The increasing risk of acute large-scale radiological/nuclear exposures of population underlines the necessity of developing new, rapid and high throughput biodosimetric tools for estimation of received dose and initial triage. We aimed to compare the induction and persistence of different radiation exposure biomarkers in human peripheral blood in vivo. Blood samples of patients with indicated radiotherapy (RT) undergoing partial body irradiation (PBI) were obtained soon before the first treatment and then after 24 h, 48 h, and 5 weeks; i.e. after 1, 2, and 25 fractionated RT procedures. We collected circulating peripheral blood from ten patients with tumor of endometrium (1.8 Gy per fraction) and eight patients with tumor of head and neck (2.0-2.121 Gy per fraction). Incidence of dicentrics and micronuclei was monitored as well as determination of apoptosis and the transcription level of selected radiation-responsive genes. Since mitochondrial DNA (mtDNA) has been reported to be a potential indicator of radiation damage in vitro, we also assessed mtDNA content and deletions by novel multiplex quantitative PCR. Cytogenetic data confirmed linear dose-dependent increase in dicentrics (p < 0.01) and micronuclei (p < 0.001) in peripheral blood mononuclear cells after PBI. Significant up-regulations of five previously identified transcriptional biomarkers of radiation exposure (PHPT1, CCNG1, CDKN1A, GADD45, and SESN1) were also found (p < 0.01). No statistical change in mtDNA deletion levels was detected; however, our data indicate that the total mtDNA content decreased with increasing number of RT fractions. Interestingly, the number of micronuclei appears to correlate with late radiation toxicity (r2 = 0.9025) in endometrial patients suggesting the possibility of predicting the severity of RT-related toxicity by monitoring this parameter. Overall, these data represent, to our best knowledge, the first study providing a multiparametric comparison of radiation biomarkers in human blood in vivo, which have potential for improving biological dosimetry.

Bundeswehr Institute of Radiobiology Munich Germany

Cancer Mechanisms and Biomarkers group Radiation Effects Department Centre for Radiation Chemical and Environmental Hazards Public Health of England Didcot United Kingdom

Department of Hygiene and Preventive Medicine Faculty of Medicine in Hradec Králové Charles University Prague Hradec Králové Czech Republic

Department of Oncology and Radiotherapy and 4th Department of Internal Medicine Hematology University Hospital Hradec Králové Czech Republic

Department of Radiation Dosimetry Nuclear Physics Institute of the Czech Academy of Sciences Prague Czech Republic

Department of Radiobiology Faculty of Military Health Sciences Hradec Králové University of Defence in Brno Hradec Králové Czech Republic

Department of Radiobiology Faculty of Military Health Sciences Hradec Králové University of Defence in Brno Hradec Králové Czech Republic Biomedical Research Centre University Hospital Hradec Králové Czech Republic

Department of Radiobiology Faculty of Military Health Sciences Hradec Králové University of Defence in Brno Hradec Králové Czech Republic Department of Oncology and Radiotherapy and 4th Department of Internal Medicine Hematology University Hospital Hradec Králové Czech Republic

Department of Toxicology Faculty of Military Health Sciences Hradec Králové University of Defence in Brno Czech Republic

Institute for Global Health Barcelona Spain

Institute for Hematology and Blood Transfusion Hospital Na Bulovce Prague Czech Republic

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$a The first in vivo multiparametric comparison of different radiation exposure biomarkers in human blood / $c A. Tichy, S. Kabacik, G. O'Brien, J. Pejchal, Z. Sinkorova, A. Kmochova, I. Sirak, A. Malkova, CG. Beltran, JR. Gonzalez, J. Grepl, M. Majewski, E. Ainsbury, L. Zarybnicka, J. Vachelova, A. Zavrelova, M. Davidkova, M. Markova Stastna, M. Abend, E. Pernot, E. Cardis, C. Badie,

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$a The increasing risk of acute large-scale radiological/nuclear exposures of population underlines the necessity of developing new, rapid and high throughput biodosimetric tools for estimation of received dose and initial triage. We aimed to compare the induction and persistence of different radiation exposure biomarkers in human peripheral blood in vivo. Blood samples of patients with indicated radiotherapy (RT) undergoing partial body irradiation (PBI) were obtained soon before the first treatment and then after 24 h, 48 h, and 5 weeks; i.e. after 1, 2, and 25 fractionated RT procedures. We collected circulating peripheral blood from ten patients with tumor of endometrium (1.8 Gy per fraction) and eight patients with tumor of head and neck (2.0-2.121 Gy per fraction). Incidence of dicentrics and micronuclei was monitored as well as determination of apoptosis and the transcription level of selected radiation-responsive genes. Since mitochondrial DNA (mtDNA) has been reported to be a potential indicator of radiation damage in vitro, we also assessed mtDNA content and deletions by novel multiplex quantitative PCR. Cytogenetic data confirmed linear dose-dependent increase in dicentrics (p < 0.01) and micronuclei (p < 0.001) in peripheral blood mononuclear cells after PBI. Significant up-regulations of five previously identified transcriptional biomarkers of radiation exposure (PHPT1, CCNG1, CDKN1A, GADD45, and SESN1) were also found (p < 0.01). No statistical change in mtDNA deletion levels was detected; however, our data indicate that the total mtDNA content decreased with increasing number of RT fractions. Interestingly, the number of micronuclei appears to correlate with late radiation toxicity (r2 = 0.9025) in endometrial patients suggesting the possibility of predicting the severity of RT-related toxicity by monitoring this parameter. Overall, these data represent, to our best knowledge, the first study providing a multiparametric comparison of radiation biomarkers in human blood in vivo, which have potential for improving biological dosimetry.

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