Complex aberrations in lymphocytes exposed to mixed beams of 241Am alpha particles and X-rays

Staaf, Elina; Deperas‐Kaminska, Marta; Brehwens, Karl; Haghdoost, Siamak; Czub, Joanna; Wójcik, Andrzej

doi:10.1016/j.mrgentox.2013.05.001

Cited by 18 publications

(33 citation statements)

References 25 publications

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“…Overall, the first set of experiments displayed clear synergy for most donors, also when the sum of the four donors was analysed. This result is in agreement with our earlier results on synergy in human PBL using micronuclei [22], chromosomal aberrations [23], comet assay and radiation-induced gene expression [18] as endpoints. Synergy was also detected at the level of 53BP1 foci and the activation of DNA repair proteins using human U2OS osteosarcoma cells [20] and as the hindered mobility of foci in mixed-beam-exposed cells as demonstrated by live cell imaging [21].…”

Section: Discussionsupporting

confidence: 93%

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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

Cheng

Brzozowska

Lisowska

et al. 2019

Cancers

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Accumulating evidence suggests a synergistic effect in cells simultaneously exposed to different types of clustered and dispersed DNA damage. We aimed to analyse the effect of mixed beams of alpha particles and X-rays (1:1 dose of each) on DNA damage response genes in human peripheral blood lymphocytes isolated from four donors. Two donors were compared upon inhibition of ATM or DNA-PK and at different sampling times. qPCR was used to measure mRNA levels of FDXR, GADD45A, BBC3, MDM2, CDKN1A, and XPC 24 h following exposure. Generally, alpha particles and mixed beams were stronger inducers of gene expression compared to X-rays, displaying saturated versus linear dose-response curves, respectively. Three out of four donors responded synergistically to mixed beams. When two donors were sampled again one year later, the former additive effect in one donor was now synergistic and no significant difference in intrinsic radiosensitivity was displayed, as determined by gamma-radiation-induced micronuclei. ATM, but not DNA-PK inhibition, reduced the radiation-induced gene expression, but differently for alpha radiation between the two donors. In conclusion, synergy was present for all donors, but the results suggest individual variability in the response to mixed beams, most likely due to lifestyle changes.

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Section: Discussionsupporting

confidence: 93%

“…IR-induced clustered damage two of the donors. The study is a continuation of our analyses of cellular effects of simultaneous exposure to alpha radiation and X-rays [18,[20][21][22][23]].…”

Section: Introductionmentioning

confidence: 99%

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

Cheng

Brzozowska

Lisowska

et al. 2019

Cancers

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“…The synergistic effect of mixed beams was not seen with all cell types and end points [ 20 ], but we consistently observed a higher than expected level of cytogenetic damage in human peripheral blood lymphocytes (PBL) [ 21 , 22 ]. The aim of the present investigation was to look more closely at the mechanism of the synergistic effect in PBL, especially with respect to the question if it is due to an augmented level of initial damage or impaired DNA repair.…”

Section: Introductionmentioning

confidence: 91%

Simultaneous induction of dispersed and clustered DNA lesions compromises DNA damage response in human peripheral blood lymphocytes

et al. 2018

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Due to its ability to induce DNA damage in a space and time controlled manner, ionising radiation is a unique tool for studying the mechanisms of DNA repair. The biological effectiveness of ionising radiation is related to the ionisation density which is defined by the linear energy transfer (LET). Alpha particles are characterised by high LET, while X-rays by low LET values. An interesting question is how cells react when exposed to a mixed beam of high and low LET radiation. In an earlier study carried out with human peripheral blood lymphocytes (PBL) we could demonstrate that alpha radiation X-rays interact in producing more chromosomal aberrations than expected based on additivity. The aim of the present investigation was to look at the mechanism of the interaction, especially with respect to the question if it is due to an augmented level of initial damage or impaired DNA repair. PBL were exposed to various doses of alpha particles, X-rays and mixed beams. DNA damage and the kinetics of damage repair was quantified by the alkaline comet assay. The levels of phosphorylated, key DNA damage response (DDR) proteins ATM, p53 and DNA-PK were measured by Western blotting and mRNA levels of 6 damage-responsive genes were measured by qPCR. Alpha particles and X-rays interact in inducing DNA damage above the level predicted by assuming additivity and that the repair of damage occurs with a delay. The activation levels of DDR proteins and mRNA levels of the studied genes were highest in cells exposed to mixed beams. The results substantiate the idea that exposure to mixed beams presents a challenge for the cellular DDR system.

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“…Experimental systems using fission neutrons are usually a mixture of differing levels of γ-rays. Yet, at least at biologically relevant moderate doses, nil or negligible levels of interaction of high– and low–linear energy transfer (LET) radiations have been reported for various biological endpoints in mixed radiation fields [34–41]; however, others have reported synergistic-like effects [42, 43]. …”

Section: Data Assessment and Results Of Analysesmentioning

confidence: 99%

Neutron relative biological effectiveness in Hiroshima and Nagasaki atomic bomb survivors: a critical review

Sasaki

Endo

Hoshi

et al. 2016

Journal of Radiation Research

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The calculated risk of cancer in humans due to radiation exposure is based primarily on long-term follow-up studies, e.g. the life-span study (LSS) on atomic bomb (A-bomb) survivors in Hiroshima and Nagasaki. Since A-bomb radiation consists of a mixture of γ-rays and neutrons, it is essential that the relative biological effectiveness (RBE) of neutrons is adequately evaluated if a study is to serve as a reference for cancer risk. However, the relatively small neutron component hampered the direct estimation of RBE in LSS data. To circumvent this problem, several strategies have been attempted, including dose-independent constant RBE, dose-dependent variable RBE, and dependence on the degrees of dominance of intermingled γ-rays. By surveying the available literature, we tested the chromosomal RBE of neutrons as the biological endpoint for its equivalence to the microdosimetric quantities obtained using a tissue-equivalent proportional counter (TEPC) in various neutron fields. The radiation weighting factor, or quality factor, Qn, of neutrons as expressed in terms of the energy dependence of the maximum RBE, RBEm, was consistent with that predicted by the TEPC data, indicating that the chromosomally measured RBE was independent of the magnitude of coexisting γ-rays. The obtained neutron RBE, which varied with neutron dose, was confirmed to be the most adequate RBE system in terms of agreement with the cancer incidence in A-bomb survivors, using chromosome aberrations as surrogate markers. With this RBE system, the cancer risk in A-bomb survivors as expressed in unit dose of reference radiation is equally compatible with Hiroshima and Nagasaki cities, and may be potentially applicable in other cases of human radiation exposure.

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Complex aberrations in lymphocytes exposed to mixed beams of 241Am alpha particles and X-rays

Cited by 18 publications

References 25 publications

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

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

Simultaneous induction of dispersed and clustered DNA lesions compromises DNA damage response in human peripheral blood lymphocytes

Neutron relative biological effectiveness in Hiroshima and Nagasaki atomic bomb survivors: a critical review

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