Effect of Linear Energy Transfer (LET) on the Complexity of α-Particle-Induced Chromosome Aberrations in Human CD34<sup>+</sup>Cells

Anderson, Rhona M.; Stevens, David L.; Sumption, Natalia D.; Townsend, K. M. S.; Goodhead, Dudley T.; Hill, Mark A.

doi:10.1667/rr0813.1

Cited by 52 publications

(39 citation statements)

References 31 publications

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“…For example, there were indications in human blood cells that chromosomal rearrangements observed after exposure to high LETcould be explained by localized movement of chromatin containing damaged DNA into local repair centers (24). Following up on this work, it was more recently shown that increasing LET of an α particle did not increase the total number of aberrations per track traversal, and instead increased the ratio of complex to total aberrations (25). Therefore, if DSB clustering occur, as LET goes up (for LET > 100 keV∕μm), RIF linear frequencies would not change significantly but each RIF would be made of more DSBs, increasing the probability of complex chromosomal rearrangements.…”

Section: Where βðDþmentioning

confidence: 83%

Evidence for formation of DNA repair centers and dose-response nonlinearity in human cells

Neumaier

Swenson

Pham

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

242

195

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The concept of DNA "repair centers" and the meaning of radiationinduced foci (RIF) in human cells have remained controversial. RIFs are characterized by the local recruitment of DNA damage sensing proteins such as p53 binding protein (53BP1). Here, we provide strong evidence for the existence of repair centers. We used live imaging and mathematical fitting of RIF kinetics to show that RIF induction rate increases with increasing radiation dose, whereas the rate at which RIFs disappear decreases. We show that multiple DNA double-strand breaks (DSBs) 1 to 2 μm apart can rapidly cluster into repair centers. Correcting mathematically for the dose dependence of induction/resolution rates, we observe an absolute RIF yield that is surprisingly much smaller at higher doses: 15 RIF∕Gy after 2 Gy exposure compared to approximately 64 RIF∕Gy after 0.1 Gy. Cumulative RIF counts from time lapse of 53BP1-GFP in human breast cells confirmed these results. The standard model currently in use applies a linear scale, extrapolating cancer risk from high doses to low doses of ionizing radiation. However, our discovery of DSB clustering over such large distances casts considerable doubts on the general assumption that risk to ionizing radiation is proportional to dose, and instead provides a mechanism that could more accurately address risk dose dependency of ionizing radiation. DNA damage-sensing proteins localize at sites of DNA double-strand breaks (DSBs) within seconds to minutes following ionizing radiation (IR) exposure, resulting in the formation of immunofluorescently stainable nuclear domains referred to as radiation-induced foci (RIF) (1-3). RIF numbers are routinely used to assess the amount of DNA damage and repair kinetics after different treatments (4). However, there is a controversy surrounding the question of whether there is a 1∶1 correspondence between RIF and DSBs. For example, pulse field gel electrophoresis (PFGE) analysis suggests that DSBs decay exponentially with time immediately after exposure (5). In contrast, DNA damage-sensing proteins do not instantaneously detect DSBs, leading to delayed kinetics for both detection and resolution. More specifically, the maximum number of 53BP1 or γH2AX RIF is not reached until 15 to 30 min after exposure, and the yield of DSBs predicted by RIF is typically lower than the expected 25-40 DSB∕Gy measured by PFGE (4).Dose response provides another assay for assessing the relationship between DSBs and RIF. Based on theoretical Monte Carlo simulations and PFGE measurements (6, 7), the frequency of DSBs should be highly correlated with radiation dose. Confirming this prediction, two research groups reported that RIF number is proportional to radiation dosage from 1 mGy to 2 Gy (8, 9). In both studies, methods were applied to identify "real" RIF at low doses, where frequencies may be close to background levels before IR (e.g., 10 mGy would lead to about 0.3 DSB∕cell). They either used cells with very low γH2AX background foci (i.e., 0.05 background foci∕cell in primary human l...

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Section: Where βðDþmentioning

confidence: 83%

Evidence for formation of DNA repair centers and dose-response nonlinearity in human cells

Neumaier

Swenson

Pham

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

242

195

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“…Radon is a radioactive noble gas, evaporating from rocks, and the major dose contribution arises from the emission of α-particles. In contrast to sparsely ionizing X-rays, α-particles are densely ionizing and have a higher relative biological effectiveness for effects that are related to DNA damage, often also with differences in the quality of damage induced (29, 30). However, the tissue response to densely ionizing irradiation, including the interaction of irradiated and non-irradiated cells is less well investigated (31).…”

