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We simulated the irradiation of human fibroblasts with γ rays, protons and helium, carbon and iron ions at a fixed dose of 5 Gy. The simulations were performed with the biophysical Monte Carlo code PARTRAC. From the output of the code, containing in particular the genomic positions of the radiation-induced DNA double-strand breaks (DSBs), we obtained the DNA fragmentation spectra. Very small fragments, in particular those related to “complex lesions” (few tens of base pairs), are probably very important for the late cellular consequences, but their detection is not possible with the common experimental techniques. We paid special attention to the differences among the various ions in the production of these very small fragments; in particular, we compared the fragmentation spectra for ions of the same specific energy and for ions of the same LET (linear energy transfer). As found previously for iron ions, we found that the RBE (relative biological effectiveness) for DSB production was considerably higher than 1 for all high-LET radiations considered. This is at variance with the results obtainable from experimental data, and it is due to the ability to count the contribution of small fragments. It should be noted that for a given LET this RBE decreases with increasing ion charge, due mainly to the increasing mean energy of secondary electrons. A precise quantification of the DNA initial damage can be of great importance for both radiation protection, particularly in open-space long-term manned missions, and hadrontherapy.
Clustered DNA damages are induced by ionizing radiation and are defined as two or more lesions within one or two helical turns. The aim of this study was to investigate the induction and repair of clustered DNA damage in cells with emphasis on the influence of structural differences in the chromatin organization. Human fibroblasts were irradiated with X rays and induced DSBs and clustered damages were quantified using pulsed-field gel electrophoresis combined with postirradiation incubation with the base excision repair endonuclease Fpg, which recognizes oxidized purines and cleaves the strand at sites inducing strand breaks. Hence clustered damages appear in enzyme-treated samples as additional DSBs. The chromatin was modified by different pretreatments that resulted in structures with varying compactness and levels of free radical scavenging capacity. We found that the induction of DSBs and clustered damages increased linearly with dose in all structures and that both types of lesions were allocated randomly within the nucleus. The induction yields increased with decreasing compactness of chromatin, and the chromatin effect was larger for clustered lesions than for DSBs. Clustered damages were processed efficiently with a fast and a slow repair component similar to that for induced DSBs.
The current international paradigm on the biological effects of radiation is based mainly on the effects of dose with some consideration for the dose rate. No allowance has been made for the potential influence of a changing dose rate (second derivative of dose), and the biological effects of exposing cells to changing dose rates have never been analyzed. This paper provides evidence that radiation effects in cells may depend on temporal changes in the dose rate. In these experiments, cells were moved toward or away from an X-ray source. The speed of movement, the time of irradiation, and the temperature during exposure were controlled. Here we report the results of the first experiments with TK6 cells that were exposed at a constant dose rate, at an increasing dose rate, or at a decreasing dose rate. The average dose rate and the total dose were same for all samples. Micronuclei were scored as the end point. The results show that the level of cytogenetic damage was higher in cells exposed to a decreasing dose rate compared to both an increasing and a constant dose rate. This finding may suggest that the second derivative of dose may influence radiation risk estimates, and the results should trigger further studies on this issue.
Electronic brachytherapy systems are being developed that can deliver X rays of varying energy depending on the material of a secondary target. A copper target produces characteristic 8 keV X rays. Our aim was to determine whether 8 keV X rays might deliver greater biological effectiveness than megavoltage photons. Cells of the U251 human glioma cell line were used to compare the biological effects of 8 keV X rays and 60Co γ rays in terms of relative biological effectiveness (RBE), oxygen enhancement ratio (OER), and DNA damage. The RBE at 50% and 10% survival was 2.6 and 1.9, respectively. At 50% survival, the OER for cells treated with 8 keV X rays was 1.6 compared with 3.0 for 60Co γ rays. The numbers of H2AX foci per Gy after treatment with 8 keV X rays and 60Co γ rays were similar; however, the size of the foci generated at 8 keV was significantly larger, possibly indicating more complex DNA damage. The mean area of H2AX foci generated by 8 keV X rays was 0.785 µm2 (95% CI: 0.756–0.814) compared with 0.491 µm2 (95% CI: 0.462–0.520) for 60Co γ rays (P < 0.0001). Characteristic 8 keV X rays produce two to three times the biological effectiveness of megavoltage photons, with a radiobiological profile similar to higher-LET radiations.
