Low-dose hypersensitivity: current status and possible mechanisms

Joiner, Michael C.; Marples, Brian; Lambin, Philippe; Short, Susan; Turesson, Ingela

doi:10.1016/s0360-3016(00)01471-1

Cited by 510 publications

(401 citation statements)

References 97 publications

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“…After few cell divisions, irradiated cell cultures show nearly the same level of ␥-H2AX foci but substantially more micronucleated and apoptotic cells than unirradiated controls, suggesting that cells with unrepaired DSBs are eliminated from the culture. This finding is supported by a significant reduction in cell survival after a dose of 1.2 mGy, an observation that may link the presence of residual DSBs to the phenomenon of low-dose hypersensitivity (25). From this point of view, it is tempting to speculate that the observed lack of DSB repair does not increase the carcinogenic risk of very low IR doses but rather represents a protective biological mechanism to reduce it.…”

Section: Discussionmentioning

confidence: 87%

Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses

Rothkamm

Löbrich

2003

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

1,468

1,051

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DNA double-strand breaks (DSBs) are generally accepted to be the most biologically significant lesion by which ionizing radiation causes cancer and hereditary disease. However, no information on the induction and processing of DSBs after physiologically relevant radiation doses is available. Many of the methods used to measure DSB repair inadvertently introduce this form of damage as part of the methodology, and hence are limited in their sensitivity. Here we present evidence that foci of ␥-H2AX (a phosphorylated histone), detected by immunofluorescence, are quantitatively the same as DSBs and are capable of quantifying the repair of individual DSBs. This finding allows the investigation of DSB repair after radiation doses as low as 1 mGy, an improvement by several orders of magnitude over current methods. Surprisingly, DSBs induced in cultures of nondividing primary human fibroblasts by very low radiation doses (Ϸ1 mGy) remain unrepaired for many days, in strong contrast to efficient DSB repair that is observed at higher doses. However, the level of DSBs in irradiated cultures decreases to that of unirradiated cell cultures if the cells are allowed to proliferate after irradiation, and we present evidence that this effect may be caused by an elimination of the cells carrying unrepaired DSBs. The results presented are in contrast to current models of risk assessment that assume that cellular responses are equally efficient at low and high doses, and provide the opportunity to employ ␥-H2AX foci formation as a direct biomarker for human exposure to low quantities of ionizing radiation.

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Section: Discussionmentioning

confidence: 87%

Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses

Rothkamm

Löbrich

2003

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

1,468

1,051

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“…The assay's sensitivity and its demonstrated applicability to CT examinations allow the investigation of normal people without clinical symptoms who are exposed to well defined radiation doses. Thus, the assay has the potential to shed light on the in vivo significance of some radiobiological phenomena that have hitherto been restricted to in vitro measurements, such as the bystander effect (25) or low-dose hypersensitivity (26,27). Moreover, the assessment of ␥-H2AX foci can serve as a biologically relevant biomarker for exposure to low levels of IR.…”

Section: Discussion An Approach To Measure Dsb Induction and Repair Imentioning

confidence: 99%

In vivo formation and repair of DNA double-strand breaks after computed tomography examinations

Löbrich

Rief

Kühne

et al. 2005

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

388

342

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Ionizing radiation can lead to a variety of deleterious effects in humans, most importantly to the induction of cancer. DNA doublestrand breaks (DSBs) are among the most significant genetic lesions introduced by ionizing radiation that can initiate carcinogenesis. We have enumerated ␥-H2AX foci as a measure for DSBs in lymphocytes from individuals undergoing computed tomography examination of the thorax and͞or the abdomen. The number of DSBs induced by computed tomography examination was found to depend linearly on the dose-length product, a radiodiagnostic unit that is proportional to both the local dose delivered and the length of the body exposed. Analysis of lymphocytes sampled up to 1 day postirradiation provided kinetics for the in vivo loss of ␥-H2AX foci that correlated with DSB repair. Interestingly, in contrast to results obtained in vitro, normal individuals repair DSBs to background levels. A patient who had previously shown severe side effects after radiotherapy displayed levels of ␥-H2AX foci at various sampling times postirradiation that were several times higher than those of normal individuals. ␥-H2AX and pulsed-field gel electrophoresis analysis of fibroblasts obtained from this patient confirmed a substantial DSB repair defect. Additionally, these fibroblasts showed significant in vitro radiosensitivity. These data show that the in vivo induction and repair of DSBs can be assessed in individuals exposed to low radiation doses, adding a further dimension to DSB repair studies and providing the opportunity to identify repair-compromised individuals after diagnostic irradiation procedures.␥-H2AX foci ͉ ionizing radiation ͉ low radiation doses ͉ radiosensitivity ͉ blood lymphocytes I onizing radiation (IR) exposure is frequently encountered in a person's life. Sources of natural radiation include cosmic rays that come from outer space and the sun and radioactive substances that exist in earth and inside the human body. In addition to occupational exposure, flights at high altitude, manned space exploration, and radiological terrorism represent significant sources of radiation risk for part of the population. Diagnostic x-ray procedures including screening tests for cancer are the largest man-made source of radiation exposure, accounting for Ϸ14% of the total exposure level worldwide (1-4).Exposure to IR can induce leukemia and other cancers. It is assumed that damage to DNA in the nucleus of a single cell can initiate carcinogenesis. Among the different types of lesions induced, DNA double-strand breaks (DSBs) are considered to be the most relevant of the deleterious effects of IR (5, 6). Remarkably, even a single radiation track and, hence, the smallest possible quantity of IR can produce this kind of damage. Estimates of cancer risk from exposure to IR are based on epidemiological studies of exposed human populations, especially the atomic bomb survivors of Hiroshima and Nagasaki. These studies have provided relatively reliable estimates of risk for moderate to high doses (1, 2). The lowest dose...

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“…Association of this region with factors such as tristetraprolin or AUF1 promotes their rapid degradation through Ub/proteasome pathways (Laroia et al, 2002). Radiation-induced impairment of proteasome activity could also be involved in hypersensitivity, adaptive responses, and bystander effects that have been observed following low-dose irradiation, and about which there is currently little mechanistic information (Joiner et al, 1999(Joiner et al, , 2001Mothersill and Seymour, 2001). …”

Section: Cellular Consequences Of Modulation Of Proteasome Activity Bmentioning

confidence: 99%

The role of the ubiquitin/proteasome system in cellular responses to radiation

et al. 2003

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Low-dose hypersensitivity: current status and possible mechanisms

Cited by 510 publications

References 97 publications

Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses

Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses

In vivo formation and repair of DNA double-strand breaks after computed tomography examinations

The role of the ubiquitin/proteasome system in cellular responses to radiation

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