Abstract
Previous investigations in gene expression changes in blood after radiation exposure have highlighted its potential to provide biomarkers of exposure. Here, FDXR transcriptional changes in blood were investigated in humans undergoing a range of external radiation exposure procedures covering several orders of magnitude (cardiac fluoroscopy, diagnostic computed tomography (CT)) and treatments (total body and local radiotherapy). Moreover, a method was developed to assess the dose to the blood using physical exposure parameters. FDXR expression was significantly up-regulated 24 hr after radiotherapy in most patients and continuously during the fractionated treatment. Significance was reached even after diagnostic CT 2 hours post-exposure. We further showed that no significant differences in expression were found between ex vivo and in vivo samples from the same patients. Moreover, potential confounding factors such as gender, infection status and anti-oxidants only affect moderately FDXR transcription. Finally, we provided a first in vivo dose-response showing dose-dependency even for very low doses or partial body exposure showing good correlation between physically and biologically assessed doses. In conclusion, we report the remarkable responsiveness of FDXR to ionising radiation at the transcriptional level which, when measured in the right time window, provides accurate in vivo dose estimates.
Highlights
Previous investigations in gene expression changes in blood after radiation exposure have highlighted its potential to provide biomarkers of exposure
Once again FDXR was seen to be the best gene for dose estimation for ex vivo irradiated blood and, it was confirmed for the first time that it could distinguish blood samples from patients prior to radiation exposure from post-irradiated patient blood samples irradiation was limited to a localised area[17] and that the dose to the blood was estimated to be extremely low compared to doses tested ex vivo so far at the exception of Manning et al 20139
For radiotherapy patients, up-regulation after the first fraction could be detected in most cases and this up-regulation was maintained during the course of radiotherapy, lasting weeks for some patients (Fig. 2, Supplementary Table S1)
Summary
Previous investigations in gene expression changes in blood after radiation exposure have highlighted its potential to provide biomarkers of exposure. We report the remarkable responsiveness of FDXR to ionising radiation at the transcriptional level which, when measured in the right time window, provides accurate in vivo dose estimates. FDXR has been reported as the only gene differentially expressed following exposure of cells to 6 out of 7 anti-cancer drugs treatment tested[23] and a transcriptional up-regulation of FDXR can be considered as a universal response to DNA damage. After exposure to ionising irradiation, FDXR produces one of the highest levels of fold changes in the blood[9] This high level of expression, combined with a relatively low level of endogenous expression and variability among individuals, allows for easy discrimination of high doses from low doses[9]. Once again FDXR was seen to be the best gene for dose estimation for ex vivo irradiated blood and, it was confirmed for the first time that it could distinguish blood samples from patients prior to radiation exposure from post-irradiated patient blood samples irradiation was limited to a localised area[17] and that the dose to the blood was estimated to be extremely low compared to doses tested ex vivo so far at the exception of Manning et al 20139
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