DNA repair and cell cycle biomarkers of radiation exposure and inflammation stress in human blood

PLoS One. 2012;7(11):e48619. doi: 10.1371/journal.pone.0048619. Epub 2012 Nov 7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Biomarkers / blood*
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Cycle / radiation effects*
  • DNA Repair / drug effects
  • DNA Repair / genetics
  • DNA Repair / radiation effects*
  • Dose-Response Relationship, Radiation
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / radiation effects
  • Humans
  • Inflammation / blood*
  • Inflammation / genetics
  • Lipopolysaccharides / pharmacology
  • Male
  • Middle Aged
  • Phosphorylation / drug effects
  • Phosphorylation / radiation effects
  • Predictive Value of Tests
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reproducibility of Results
  • Stress, Physiological / drug effects
  • Stress, Physiological / genetics
  • Stress, Physiological / radiation effects*
  • Time Factors
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / radiation effects
  • X-Rays
  • Young Adult

Substances

  • Biomarkers
  • Lipopolysaccharides
  • RNA, Messenger

Grant support

This work was performed under the auspices of the U.S. Department of Energy by the University of California, Lawrence Berkeley National Laboratory under DOE contract No. DE-AC02-05CH11231. This project has been funded in whole or in part by Federal funds from the Biomedical Advanced Research and Development Authority, Office of the Assistant Secretary for Preparedness and Response, Office of the Secretary, Department of Health and Human Services, under Contract No. HHSO100201000006C. The Armed Forces Radiobiology Research Institute (AFRRI) supported the involvement of WFB in this research under AFRRI work units RBB4AR and RAB4AU; views presented in this manuscript are those of the authors; no endorsement by the Department of Defense has been given or should be inferred. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.