Novel biodosimetry assays for use in preparedness and response to potential malicious attacks or nuclear accidents would ideally provide accurate dose reconstruction independent of the idiosyncrasies of a complex exposure to ionizing radiation. Complex exposures will consist of dose rates spanning the low dose rates (LDR) to very high-dose rates (VHDR) that need to be tested for assay validation. Here, we investigate how a range of relevant dose rates affect metabolomic dose reconstruction at potentially lethal radiation exposures (8 Gy in mice) from an initial blast or subsequent fallout exposures compared to zero or sublethal exposures (0 or 3 Gy in mice) in the first 2 days, which corresponds to an integral time individuals will reach medical facilities after a radiological emergency. Biofluids (urine and serum) were collected from both male and female 9–10-week-old C57BL/6 mice at 1 and 2 days postirradiation (total doses of 0, 3 or 8 Gy) after a VHDR of 7 Gy/s. Additionally, samples were collected after a 2-day exposure consisting of a declining dose rate (1 to 0.004 Gy/min) recapitulating the 7:10 rule-of-thumb time dependency of nuclear fallout. Overall similar perturbations were observed in both urine and serum metabolite concentrations irrespective of sex or dose rate, with the exception of xanthurenic acid in urine (female specific) and taurine in serum (VHDR specific). In urine, we developed identical multiplex metabolite panels (N6, N6,N6-trimethyllysine, carnitine, propionylcarnitine, hexosamine-valine-isoleucine, and taurine) that could identify individuals receiving potentially lethal levels of radiation from the zero or sublethal cohorts with excellent sensitivity and specificity, with creatine increasing model performance at day 1. In serum, individuals receiving a 3 or 8 Gy exposure could be identified from their pre-irradiation samples with excellent sensitivity and specificity, however, due to a lower dose response the 3 vs. 8 Gy groups could not be distinguished from each other. Together with previous results, these data indicate that dose-rate-independent small molecule fingerprints have potential in novel biodosimetry assays.
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July 2023
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May 22 2023
Variable Dose Rates in Realistic Radiation Exposures: Effects on Small Molecule Markers of Ionizing Radiation in the Murine Model
Evan L. Pannkuk;
Evan L. Pannkuk
1
a Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC
b Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC
c Center for Metabolomic Studies, Georgetown University, Washington, DC
1 Address for correspondence: Georgetown University, 3970 Reservoir Road, NW, New Research Building, Room EP11, Washington, DC 20057; email: [email protected].
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Evagelia C. Laiakis;
Evagelia C. Laiakis
a Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC
b Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC
c Center for Metabolomic Studies, Georgetown University, Washington, DC
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Guy Garty;
Guy Garty
d Radiological Research Accelerator Facility, Columbia University, Irvington, New York
e Center for Radiological Research, Columbia University Irving Medical Center, New York, New York
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Brian Ponnaiya;
Brian Ponnaiya
e Center for Radiological Research, Columbia University Irving Medical Center, New York, New York
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Xuefeng Wu;
Xuefeng Wu
e Center for Radiological Research, Columbia University Irving Medical Center, New York, New York
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Igor Shuryak;
Igor Shuryak
e Center for Radiological Research, Columbia University Irving Medical Center, New York, New York
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Shanaz A. Ghandhi;
Shanaz A. Ghandhi
e Center for Radiological Research, Columbia University Irving Medical Center, New York, New York
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Sally A. Amundson;
Sally A. Amundson
e Center for Radiological Research, Columbia University Irving Medical Center, New York, New York
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David J. Brenner;
David J. Brenner
e Center for Radiological Research, Columbia University Irving Medical Center, New York, New York
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Albert J. Fornace, Jr
Albert J. Fornace, Jr
a Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC
b Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC
c Center for Metabolomic Studies, Georgetown University, Washington, DC
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Radiat Res (2023) 200 (1): 1–12.
Article history
Received:
December 01 2022
Accepted:
April 27 2023
Citation
Evan L. Pannkuk, Evagelia C. Laiakis, Guy Garty, Brian Ponnaiya, Xuefeng Wu, Igor Shuryak, Shanaz A. Ghandhi, Sally A. Amundson, David J. Brenner, Albert J. Fornace; Variable Dose Rates in Realistic Radiation Exposures: Effects on Small Molecule Markers of Ionizing Radiation in the Murine Model. Radiat Res 1 July 2023; 200 (1): 1–12. doi: https://doi.org/10.1667/RADE-22-00211.1
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