Pilib Ó Broin1, Bhavapriya Vaitheesvaran2, Subhrajit Saha3, Kirsten Hartil2, Emily I Chen4, Devorah Goldman5, William Harv Fleming5, Irwin J Kurland2, Chandan Guha6, Aaron Golden7. 1. Department of Genetics, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York; Department of Mathematical Sciences, Yeshiva University, New York, New York. 2. Department of Medicine, Diabetes Center, Stable Isotope and Metabolomics Core Facility, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York. 3. Department of Radiation Oncology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York. 4. Department of Pharmacology, Proteomics Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. 5. Department of Medicine, Oregon Health and Science University, Portland, Oregon. 6. Department of Radiation Oncology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York. Electronic address: cguha@montefiore.org. 7. Department of Genetics, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York; Department of Mathematical Sciences, Yeshiva University, New York, New York. Electronic address: aaron.golden@einstein.yu.edu.
Abstract
PURPOSE: Assessing whole-body radiation injury and absorbed dose is essential for remediation efforts following accidental or deliberate exposure in medical, industrial, military, or terrorist incidents. We hypothesize that variations in specific metabolite concentrations extracted from blood plasma would correlate with whole-body radiation injury and dose. METHODS AND MATERIALS: Groups of C57BL/6 mice (n=12 per group) were exposed to 0, 2, 4, 8, and 10.4 Gy of whole-body gamma radiation. At 24 hours after treatment, all animals were euthanized, and both plasma and liver biopsy samples were obtained, the latter being used to identify a distinct hepatic radiation injury response within plasma. A semiquantitative, untargeted metabolite/lipid profile was developed using gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry, which identified 354 biochemical compounds. A second set of C57BL/6 mice (n=6 per group) were used to assess a subset of identified plasma markers beyond 24 hours. RESULTS: We identified a cohort of 37 biochemical compounds in plasma that yielded the optimal separation of the irradiated sample groups, with the most correlated metabolites associated with pyrimidine (positively correlated) and tryptophan (negatively correlated) metabolism. The latter were predominantly associated with indole compounds, and there was evidence that these were also correlated between liver and plasma. No evidence of saturation as a function of dose was observed, as has been noted for studies involving metabolite analysis of urine. CONCLUSIONS: Plasma profiling of specific metabolites related to pyrimidine and tryptophan pathways can be used to differentiate whole-body radiation injury and dose response. As the tryptophan-associated indole compounds have their origin in the intestinal microbiome and subsequently the liver, these metabolites particularly represent an attractive marker for radiation injury within blood plasma.
PURPOSE: Assessing whole-body radiation injury and absorbed dose is essential for remediation efforts following accidental or deliberate exposure in medical, industrial, military, or terrorist incidents. We hypothesize that variations in specific metabolite concentrations extracted from blood plasma would correlate with whole-body radiation injury and dose. METHODS AND MATERIALS: Groups of C57BL/6 mice (n=12 per group) were exposed to 0, 2, 4, 8, and 10.4 Gy of whole-body gamma radiation. At 24 hours after treatment, all animals were euthanized, and both plasma and liver biopsy samples were obtained, the latter being used to identify a distinct hepatic radiation injury response within plasma. A semiquantitative, untargeted metabolite/lipid profile was developed using gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry, which identified 354 biochemical compounds. A second set of C57BL/6 mice (n=6 per group) were used to assess a subset of identified plasma markers beyond 24 hours. RESULTS: We identified a cohort of 37 biochemical compounds in plasma that yielded the optimal separation of the irradiated sample groups, with the most correlated metabolites associated with pyrimidine (positively correlated) and tryptophan (negatively correlated) metabolism. The latter were predominantly associated with indole compounds, and there was evidence that these were also correlated between liver and plasma. No evidence of saturation as a function of dose was observed, as has been noted for studies involving metabolite analysis of urine. CONCLUSIONS: Plasma profiling of specific metabolites related to pyrimidine and tryptophan pathways can be used to differentiate whole-body radiation injury and dose response. As the tryptophan-associated indole compounds have their origin in the intestinal microbiome and subsequently the liver, these metabolites particularly represent an attractive marker for radiation injury within blood plasma.
Authors: Christian Lanz; Andrew D Patterson; Josef Slavík; Kristopher W Krausz; Monika Ledermann; Frank J Gonzalez; Jeffrey R Idle Journal: Radiat Res Date: 2009-08 Impact factor: 2.841
Authors: John B Tyburski; Andrew D Patterson; Kristopher W Krausz; Josef Slavík; Albert J Fornace; Frank J Gonzalez; Jeffrey R Idle Journal: Radiat Res Date: 2008-07 Impact factor: 2.841
Authors: Ludy C H W Lutgens; Nicolaas E P Deutz; John Gueulette; Jack P M Cleutjens; Martijn P F Berger; Bradly G Wouters; Maarten F von Meyenfeldt; Philippe Lambin Journal: Int J Radiat Oncol Biol Phys Date: 2003-11-15 Impact factor: 7.038
Authors: Evan L Pannkuk; Evagelia C Laiakis; Albert J Fornace; Oluseyi O Fatanmi; Vijay K Singh Journal: Health Phys Date: 2018-07 Impact factor: 1.316
Authors: Evan L Pannkuk; Evagelia C Laiakis; Tytus D Mak; Giuseppe Astarita; Simon Authier; Karen Wong; Albert J Fornace Journal: Metabolomics Date: 2016-03-15 Impact factor: 4.290
Authors: Brynn A Hollingsworth; David R Cassatt; Andrea L DiCarlo; Carmen I Rios; Merriline M Satyamitra; Thomas A Winters; Lanyn P Taliaferro Journal: Front Pharmacol Date: 2021-05-18 Impact factor: 5.810