Section: Introductionmentioning

confidence: 99%

Measuring Leukocyte Adhesion to (Primary) Endothelial Cells after Photon and Charged Particle Exposure with a Dedicated Laminar Flow Chamber

et al. 2017

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The vascular endothelium interacts with all types of blood cells and is a key modulator of local and systemic inflammatory processes, for example, in the adhesion of blood leukocytes to endothelial cells (EC) and the following extravasation into the injured tissue. The endothelium is constantly exposed to mechanical forces caused by blood flow, and the resulting shear stress is essential for the maintenance of endothelial function. Changes in local hemodynamics are sensed by EC, leading to acute or persistent changes. Therefore, in vitro assessment of EC functionality should include shear stress as an essential parameter. Parallel-plate flow chambers with adjustable shear stress can be used to study EC properties. However, commercially available systems are not suitable for radiation experiments, especially with charged particles, which are increasingly used in radiotherapy of tumors. Therefore, research on charged-particle-induced vascular side effects is needed. In addition, α-particle emitters (e.g., radon) are used to treat inflammatory diseases at low doses. In the present study, we established a flow chamber system, applicable for the investigation of radiation induced changes in the adhesion of lymphocytes to EC as readout for the onset of an inflammatory reaction or the modification of a pre-existing inflammatory state. In this system, primary human EC are cultured under physiological laminar shear stress, subjected to a proinflammatory treatment and/or irradiation with X-rays or charged particles, followed by a coincubation with primary human lymphocytes (peripheral blood lymphocytes (PBL)). Analysis is performed by semiautomated quantification of fluorescent staining in microscopic pictures. First results obtained after irradiation with X-rays or helium ions indicate decreased adhesion of PBL to EC under laminar conditions for both radiation qualities, whereas adhesion of PBL under static conditions is not clearly affected by irradiation. Under static conditions, no radiation-induced changes in surface expression of adhesion molecules and activation of nuclear factor kappa B (NF-κB) signaling were observed after single cell-based high-throughput analysis. In subsequent studies, these investigations will be extended to laminar conditions.

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“…In vitro studies on the induction of chromosome aberrations by a-particle radiation have revealed the complexity of the damage (Anderson et al 2000;Moquet et al 2001;Anderson et al 2002Anderson et al , 2003Barquinero et al 2004;Anderson et al 2007;Tawn et al 2007Tawn et al , 2008Curwen et al 2012). A densely ionizing a-particle will only intersect a small fraction of the cell volume and the deposition of energy and resulting DNA damage will be localized along the particle track, resulting in multiple rearrangements.…”

Section: Introductionmentioning

confidence: 99%

Chromosome aberrations in workers with exposure to α-particle radiation from internal deposits of plutonium: expectations from in vitro studies and comparisons with workers with predominantly external γ-radiation exposure

Sotnik

et al. 2015

Radiat Environ Biophys

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mFISH analysis of chromosome aberration profiles of 47 and 144 h lymphocyte cultures following exposure to 193 mGy α-particle radiation confirmed that the frequency of stable aberrant cells and stable cells carrying translocations remains constant through repeated cell divisions. Age-specific rates and in vitro dose-response curves were used to derive expected translocation yields in nine workers from the Mayak nuclear facility in Russia. Five had external exposure to γ-radiation, two of whom also had exposure to neutrons, and four had external exposure to γ-radiation and internal exposure to α-particle radiation from incorporated plutonium. Doubts over the appropriateness of the dose response used to estimate translocations from the neutron component made interpretation difficult in two of the workers with external exposure, but the other three had translocation yields broadly in line with expectations. Three of the four plutonium workers had translocation yields in line with expectations, thus supporting the application of the recently derived in vitro α-particle dose response for translocations in stable cells. Overall this report demonstrates that with adequate reference in vitro dose-response curves, translocation yield has the potential to be a useful tool in the validation of red bone marrow doses resulting from mixed exposure to external and internal radiation.

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Effect of Linear Energy Transfer (LET) on the Complexity of α-Particle-Induced Chromosome Aberrations in Human CD34⁺Cells

Cited by 52 publications

References 31 publications

Evidence for formation of DNA repair centers and dose-response nonlinearity in human cells

Evidence for formation of DNA repair centers and dose-response nonlinearity in human cells

Measuring Leukocyte Adhesion to (Primary) Endothelial Cells after Photon and Charged Particle Exposure with a Dedicated Laminar Flow Chamber

Chromosome aberrations in workers with exposure to α-particle radiation from internal deposits of plutonium: expectations from in vitro studies and comparisons with workers with predominantly external γ-radiation exposure

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Effect of Linear Energy Transfer (LET) on the Complexity of α-Particle-Induced Chromosome Aberrations in Human CD34+Cells

Cited by 52 publications

References 31 publications

Evidence for formation of DNA repair centers and dose-response nonlinearity in human cells

Evidence for formation of DNA repair centers and dose-response nonlinearity in human cells

Measuring Leukocyte Adhesion to (Primary) Endothelial Cells after Photon and Charged Particle Exposure with a Dedicated Laminar Flow Chamber

Chromosome aberrations in workers with exposure to α-particle radiation from internal deposits of plutonium: expectations from in vitro studies and comparisons with workers with predominantly external γ-radiation exposure

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Effect of Linear Energy Transfer (LET) on the Complexity of α-Particle-Induced Chromosome Aberrations in Human CD34⁺Cells