Combined approach of hematological biomarkers and plasma protein SAA for improvement of radiation dose assessment triage in biodosimetry applications,” Health Phys., vol. 98, no. 2, pp. 204 - 208, Feb. 2010.
    DOI: 10.1097/HP.0b013e3181abaabf
    PMid: 20065684
  6. P. G. Prasanna et al., “Synopsis of partial-body radiation diagnostic biomarkers and medical management of radiation injury workshop,” Radiat. Res., vol. 173, no. 2, pp. 245 - 253, Feb. 2010.
    DOI: 10.1667/RR1993.1
    PMid: 20095857
  7. T. Straume et al., “NASA Radiation Biomarker Workshop, September 27-28, 2007,” Radiat. Res., vol. 170, no. 3, pp. 393 - 405, Sep. 2008.
    DOI: 10.1667/RR1382.1
    PMid: 18763867
  8. C. Gabay and I. Kushner, “Acute-phase proteins and other systemic responses to inflammation,” N. Engl. J. Med., vol. 340, no. 6, pp. 448 - 454, Feb, 1999.
    DOI: 10.1056/NEJM199902113400607
    PMid: 9971870
  9. H. Youssoufian et al., “Targeting FMS-related tyrosine kinase receptor 3 with the human immunoglobulin G1 monoclonal antibody IMC-EB10,” Cancer, vol. 116, no. suppl. 4, pp. 1013 - 1017, Feb. 2010.
    DOI: 10.1002/cncr.24787
    PMid: 20127944
  10. J. M. Bertho, et al., “Level of Flt3-ligand in plasma: a possible new bio-indicator for radiation-induced aplasia,” Int. J. Radiat. Biol., vol. 77, no. 6, pp. 703 - 712, Jun. 2001.
    DOI: 10.1080/09553000110043711
    PMid: 11403710
  11. M. Prat et al., “Radiation-induced increase in plasma Flt3 ligand concentration in mice: evidence for the implication of several cell types,” Radiat. Res., vol. 163, no. 4, pp. 408 - 417, Apr. 2005.
    DOI: 10.1667/RR3340
    PMid: 15799697
  12. M. Prat et al., “Use of flt3 ligand to evaluate residual hematopoiesis after heterogeneous irradiation in mice,” Radiat. Res., vol. 166, no. 3, pp. 504 - 511, Sep. 2006.
    DOI: 10.1667/RR0568.1
    PMid: 16953669
  13. A. Huchet et al., “Plasma Flt-3 ligand concentration correlated with radiation-induced bone marrow damage during local fractionated radiotherapy,” Int. J. Radiat. Oncol. Biol. Phys, vol. 57, no. 2, pp. 508 - 515, Oct. 2003.
    DOI: 10.1016/S0360-3016(03)00584-4
  14. J. M. Bertho et al., “Initial evaluation and follow-up of acute radiation syndrome in two patients from the Dakar accident,” Biomarkers, vol. 14, no. 2, pp. 94 - 102, 2009.
    DOI: 10.1080/13547500902773904
    PMid: 19330587
  15. J. M. Bertho, et al., “New biological indicators to evaluate and monitor radiation-induced damage: an accident case report,” Radiat. Res., vol. 169, no. 5, pp. 543 - 550, May 2008.
    DOI: 10.1667/RR1259.1
    PMid: 18439044
  16. M. Drouet and F. Hérodin, “Radiation victim management and the haematologist in the future: time to revisit therapeutic guidelines?” Int. J. Radiat. Biol., vol. 86, no. 8, pp. 636 - 648, Jul. 2010.
    DOI: 10.3109/09553001003789604
    PMid: 20597842
  17. Q. Liu et al., “Clinical report of three cases of acute radiation sickness from a (60)Co radiation accident in Henan Province in China,” J. Radiat. Res., vol. 49, no. 1, pp. 63 - 69, Jan. 2008.
    DOI: 10.1269/jrr.07071
  18. L. Heslet, C. Bay and S. Nepper-Christensen, “Acute radiation syndrome (ARS) - treatment of the reduced host defense,” Int. J. Gen. Med., vol. 5, pp. 105 - 115, 2012.
    DOI: 10.2147/IJGM.S22177
    PMid: 22319248
    PMCid: PMC3273373
  19. N. I. Ossetrova et al., “Non-human Primate Total-body Irradiation Model with Limited and Full Medical Supportive Care Including Filgrastim for Biodosimetry and Injury Assessment,” Radiat. Prot. Dosimetry, vol. 172, no. 1-3, pp. 174 - 191, Dec. 2016.
    DOI: 10.1093/rpd/ncw176
    PMid: 27473690
  20. S. Desai et al., “Cytokine profile of conditioned medium from human tumor cell lines after acute and fractionated doses of gamma radiation and its effect on survival of bystander tumor cells,” Cytokine, vol. 61, no. 1, pp. 54 - 62, Jan. 2013.
    DOI: 10.1016/j.cyto.2012.08.022
    PMid: 23022376
  21. C. J. Maks et al., “Analysis of white blood cell counts in mice after gamma- or proton-radiation exposure,” Radiat. Res., vol. 176, no. 2, pp. 170 - 176, Aug. 2011.
    DOI: 10.1667/RR2413.1
    PMid: 21476859
    PMCid: PMC3575683
  22. M. J. Pecaut, G. A. Nelson and D. S. Gridley, “Dose and dose rate effects of whole-body gamma-irradiation: I. Lymphocytes and lymphoid organs,” In Vivo, vol. 15, no. 3, pp. 195 - 208, May-Jun. 2001.
    PMid: 11491014
  23. D. S. Gridley et al., “Dose and dose rate effects of whole-body gamma-irradiation: II. Hematological variables and cytokines,” In Vivo, vol. 15, no. 3, pp. 209 - 216, May-Jun. 2001.
    PMid: 11491015
  24. D. S. Gridley et al., “Low dose, low dose rate photon radiation modifies leukocyte distribution and gene expression in CD4(+) T cells,” J. Radiat. Res., vol. 50, no. 2, pp. 139 - 150, Mar. 2009.
    DOI: 10.1269/jrr.08095
  25. J. G. Kiang et al., “Wound trauma increases radiation-induced mortality by activation of iNOS pathway and elevation of cytokine concentrations and bacterial infection,” Radiat. Res., vol. 173, no. 3, pp. 319 - 332, Mar. 2010.
    DOI: 10.1667/RR1892.1
    PMid: 20199217
  26. A. B. Dey et al., “Radiation accident at Mayapuri scrap market, Delhi, 2010,” Radiat. Prot. Dosimetry, vol. 151, no. 4, pp. 645 - 651, Oct. 2012.
    DOI: 10.1093/rpd/ncs162
    PMid: 22914329