DNA Repair and Cell Cycle Biomarkers of Radiation Exposure and Inflammation Stress in Human Blood

• Published in: PloS one Vol. 7; no. 11; p. e48619
• Main Authors: Budworth, Helen, Snijders, Antoine M., Marchetti, Francesco, Mannion, Brandon, Bhatnagar, Sandhya, Kwoh, Ely, Tan, Yuande, Wang, Shan X., Blakely, William F., Coleman, Matthew, Peterson, Leif, Wyrobek, Andrew J.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.11.2012; Public Library of Science (PLoS)
• Subjects: Adult; Apoptosis; Bacteria; BASIC BIOLOGICAL SCIENCES; BAX protein; Bioindicators; Biology; Biomarkers; Biomarkers - blood; Blood; Cancer; Cell cycle; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Cycle - radiation effects; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; DNA Repair - drug effects; DNA Repair - genetics; DNA Repair - radiation effects; Dose-Response Relationship, Radiation; Endotoxins; Exposure; Female; Gadd45A protein; Gene expression; Gene Expression Regulation - drug effects; Gene Expression Regulation - radiation effects; Genes; Human subjects; Humans; Inflammation; Inflammation - blood; Inflammation - genetics; Ionizing radiation; Kinases; Laboratories; Life sciences; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Male; Medicine; Middle Aged; Mitogens; Phosphorylation - drug effects; Phosphorylation - radiation effects; Predictive Value of Tests; Proliferating cell nuclear antigen; Proteins; Radiation; Radiation damage; Radiation effects; Radiation exposure; Repair; Reproducibility of Results; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science & Technology - Other Topics; Smoking; Stress; Stress (physiology); Stress, Physiological - drug effects; Stress, Physiological - genetics; Stress, Physiological - radiation effects; Stresses; Time Factors; Transcription; Transcription, Genetic - drug effects; Transcription, Genetic - radiation effects; X-Rays; XPC protein; Young Adult; United States > US; Texas; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0048619

DNA damage and repair are hallmarks of cellular responses to ionizing radiation. We hypothesized that monitoring the expression of DNA repair-associated genes would enhance the detection of individuals exposed to radiation versus other forms of physiological stress. We employed the human blood ex vivo radiation model to investigate the expression responses of DNA repair genes in repeated blood samples from healthy, non-smoking men and women exposed to 2 Gy of X-rays in the context of inflammation stress mimicked by the bacterial endotoxin lipopolysaccharide (LPS). Radiation exposure significantly modulated the transcript expression of 12 genes of 40 tested (2.2E-06<p<0.03), of which 8 showed no overlap between unirradiated and irradiated samples (CDKN1A, FDXR, BBC3, PCNA, GADD45a, XPC, POLH and DDB2). This panel demonstrated excellent dose response discrimination (0.5 to 8 Gy) in an independent human blood ex vivo dataset, and 100% accuracy for discriminating patients who received total body radiation. Three genes of this panel (CDKN1A, FDXR and BBC3) were also highly sensitive to LPS treatment in the absence of radiation exposure, and LPS co-treatment significantly affected their radiation responses. At the protein level, BAX and pCHK2-thr68 were elevated after radiation exposure, but the pCHK2-thr68 response was significantly decreased in the presence of LPS. Our combined panel yields an estimated 4-group accuracy of ∼90% to discriminate between radiation alone, inflammation alone, or combined exposures. Our findings suggest that DNA repair gene expression may be helpful to identify biodosimeters of exposure to radiation, especially within high-complexity exposure scenarios.