Recent studies have suggested a bystander effect in nonirradiated cells adjacent to irradiated cells; however, the mechanism is poorly understood. In this study, we investigated the involvement of both extracellular nucleotides and activation of P2 receptors in cellular responses to γ radiation using human HaCaT keratinocytes. The concentration of ATP in culture medium was increased after γ irradiation (0.1–1.0 Gy), suggesting that radiation induces ATP release from cells. Intracellular Ca2 concentration was elevated when conditioned medium from irradiated cells was transferred to nonirradiated cells, and this elevation was suppressed by apyrase (ecto-nucleotidase), indicating the involvement of extracellular nucleotides in this event. Further, we examined the activation of ERK1/2 by γ radiation and nucleotides (ATP and UTP). Both γ radiation and nucleotides induced activation of ERK1/2. Next, the effect of inhibitors of P2 receptors on radiation-induced activation of ERK1/2 was examined. The activation of ERK1/2 was blocked by suramin (P2Y inhibitor), MRS2578 (P2Y6 antagonist) and apyrase. These results suggest that both released nucleotides and activation of P2Y receptors are involved in γ-radiation-induced activation of ERK1/2. We conclude that ionizing radiation induces release of nucleotides from cells, leading to activation of P2Y receptors, which in turn would result in a variety of biological effects.
We examined the response of the developing mouse intestine to X radiation using neonates (1 day postpartum), infants (2 weeks postpartum) and adults (7 weeks postpartum). Irradiated adult small intestinal crypts displayed two waves of apoptosis. The first wave peaked at 3 h and was followed by a broad wave with a peak persisting from 24 to 48 h. p53 was expressed during the first wave but not the second wave. For the infant small intestine, the intensity of the first wave was approximately half that of the adult wave, and for the colon the intensity was even smaller. In neonates, apoptosis was delayed, peaking at 6 h for small intestinal crypts and at 24 h for colonic crypts. Although no apoptosis occurred at 3 h postirradiation in neonates, p53 was present in both the small intestine and colon, owing at least in part to the inability of p53 to increase the level of Noxa, a p53-dependent pro-apoptosis protein, suggesting a discontinuity in the p53-Noxa-caspase pathway in neonates. By contrast, the induction of p21, a pro-survival protein, was greater in neonatal cells than in adult cells. Thus it appears that the developing and adult intestine mount distinct apoptotic responses to radiation.
Although it is documented that concurrent wounding increases mortality from radiation injury, the molecular mechanism of combined injury is unknown. In this study, mice were exposed to γ radiation followed by skin wounding. Wound trauma exacerbated radiation-induced mortality, reducing the LD50/30 from 9.65 Gy to 8.95 Gy. Analyses of histopathology, inducible nitric oxide synthase (iNOS), and serum cytokines were performed on mouse ileum and skin at various times after 9.75 Gy and/or wounding. In the ileum, the villi were significantly shortened 3 days postirradiation but not after wounding; combined injury resulted in decreased villus width and tunica muscularis thickness. The skin of mice subjected to combined injury was less cellular and had a smaller healing bud than the skin of mice subjected to wounding alone. Combined injury significantly delayed wound closure times; it also prolonged the increased levels of iNOS protein in the skin and ileum. iNOS up-regulation was correlated with increases in transcription factors, including NF-κB and NF-IL6. The increase in NF-IL6 may be due to increases in cytokines, including IL-1β, -6, -8, -9, -10 and -13, G-CSF, eotaxin, INF-γ, MCP-1, MIP-1α and MIP-1β. Combined injury resulted in early detection of bacteria in the blood of the heart and liver, whereas radiation alone resulted in later detection of bacteria; only a transient bacteremia occurred after wounding alone. Results suggest that enhancement of iNOS, cytokines and bacterial infection triggered by combined injury may contribute to mortality. Agents that inhibit these responses may prove to be therapeutic for combined injury and may reduce related mortality.
