Identification of Urinary Biomarkers from X-Irradiated Mice Using NMR Spectroscopy

Chen, Congju; Brenner, David J.; Brown, Truman R.

doi:10.1667/rr2388.1

Cited by 36 publications

(33 citation statements)

References 36 publications

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“…Recently, NMR has been used to identify small molecule metabolites as biomarkers in mouse urine after exposure to 8 Gy wholebody X rays. Changes in these biomarkers were detected on the first day after irradiation, and typically reached their maximum on the third and fourth days after irradiation (24). In this study, the biomarker was temporally dependent, suggesting this biomarker is useful only at certain times following irradiation.…”

Section: Discussionmentioning

confidence: 57%

Intestinal Microbiota as Novel Biomarkers of Prior Radiation Exposure

et al. 2012

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Intestinal Microbiota as Novel Biomarkers of Prior Radiation Exposure. Radiat. Res. 177, 573-583 (2012).There is an urgent need for rapid, accurate, and sensitive diagnostic platforms to confirm exposure to radiation and estimate the dose absorbed by individuals subjected to acts of radiological terrorism, nuclear power plant accidents, or nuclear warfare. Clinical symptoms and physical dosimeters, even when available, do not provide adequate diagnostic information to triage and treat life-threatening radiation injuries. We hypothesized that intestinal microbiota act as novel biomarkers of prior radiation exposure. Adult male Wistar rats (n ¼ 5/group) received single or multiple fraction total-body irradiation of 10.0 Gy and 18.0 Gy, respectively. Fresh fecal pellets were obtained from each rat prior to (day 0) and at days 4, 11, and 21 post-irradiation. Fecal microbiota composition was determined using microarray and quantitative PCR (polymerase chain reaction) analyses. The radiation exposure biomarkers consisted of increased 16S rRNA levels of 12 members of the Bacteroidales, Lactobacillaceae, and Streptococcaceae after radiation exposure, unchanged levels of 98 Clostridiaceae and Peptostreptococcaceae, and decreased levels of 47 separate Clostridiaceae members; these biomarkers are present in human and rat feces. As a result of the ubiquity of these biomarkers, this biomarker technique is non-invasive; microbiota provide a sustained level of reporting signals that are increased several-fold following exposure to radiation, and intestinal microbiota that are unaffected by radiation serve as internal controls. We conclude that intestinal microbiota serve as novel biomarkers of prior radiation exposure, and may be able to complement conventional chromosome aberrational analysis to significantly enhance biological dose assessments.

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Section: Discussionmentioning

confidence: 57%

Intestinal Microbiota as Novel Biomarkers of Prior Radiation Exposure

et al. 2012

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“…In this study, we expand upon earlier published observations of that have reported on the urinary and serum response of the mouse (Amendola et al 2006; Lee et al 2007; Tyburski et al 2008; 2009; Ossetrova et al 2010; Partridge et al 2010; Chen et al 2011) and rat(Randic & Supek 1961; Porciani et al 2001; Lanz et al 2009; Johnson et al 2011; Tang et al 2013; Zhang et al 2014) to γ radiation exposures. Using Ultra-Performance ® liquid chromatography (UPLC) in conjunction with time-of-flight mass spectrometry (TOFMS), we analyzed urine collected from rats prior to and at four time points after exposure to six different doses of gamma radiation ranging from 0.5 to 10 Gy at high dose rate.…”

Section: Introductionmentioning

confidence: 58%

Exposure to ionizing radiation reveals global dose- and time-dependent changes in the urinary metabolome of rat

et al. 2014

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The potential for exposures to ionizing radiation has increased in recent years. Although advances have been made, understanding the global metabolic response as a function of both dose and exposure time is challenging considering the complexity of the responses. Herein we report our findings on the dose- and time-dependency of the urinary response to ionizing radiation in the male rat using radiation metabolomics. Urine samples were collected from adult male rats, exposed to 0.5 to 10 Gy γ–radiation, both before from 6 to 72 h following exposures. Samples were analyzed by liquid chromatography coupled with time-of-flight mass spectrometry, and deconvoluted mass chromatographic data were initially analyzed by principal component analysis. However, the breadth and complexity of the data necessitated the development of a novel approach to summarizing biofluid constituents after exposure, called Visual Analysis of Metabolomics Package (VAMP). VAMP revealed clear urine metabolite profile differences to as little as 0.5 Gy after 6 h exposure. Via VAMP, it was discovered that the response to radiation exposure found in rat urine is characterized by an overall net down-regulation of ion excretion with only a modest number of ions excreted in excess over pre-exposure levels. Our results show both similarities and differences with the published mouse urine response and a dose- and time-dependent net decrease in urine ion excretion associated with radiation exposure. These findings mark an important step in the development of minimally invasive radiation biodosimetry. VAMP should have general applicability in metabolomics to visualize overall differences and trends in many sample sets.

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“…While cytogenetics remains the gold standard for biological dosimetry and refinement of dose and potential future cancer risk, metabolomics can provide a first assessment (triage) of exposed individuals. Metabolomics has been used with success in the past to identify biomarkers of radiation exposure in easily accessible biofluids, i.e., urine, in animal models such as mice (4, 19, 20, 25), rats (17, 26) and nonhuman primates (16). In this study we extended the metabolomics approach to urine from humans exposed to TBI that was used as a precursor to HSCT.…”

Section: Discussionmentioning

confidence: 99%

Development of a Metabolomic Radiation Signature in Urine from Patients Undergoing Total Body Irradiation

et al. 2014

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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 β-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.

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Identification of Urinary Biomarkers from X-Irradiated Mice Using NMR Spectroscopy

Cited by 36 publications

References 36 publications

Intestinal Microbiota as Novel Biomarkers of Prior Radiation Exposure

Intestinal Microbiota as Novel Biomarkers of Prior Radiation Exposure

Exposure to ionizing radiation reveals global dose- and time-dependent changes in the urinary metabolome of rat

Development of a Metabolomic Radiation Signature in Urine from Patients Undergoing Total Body Irradiation

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