FDXR is a biomarker of radiation exposure in vivo

Gráinne O'Brien; Lourdes Cruz-Garcia; Matthäus Majewski; Jakub Grepl; Michael Abend; Matthias Port; Aleš Tichý; Igor Sirak; Andrea Malkova; Ellen Donovan; Lone Gothard; Sue Boyle; Navita Somaiah; Elizabeth Ainsbury; Lucyna Ponge; Krzysztof Slosarek; Leszek Miszczyk; Piotr Widlak; Edward Green; Neel Patel; Mahesh Kudari; Fergus Gleeson; Volodymyr Vinnikov; Viktor Starenkiy; Sergii Artiukh; Leonid Vasyliev; Azfar Zaman; Christophe Badie

doi:10.1038/s41598-017-19043-w

FDXR is a biomarker of radiation exposure in vivo

Gráinne O'Brien, Lourdes Cruz-Garcia, Matthäus Majewski, Jakub Grepl, Michael Abend, Matthias Port, Aleš Tichý, Igor Sirak, Andrea Malkova, Ellen Donovan, Lone Gothard, Sue Boyle, Navita Somaiah, Elizabeth Ainsbury, Lucyna Ponge, Krzysztof Slosarek, Leszek Miszczyk, Piotr Widlak, Edward Green, Neel PatelMahesh Kudari, Fergus Gleeson, Volodymyr Vinnikov, Viktor Starenkiy, Sergii Artiukh, Leonid Vasyliev, Azfar Zaman, Christophe Badie^*

^*Corresponding author for this work

Radiation Effects

Research output: Contribution to journal › Article › peer-review

103 Citations (Scopus)

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.

Original language	English
Article number	684
Journal	Scientific Reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-19043-w
Publication status	Published - 1 Dec 2018

Bibliographical note

Funding Information:
This work was supported by the EU within the 7th Framework Programme (RENEB project, grant agreement No. 295513) and financial support was provided by the National Institute for Health Research Centre for Research in Public Health Protection at the Public Health England, Ministry of Defence of the Czech Republic (long-term organization development plan Medical Aspects of Weapons of Mass Destruction of the Faculty of Military Health Sciences, University of Defence) and Ministry of Interior Affairs of the Czech Republic (project VH20172020010). We acknowledge NHS funding to the NIHR Biomedical Research Centre at The Royal Marsden and ICR. This work was partly supported by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Chemical & Radiation Threats & Hazards at Newcastle University in partnership with Public Health England (PHE). The RTGene project received funding from US NIH CMCR pilot programme, in collaboration with Columbia University. This work has received funding from the European Union FP7 Euratom Programme project OPERRA (grant agreement no 604984).

Publisher Copyright:
© 2018 The Author(s).

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O'Brien, G., Cruz-Garcia, L., Majewski, M., Grepl, J., Abend, M., Port, M., Tichý, A., Sirak, I., Malkova, A., Donovan, E., Gothard, L., Boyle, S., Somaiah, N., Ainsbury, E., Ponge, L., Slosarek, K., Miszczyk, L., Widlak, P., Green, E., ... Badie, C. (2018). FDXR is a biomarker of radiation exposure in vivo. Scientific Reports, 8(1), Article 684. https://doi.org/10.1038/s41598-017-19043-w

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title = "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.",

author = "Gr{\'a}inne O'Brien and Lourdes Cruz-Garcia and Matth{\"a}us Majewski and Jakub Grepl and Michael Abend and Matthias Port and Ale{\v s} Tich{\'y} and Igor Sirak and Andrea Malkova and Ellen Donovan and Lone Gothard and Sue Boyle and Navita Somaiah and Elizabeth Ainsbury and Lucyna Ponge and Krzysztof Slosarek and Leszek Miszczyk and Piotr Widlak and Edward Green and Neel Patel and Mahesh Kudari and Fergus Gleeson and Volodymyr Vinnikov and Viktor Starenkiy and Sergii Artiukh and Leonid Vasyliev and Azfar Zaman and Christophe Badie",

note = "Funding Information: This work was supported by the EU within the 7th Framework Programme (RENEB project, grant agreement No. 295513) and financial support was provided by the National Institute for Health Research Centre for Research in Public Health Protection at the Public Health England, Ministry of Defence of the Czech Republic (long-term organization development plan Medical Aspects of Weapons of Mass Destruction of the Faculty of Military Health Sciences, University of Defence) and Ministry of Interior Affairs of the Czech Republic (project VH20172020010). We acknowledge NHS funding to the NIHR Biomedical Research Centre at The Royal Marsden and ICR. This work was partly supported by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Chemical & Radiation Threats & Hazards at Newcastle University in partnership with Public Health England (PHE). The RTGene project received funding from US NIH CMCR pilot programme, in collaboration with Columbia University. This work has received funding from the European Union FP7 Euratom Programme project OPERRA (grant agreement no 604984). Publisher Copyright: {\textcopyright} 2018 The Author(s).",

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doi = "10.1038/s41598-017-19043-w",

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O'Brien, G , Cruz-Garcia, L, Majewski, M, Grepl, J, Abend, M, Port, M, Tichý, A, Sirak, I, Malkova, A, Donovan, E, Gothard, L, Boyle, S, Somaiah, N, Ainsbury, E, Ponge, L, Slosarek, K, Miszczyk, L, Widlak, P, Green, E, Patel, N, Kudari, M, Gleeson, F, Vinnikov, V, Starenkiy, V, Artiukh, S, Vasyliev, L, Zaman, A & Badie, C 2018, 'FDXR is a biomarker of radiation exposure in vivo', Scientific Reports, vol. 8, no. 1, 684. https://doi.org/10.1038/s41598-017-19043-w

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AU - O'Brien, Gráinne

AU - Cruz-Garcia, Lourdes

AU - Majewski, Matthäus

AU - Grepl, Jakub

AU - Abend, Michael

AU - Port, Matthias

AU - Tichý, Aleš

AU - Sirak, Igor

AU - Malkova, Andrea

AU - Donovan, Ellen

AU - Gothard, Lone

AU - Boyle, Sue

AU - Somaiah, Navita

AU - Ainsbury, Elizabeth

AU - Ponge, Lucyna

AU - Slosarek, Krzysztof

AU - Miszczyk, Leszek

AU - Widlak, Piotr

AU - Green, Edward

AU - Patel, Neel

AU - Kudari, Mahesh

AU - Gleeson, Fergus

AU - Vinnikov, Volodymyr

AU - Starenkiy, Viktor

AU - Artiukh, Sergii

AU - Vasyliev, Leonid

AU - Zaman, Azfar

AU - Badie, Christophe

N1 - Funding Information: This work was supported by the EU within the 7th Framework Programme (RENEB project, grant agreement No. 295513) and financial support was provided by the National Institute for Health Research Centre for Research in Public Health Protection at the Public Health England, Ministry of Defence of the Czech Republic (long-term organization development plan Medical Aspects of Weapons of Mass Destruction of the Faculty of Military Health Sciences, University of Defence) and Ministry of Interior Affairs of the Czech Republic (project VH20172020010). We acknowledge NHS funding to the NIHR Biomedical Research Centre at The Royal Marsden and ICR. This work was partly supported by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Chemical & Radiation Threats & Hazards at Newcastle University in partnership with Public Health England (PHE). The RTGene project received funding from US NIH CMCR pilot programme, in collaboration with Columbia University. This work has received funding from the European Union FP7 Euratom Programme project OPERRA (grant agreement no 604984). Publisher Copyright: © 2018 The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

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FDXR is a biomarker of radiation exposure in vivo

Abstract

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