We previously reported significant increases in body weight in B6C3F1 mice continuously exposed to low-dose-rate (21 mGy/day) γ rays compared to that of nonirradiated control mice (Tanaka et al., Radiat. Res.167, 417–437, 2007). To further study the underlying cause of the increase in body weight, feed consumption, adipose tissue weight, liver and serum lipid contents, and selected factors related to glucose and lipid metabolism such as serum levels of insulin and adipocytokines were examined in female B6C3F1 mice irradiated continuously with γ rays at 20 mGy/day in group-housed or individually housed rearing conditions. Increased body weight, adipose tissue weight, serum levels of leptin, and lipid contents of the liver and serum were observed in both group-housed (accumulated dose = 6 Gy, 43 weeks from start of irradiation) and individually housed (accumulated dose = 4.4 Gy, 31 weeks from start of irradiation) irradiated mice compared to nonirradiated controls. Feed consumption measurements, however, revealed no significant difference between irradiated mice and nonirradiated controls when mice were housed individually. Our results show for the first time that the increase in the body weight of mice continuously irradiated with low-dose-rate γ rays is due to adiposity with no corresponding increase in feed consumption.
An unavoidable complication of space travel is exposure to high-charge, high-energy (HZE) particles. In animal studies, exposure of the CNS to HZE-particle radiation leads to neurological alterations similar to those seen in aging or Alzheimer's disease. In this study we examined whether HZE-particle radiation accelerated the age-related neuronal dysfunction that was previously described in transgenic mice overexpressing human amyloid precursor protein (APP). These APP23 transgenic mice exhibit age-related behavioral abnormalities and deficits in synaptic transmission. We exposed 7-week-old APP23 transgenic males to brain-only 56Fe-particle radiation (600 MeV/nucleon; 1, 2, 4 Gy) and recorded synaptic transmission in hippocampal slices at 2, 6, 9, 14 and 18–24 months. We stimulated Schaeffer collaterals and recorded field excitatory postsynaptic potentials (fEPSP) and population spikes (PS) in CA1 neurons. Radiation accelerated the onset of age-related fEPSP decrements recorded at the PS threshold from 14 months of age to 9 months and reduced synaptic efficacy. At 9 months, radiation also reduced PS amplitudes. At 6 months, we observed a temporary deficit in paired-pulse inhibition of the PS at 2 Gy. Radiation did not significantly affect survival of APP23 transgenic mice. We conclude that irradiation of the brain with HZE particles accelerates Alzheimer's disease-related neurological deficits.
The present study was undertaken to investigate the ability of dietary supplements to reduce the formation and severity of cataracts in mice irradiated with high-energy protons or iron ions, which are important components of the radiation encountered by astronauts during space travel. The mice were exposed to proton or iron-ion radiation and fed with a control diet or diets supplemented with the soybean-derived protease inhibitor, Bowman-Birk inhibitor (BBI), in the form of BBI Concentrate (BBIC) or an antioxidant formulation [containing l-selenomethionine (SeM), N-acetyl cysteine (NAC), ascorbic acid, co-enzyme Q10, α-lipoic acid and vitamin E succinate] both before and after the radiation exposure. At approximately 2 years after the radiation exposure, the animals were killed humanely and lenses were harvested and characterized using an established classification system that assigns discrete scores based on the severity of the lens opacifications. The results showed that exposure to 1 GeV/nucleon proton (3 Gy) or iron-ion (50 cGy) radiation significantly increased the cataract prevalence and severity in CBA/J mice to levels above the baseline levels of age-induced cataract formation in this mouse strain. Treatment with BBIC or the antioxidant formulation significantly reduced the prevalence and severity of the lens opacifications in the mice exposed to iron-ion radiation. Treatment with BBIC or the antioxidant formulation also decreased the severity of the lens opacifications in the mice exposed to proton radiation; however, the decrease did not reach statistical significance. These results indicate that BBIC and the antioxidant formulation evaluated in this study could be useful for protecting astronauts against space radiation-induced cataracts during or after long-term manned space missions.
