title: Implications of genotypic differences in the generation of a urinary metabolomics radiation signature.
abstract: The increased threat of radiological terrorism and accidental nuclear exposures, together with increased usage of radiation-based medical procedures, has made necessary the development of minimally invasive methods for rapid identification of exposed individuals. Genetically predisposed radiosensitive individuals comprise a significant number of the population and require specialized attention and treatments after such events. Metabolomics, the assessment of the collective small molecule content in a given biofluid or tissue, has proven effective in the rapid identification of radiation biomarkers and metabolic perturbations. To investigate how the genotypic background may alter the ionizing radiation (IR) signature, we analyzed urine from Parp1(-/-) mice, as a model radiosensitive genotype, exposed to IR by utilizing the analytical power of liquid chromatography coupled with mass spectrometry (LC-MS), as urine has been thoroughly investigated in wild type (WT) mice in previous studies from our laboratory. Samples were collected at days one and three after irradiation, time points that are important for the early and efficient triage of exposed individuals. Time-dependent perturbations in metabolites were observed in the tricarboxylic acid pathway (TCA). Other differentially excreted metabolites included amino acids and metabolites associated with dysregulation of energy metabolism pathways. Time-dependent apoptotic pathway activation between WT and mutant mice following IR exposure may explain the altered excretion patterns, although the origin of the metabolites remains to be determined. This first metabolomics study in urine from radiation exposed genetic mutant animal models provides evidence that this technology can be used to dissect the effects of genotoxic agents on metabolism by assessing easily accessible biofluids and identify biomarkers of radiation exposure. Applications of metabolomics could be incorporated in the future to further elucidate the effects of IR on the metabolism of Parp1(-/-) genotype by assessing individual tissues.
authors.affiliation: Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington DC, USA. Electronic address: ecl28@georgetown.edu.
authors.forename: Evagelia C
authors.initials: EC
authors.lastname: Laiakis
authors.affiliation: Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington DC, USA.
authors.forename: Evan L
authors.initials: EL
authors.lastname: Pannkuk
authors.affiliation: Pediatrics, Division of Developmental Nutrition, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Diaz-Rubio
authors.affiliation: Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington DC, USA.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Wang
authors.affiliation: Mass Spectrometry Data Center, National Institute of Standards and Technology (NIST), Gaithersburg MD, USA.
authors.forename: Tytus D
authors.initials: TD
authors.lastname: Mak
authors.affiliation: Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington DC, USA.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Simbulan-Rosenthal
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Brenner
authors.affiliation: Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington DC, USA; Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, USA; Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah 22254, Saudi Arabia.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Fornace
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000652:urine*; D004307:Dose-Response Relationship, Radiation; D005838:Genotype; D008297:Male; D055442:Metabolome / Q000528:radiation effects*; D055432:Metabolomics; D018345:Mice, Knockout; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000235:genetics*; D011829:Radiation Dosage; D011839:Radiation, Ionizing
chemical_list: D015415:Biomarkers; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1
keywords: Biomarkers; DNA repair; Ionizing radiation; Metabolomics; Urine