FDXR is a biomarker of radiation exposure in vivo

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.

Impact of ATM and DNA-PK Inhibition on Gene Expression and Individual Response of Human Lymphocytes to Mixed Beams of Alpha Particles and X-Rays

“…Radiation-induced gene expression in PBL is regarded as a promising retrospective biological dosimeter [32,33]. Due to its high responsiveness to radiation, the FDXR gene appears as a particularly suitable biodosimeter in cases where sample collection is possible within a short time after exposure [24]. Our results support this conclusion, as the FDXR gene showed the highest level of induction in PBL of all donors.…”

“…The FDXR gene was chosen for the envelopes of additivity analysis due to its high sensitivity to radiation exposure, as shown by us and others [24]. It was used to verify if the mixed beam exposure induced a synergistic, additive or sub-additive effect.…”

Generation of a Transcriptional Radiation Exposure Signature in Human Blood Using Long-Read Nanopore Sequencing

“…Nanopore sequencing analysis of human PBMCs irradiated ex vivo has identified over 25,000 different transcripts with 46 genes showing a radiation-dependent significant shift in expression; in particular, two of these genes, APOBEC3H and FDXR, were clearly the most significantly responsive genes to ionizing radiation, with fold changes between 25 to 28 fold in average for the dose delivered (2 Gy). Identifying FDXR was reassuring, and validated the long-read sequencing technology, as it has been previously characterized ex vivo by other methods (8,10,15,16,23) and validated in human in vivo, demonstrating its suitability to provide accurate dose estimation in in vivo partial-or totalbody irradiated individuals (14). However, although APOBEC3H has been previously mentioned as a radiation-responsive gene (41), it had not been very well characterized.…”

“…Over the last decade, gene expression analysis has emerged as a realistic approach for assessing radiation exposure in human blood samples after medical exposure or during emergency situations, due to its high throughput and time efficiency (1)(2)(3)(4). Although many studies have used microarrays (5,6), qPCR analyses have proven to provide accurate dose estimates by focusing on specific radiationresponsive genes (7)(8)(9)(10)(11)(12)(13)(14)(15) in only 7 h (16) and now in only 4 h (17). This methodology has been validated through several NATO and RENEB exercises (16,18,19).…”

“…This methodology has been validated through several NATO and RENEB exercises (16,18,19). A single gene expression analysis [e.g., ferredoxin reductase, (FDXR), also reported to be a protein biomarker of radiation exposure, (20)] can offer accurate information on dose received in vivo in humans across a large range of doses from CT scan to total-body exposure (14). However, a radiation signature can provide further information about homogeneity of exposure (21), mixed exposure (22) or dose rate (11).…”