Dataset Information

The urine proteome for radiation biodosimetry: effect of total body vs. local kidney irradiation.

ABSTRACT: Victims of nuclear accidents or radiological terrorism are likely to receive varying doses of ionizing radiation inhomogeneously distributed over the body. Early biomarkers may be useful in determining organ-specific doses due to total body irradiation (TBI) or partial body irradiation. The authors used liquid chromatography and mass spectrometry to compare the effect of TBI and local kidney irradiation (LKI) on the rat urine proteome using a single 10-Gy dose of x-rays. Both TBI and LKI altered the urinary protein profile within 24 h with noticeable differences in gene ontology categories. Some proteins, including fetuin-B, tissue kallikrein, beta-glucuronidase, vitamin D-dependent calcium binding protein and chondroitin sulfate proteoglycan NG2, were detected only in the TBI group. Some other proteins, including major urinary protein-1, RNA binding protein 19, neuron navigator, Dapper homolog 3, WD repeat and FYVE domain containing protein 3, sorting nexin-8, ankycorbin and aquaporin were detected only in the LKI group. Protease inhibitors and kidney proteins were more abundant (fraction of total scans) in the LKI group. Urine protein (Up) and creatinine (Uc) (Up/Uc) ratios and urinary albumin abundance decreased in both TBI and LKI groups. Several markers of acute kidney injury were not detectable in either irradiated group. Present data indicate that abundance and number of proteins may follow opposite trends. These novel findings demonstrate intriguing differences between TBI and LKI, and suggest that urine proteome may be useful in determining organ-specific changes caused by partial body irradiation.

SUBMITTER: Sharma M

PROVIDER: S-EPMC2920640 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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The urine proteome for radiation biodosimetry: effect of total body vs. local kidney irradiation.

Sharma Mukut M Halligan Brian D BD Halligan Brian D BD Wakim Bassam T BT Savin Virginia J VJ Cohen Eric P EP Moulder John E JE

Health physics 20100201 2

Victims of nuclear accidents or radiological terrorism are likely to receive varying doses of ionizing radiation inhomogeneously distributed over the body. Early biomarkers may be useful in determining organ-specific doses due to total body irradiation (TBI) or partial body irradiation. The authors used liquid chromatography and mass spectrometry to compare the effect of TBI and local kidney irradiation (LKI) on the rat urine proteome using a single 10-Gy dose of x-rays. Both TBI and LKI altered ...[more]

PMID: 20065682

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Project description:The emergence of the threat of radiological terrorism and other radiological incidents has led to the need for development of fast, accurate and noninvasive methods for detection of radiation exposure. The purpose of this study was to extend radiation metabolomic biomarker discovery to humans, as previous studies have focused on mice. Urine was collected from patients undergoing total body irradiation at Memorial Sloan-Kettering Cancer Center prior to hematopoietic stem cell transplantation at 4-6 h postirradiation (a single dose of 1.25 Gy) and 24 h (three fractions of 1.25 Gy each). Global metabolomic profiling was obtained through analysis with ultra performance liquid chromatography coupled to time-of-flight mass spectrometry (TOFMS). Prior to further analyses, each sample was normalized to its respective creatinine level. Statistical analysis was conducted by the nonparametric Kolmogorov-Smirnov test and the Fisher's exact test and markers were validated against pure standards. Seven markers showed distinct differences between pre- and post-exposure samples. Of those, trimethyl-l-lysine and the carnitine conjugates acetylcarnitine, decanoylcarnitine and octanoylcarnitine play an important role in the transportation of fatty acids across mitochondria for subsequent fatty acid ?-oxidation. The remaining metabolites, hypoxanthine, xanthine and uric acid are the final products of the purine catabolism pathway, and high levels of excretion have been associated with increased oxidative stress and radiation induced DNA damage. Further analysis revealed sex differences in the patterns of excretion of the markers, demonstrating that generation of a sex-specific metabolomic signature will be informative and can provide a quick and reliable assessment of individuals in a radiological scenario. This is the first radiation metabolomics study in human urine laying the foundation for the use of metabolomics in biodosimetry and providing confidence in biomarker identification based on the overlap between animal models and humans.

Project description:In the event of a radiological or nuclear attack, advanced clinical countermeasures are needed for screening and medical management of the exposed population. In such a scenario, minimally invasive biomarkers that can accurately quantify radiation exposure would be useful for triage management by first responders. In this murine study, we evaluated the efficacy of a novel combination of radiation responsive proteins, Flt3 ligand (FL), serum amyloid A (SAA), matrix metalloproteinase 9 (MMP9), fibrinogen beta (FGB) and pentraxin 3 (PTX3) to predict the received dose after whole- or partial-body irradiation. Ten-week-old female C57BL6 mice received a single whole-body or partial-body dose of 18 Gy from a Pantak X-ray source at a dose rate of 2.28 Gy/min. Plasma was collected by cardiac puncture at 24, 48, 72 h and 1 week postirradiation. Plasma protein levels were determined via commercially available ELISA assay. A multivariate discriminant analysis was utilized to generate best-fit dose prediction models for whole-body exposures using the selected biomarker panel and its potential application to partial-body exposures was examined. The combination of values from FL, SAA, MMP9, FGB and PTX3 between 24 h and 1 week postirradiation yielded novel dose-response relationships. For day 1 postirradiation, the best-fit model yielded a predictive accuracy of 81% utilizing FL alone. The use of additional proteins did not enhance the model accuracy whereas, at day 2 postirradiation, the addition of PTX3 and FGB to FL increased the accuracy to 100%. At day 3 the use of FL and PTX3 yielded a predictive accuracy of 93% and at day 7 use of FL and SAA had an accuracy of 90%. Dose prediction of partial-body exposures based on the TBI model had a higher predictive accuracy when the percentage of the body exposed to radiation increased. Our findings indicate that this novel combination of radiation responsive biomarker proteins are an efficient method for predicting radiation exposure and are more accurate when used in concert compared to using any single biomarker protein alone.

Dataset Information

The urine proteome for radiation biodosimetry: effect of total body vs. local kidney irradiation.

Publications

The urine proteome for radiation biodosimetry: effect of total body vs. local kidney irradiation.

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