title: DNA repair and cell cycle biomarkers of radiation exposure and inflammation stress in human blood.
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.
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Budworth
authors.forename: Antoine M
authors.initials: AM
authors.lastname: Snijders
authors.forename: Francesco
authors.initials: F
authors.lastname: Marchetti
authors.forename: Brandon
authors.initials: B
authors.lastname: Mannion
authors.forename: Sandhya
authors.initials: S
authors.lastname: Bhatnagar
authors.forename: Ely
authors.initials: E
authors.lastname: Kwoh
authors.forename: Yuande
authors.initials: Y
authors.lastname: Tan
authors.forename: Shan X
authors.initials: SX
authors.lastname: Wang
authors.forename: William F
authors.initials: WF
authors.lastname: Blakely
authors.forename: Matthew
authors.initials: M
authors.lastname: Coleman
authors.forename: Leif
authors.initials: L
authors.lastname: Peterson
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wyrobek
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000528:radiation effects; D014965:X-Rays; D055815:Young Adult
chemical_list: D015415:Biomarkers; D008070:Lipopolysaccharides; D012333:RNA, Messenger