title: Radiation dose-rate effects on gene expression for human biodosimetry.
abstract: BACKGROUND
  The effects of dose-rate and its implications on radiation biodosimetry methods are not well studied in the context of large-scale radiological scenarios. There are significant health risks to individuals exposed to an acute dose, but a realistic scenario would include exposure to both high and low dose-rates, from both external and internal radioactivity. It is important therefore, to understand the biological response to prolonged exposure; and further, discover biomarkers that can be used to estimate damage from low-dose rate exposures and propose appropriate clinical treatment.
  
  
  METHODS
  We irradiated human whole blood ex vivo to three doses, 0.56 Gy, 2.23 Gy and 4.45 Gy, using two dose rates: acute, 1.03 Gy/min and a low dose-rate, 3.1 mGy/min. After 24 h, we isolated RNA from blood cells and these were hybridized to Agilent Whole Human genome microarrays. We validated the microarray results using qRT-PCR.
  
  
  RESULTS
  Microarray results showed that there were 454 significantly differentially expressed genes after prolonged exposure to all doses. After acute exposure, 598 genes were differentially expressed in response to all doses. Gene ontology terms enriched in both sets of genes were related to immune processes and B-cell mediated immunity. Genes responding to acute exposure were also enriched in functions related to natural killer cell activation and cell-to-cell signaling. As expected, the p53 pathway was found to be significantly enriched at all doses and by both dose-rates of radiation. A support vectors machine classifier was able to distinguish between dose-rates with 100 % accuracy using leave-one-out cross-validation.
  
  
  CONCLUSIONS
  In this study we found that low dose-rate exposure can result in distinctive gene expression patterns compared with acute exposures. We were able to successfully distinguish low dose-rate exposed samples from acute dose exposed samples at 24 h, using a gene expression-based classifier. These genes are candidates for further testing as markers to classify exposure based on dose-rate.
authors.affiliation: Center for Radiological Research, Columbia University, VC11-237, 630 West 168th Street, New York, NY, 10032, USA. sg2423@cumc.columbia.edu.
authors.forename: Shanaz A
authors.initials: SA
authors.lastname: Ghandhi
authors.affiliation: Center for Radiological Research, Columbia University, VC11-237, 630 West 168th Street, New York, NY, 10032, USA. lbs5@cumc.columbia.edu.
authors.forename: Lubomir B
authors.initials: LB
authors.lastname: Smilenov
authors.affiliation: Center for Radiological Research, Columbia University, VC11-237, 630 West 168th Street, New York, NY, 10032, USA. CElliston@maimonidesmed.org.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Elliston
authors.affiliation: Center for Radiological Research, Columbia University, VC11-237, 630 West 168th Street, New York, NY, 10032, USA. mc3102@columbia.edu.
authors.forename: Mashkura
authors.initials: M
authors.lastname: Chowdhury
authors.affiliation: Center for Radiological Research, Columbia University, VC11-237, 630 West 168th Street, New York, NY, 10032, USA. saa2108@cumc.columbia.edu.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Amundson
mesh_terms: D000328:Adult; D001769:Blood / Q000378:metabolism / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011874:Radiometry; D015203:Reproducibility of Results; D059467:Transcriptome / Q000528:radiation effects*