Radiation metabolomics. 2. Dose- and time-dependent urinary excretion of deaminated purines and pyrimidines after sublethal gamma-radiation exposure in mice.
Gamma-radiation exposure of humans is a major public health concern as the threat of terrorism and potential hostile use of radiological devices increases worldwide. We report here the effects of sublethal gamma-radiation exposure on the mouse urinary metabolome determined using ultra-performance liquid chromatography-coupled time-of-flight mass spectrometry-based metabolomics. Five urinary biomarkers of sublethal radiation exposure that were statistically significantly elevated during the first 24 h after exposure to doses ranging from 1 to 3 Gy were unequivocally identified by tandem mass spectrometry. These are deaminated purine and pyrimidine derivatives, namely, thymidine, 2'-deoxyuridine, 2'-deoxyxanthosine, xanthine and xanthosine. Furthermore, the aminopyrimidine 2'-deoxycytidine appeared to display reduced urinary excretion at 2 and 3 Gy. The elevated biomarkers displayed a time-dependent excretion, peaking in urine at 8-12 h but returning to baseline by 36 h after exposure. It is proposed that 2'-deoxyuridine and 2'-deoxyxanthosine arise as a result of gamma irradiation by nitrosative deamination of 2'-deoxycytidine and 2'-deoxyguanosine, respectively, and that this further leads to increased synthesis of thymidine, xanthine and xanthosine. The urinary excretion of deaminated purines and pyrimidines, at the expense of aminopurines and aminopyrimidines, appears to form the core of the urinary radiation metabolomic signature of mice exposed to sublethal doses of ionizing radiation.
Tyburski
John B
JB
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Patterson
Andrew D
AD
Krausz
Kristopher W
KW
Slavík
Josef
J
Fornace
Albert J
AJ
Gonzalez
Frank J
FJ
Idle
Jeffrey R
JR
D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000652:urine; D003641:Deamination; D003853:Deoxyribonucleosides / Q000652:urine; D003857:Deoxyuridine / Q000652:urine; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015999:Multivariate Analysis; D011687:Purines / Q000378:metabolism / Q000652:urine*; D011743:Pyrimidines / Q000378:metabolism / Q000652:urine*; D012263:Ribonucleosides / Q000652:urine; D053719:Tandem Mass Spectrometry; D013936:Thymidine / Q000652:urine; D013997:Time Factors; D019820:Xanthine / Q000652:urine; D014970:Xanthines
D015415:Biomarkers; D003853:Deoxyribonucleosides; D011687:Purines; D011743:Pyrimidines; D012263:Ribonucleosides; D014970:Xanthines; D019820:Xanthine; C077801:2'-deoxyxanthosine; C005893:xanthosine; D013936:Thymidine; D003857:Deoxyuridine