The recent steep increase in the number of users of cellular phones is resulting in marked increase of exposure of humans to radiofrequency electromagnetic fields (EMFs). Children are of particular concern. Our goal was to evaluate potential adverse effects of long-term whole-body exposure to EMFs simulating those from base stations for cellular phone communication. Pregnant rats were given low, high or no exposure. At the high level, the average specific absorption rate (SAR)for the dams was 0.066–0.093 W/kg. The SAR for the fetuses and the F1 progeny was 0.068–0.146 W/kg. At the low level, the SARs were about 43% of these. The 2.14 GHz signals were applied for 20 h per day during the gestation and lactation periods. No abnormal findings were observed in either the dams or the F1 generation exposed to the EMF or in the F2 offspring. Parameters evaluated included growth, gestational condition and organ weights for dams and survival rates, development, growth, physical and functional development, hormonal status, memory function and reproductive ability of the F1 offspring (at 10 weeks of age) along with embryotoxicity and teratogenicity in the F2 rats. Thus, under our experimental conditions, whole-body exposure to 2.14 GHz for 20 h per day during gestation and lactation did not cause any adverse effects on pregnancy or the development of rats.
This paper reports on the variation of UV radiation in full sun and in shade and how this relates to the physiological production of vitamin D3 for various latitudes. Calibrated spectral measurements were used to measure the UV radiation in the shade of numerous shade environments for varying solar zenith angles and seasons. This was for exposures to the horizontal, 45° and vertical planes for the solar zenith angle (SZA) range of approximately 5° to 80°. For an SZA of approximately 5°, average UV irradiances required for vitamin D3 production (UVD3) were 0.67 W/m2 and 0.20 W/m2 for global and for shade with a sky view of greater than 40%, respectively. The best time to expose the human body to UV radiation while using shaded environments with a sky view of greater than 40% for vitamin D3 synthesis is for SZAs less than approximately 45°. Shade can be used throughout Australia during summer and winter. However, winter exposure times will vary depending on the latitude. Using shade for UVD3 exposures can reduce total UV-radiation exposure by 37% to 58% compared to full sun UVD3 exposures. This research indicates that an improved approach to optimize UV-radiation exposures for the production of vitamin D3 is to use diffuse UV radiation under shade in and around the middle of the day.
The radiation-induced bystander response is defined as a response in cells that have not been directly targeted by radiation but that are in the neighborhood of cells that have been directly exposed. In the work described here, it is shown that bystander cell killing of normal human fibroblast WI-38 cells was induced by synchrotron microbeam X radiation. Cell nuclei in confluent WI-38 cells were irradiated with the microbeam. All of the cells on the dish were harvested and plated 24 h after irradiation. It was found that the bystander cell killing effect showed a parabolic relationship to the radiation dose when five cells were irradiated. At doses above 1.9 Gy, the surviving fraction increased to approximately 1.0. This suggests that induction of bystander cell killing may require some type of activity in the targeted cells, because the dose resulting in 37% cell survival was about 2.0 Gy. Bystander cell killing was suppressed by a pretreatment with aminoguanidine [an inhibitor of inducible nitric oxide (NO) synthase] or carboxy-PTIO (a scavenger of NO). These results suggest that NO is the chief initiator/mediator of bystander cell killing induced by X-ray microbeams.
To establish a basis for a possible strategy for bone marrow ablation or therapy, we examined the effect of bromodeoxyuridine (BrdU) incorporation into DNA on the genotoxic and cytotoxic effects of samarium-153 ethylenediaminetetramethylene phosphonate (153Sm-EDTMP) in normoblasts in vivo. Cytotoxicity and genotoxicity were established by time–response curves of polychromatic erythrocyte (PCE) and micronucleated polychromatic erythrocyte (MN-PCE) frequencies, respectively, in mouse peripheral blood samples. The group treated with 153Sm-EDTMP showed a clear induction of MN-PCEs; however, the group treated with BrdU plus 153Sm-EDTMP paradoxically showed only a slight increase with respect to untreated controls. Treatment with 53Sm-EDTMP caused a small reduction in PCE frequency, but exposure to BrdU or to BrdU plus 53Sm-EDTMP reduced the PCE frequency significantly from 32 h to the end of the experiment. The PCE frequencies in the BrdU plus 53Sm-EDTMP group were significantly lower than in the BrdU control group at the final time and were much lower than the group treated with only 53Sm-EDTMP, which returned to basal values. The results suggest the radioinduction of a lethal lesion in BrdU-substituted DNA that cannot be repaired easily and does not permit cell division and micronucleus formation.
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