Low-dose ionizing radiation effects on differentiation of HL-60 cells

The biological effects of low-dose radiation have attracted attention, but data are currently insufficient to fully understand the beneficial role of the phenomenon. In the present study, we have investigated the effects of low doses of gamma-irradiation alone and in combination with all-trans-retinoic acid (RA) on proliferation, apoptosis and differentiation of the human promyelocytic leukemia HL-60 cells. Changes in cell behavior and protein expression were determined with the use of light and fluorescent microscopy, immunocytochemical and Western blot analysis. Low-dose irradiation with 1–100 cGy caused a dose-dependent inhibition of HL-60 cell proliferation, and induced apoptosis and differentiation to granulocytes with an increase in the number of CD15-positive cells. Pre-irradiation with 1–100 cGy for 24 h before treatment with RA promoted apoptosis but did not impair RA-induced differentiation. Both processes were associated with a decrease in the expression of the proliferating cell nuclear antigen (PCNA), BCL-2, c-MYC, and changes in both cytosolic and nuclear levels of protein tyrosine-phosphorylation as well as protein kinase C alpha or beta isoforms. These results demonstrate the beneficial role of low-dose irradiation in modulating leukemia cell proliferation, differentiation and apoptosis.     

Cell-density dependent effects of low-dose ionizing radiation on E. coli cells

The changes in genome conformational state (GCS) induced by low-dose ionizing radiation in E. coli cells were measured by the method of anomalous viscosity time dependence (AVTD) in cellular lysates. Effects of X-rays at doses 0.1 cGy--1 Gy depended on post-irradiation time. Significant relaxation of DNA loops followed by a decrease in AVTD. The time of maximum relaxation was between 5-80 min depending on the dose of irradiation. U-shaped dose response was observed with increase of AVTD in the range of 0.1-4 Gy and decrease in AVTD at higher doses. No such increase in AVTD was seen upon irradiation of cells at the beginning of cell lysis while the AVTD decrease was the same. Significant differences in the effects of X-rays and gamma-rays at the same doses were observed suggesting a strong dependence of low-dose effects on LET. Effects of 0.01 cGy gamma-rays were studied at different cell densities during irradiation. We show that the radiation-induced changes in GCS lasted longer at higher cell density as compared to lower cell density. Only small amount of cells were hit at this dose and the data suggest cell-to-cell communication in response to low-dose ionizing radiation. This prolonged effect was also observed when cells were irradiated at high cell density and diluted to low cell density immediately after irradiation. These data suggest that cell-to-cell communication occur during irradiation or within 3 min post-irradiation. The cell-density dependent response to low-dose ionizing radiation was compared with previously reported data on exposure of E. coli cells to electromagnetic fields of extremely low frequency and extremely high frequency (millimeter waves). The body of our data show that cells can communicate in response to electromagnetic fields and ionizing radiation, presumably by reemission of secondary photons in infrared-submillimeter frequency range.     

The psychological effects of ionizing radiation

This paper presents a case study of eleven men who were exposed to non-background ionizing radiation as active participants in the United States' atmospheric nuclear tests. Each of the subjects has developed a virtually identical complex of debilitating psychiatric symptoms. The content of these symptoms is almost entirely focused upon the health effects of the radiation to which each of the subjects was exposed. This symptom complex appears to comprise a syndrome. The symptom structure and course of this syndrome suggests three hypotheses: The syndrome appears to be a pathological development of the self diagnostic belief (that one has been physically harmed by radiation) into a set of symptoms that elaborate upon and express this belief. The self diagnostic belief develops as a means of resolving any one of the various medical mysteries that an individual can experience subsequent to exposure to radiation. Development of the syndrome is a consequence of exposure to non-background ionizing radiation. The paper discusses the evidence for these hypotheses and suggests future research directions.     

The induction by ionizing radiation of chromosomal aberrations in rhesus monkey pre-meiotic germ cells: effects of dose rate and radiation quality

The induction of reciprocal translocations in rhesus monkey stem-cell spermatogonia was studied using multivalent analysis at metaphase of primary spermatocytes. Animals were exposed to 1 Gy gamma-rays at dose rates of 140 and 0.2 mGy/min or to 0.25 Gy acute 2 MeV neutrons. Reduction of the dose rate from 140 mGy/min to 0.2 mGy/min did not result in a lowering of the frequencies of recovered translocations of 0.43%. The neutron data indicated an RBE (neutrons vs. X-rays) of 2.1, which is clearly lower than the value of 4 obtained in the mouse. It is made plausible that in general mammalian species with high sensitivities for the cytotoxic effects of ionizing radiation, such as the rhesus monkey, will exhibit relatively high threshold dose rates below which no further reduction in aberration yield occurs, whereas in more resistant species, such as the mouse, the threshold dose rate will be at a very low level. Similarly, resistant species will show relatively high RBE values for neutron irradiation and sensitive species low ones.     

Membrane effects of ionizing radiation and hyperthermia

Results of numerous studies demonstrate that membranes are important sites of cell damage by both ionizing radiation and hyperthermia. Modification of membrane properties (mainly lipid fluidity) affects the cellular responses to radiation and hyperthermia but former concepts that membrane rigidification sensitizes cells to radiation while membrane fluidization potentiates hyperthermic damage have now been seriously challenged. It seems that the effects of membrane fluidity on cell responses to hyperthermia and radiation are due to an indirect influence on functional membrane proteins. The major role of lipid peroxidation in radiation damage to membranes has also been questioned. The existing evidence makes it unlikely that the interaction between radiation and hyperthermia is determined by the action of both agents on the same membrane components.     

The acute effects of ionizing radiation on DNA synthesis and the development of antibody-producing cells

Ionizing radiation inhibited the development of specific haemolysin-producing cells (PFC) and depressed the incorporation of (3H) thymidine by rabbit spleen explants responding to SRC in the culture medium. In contrast to these effects, the rates of incorporation of precursors for protein and RNA synthesis were much less affected. The depression of (3H) thymidine incorporation was found to result from a quantitative reduction of new DNA synthesis, without any change in the proportion of labelled cells, at any time after irradiation. The DNA synthesis occurring in these cells preparing to develop antibody-producing capacity was thus radio-sensitive, but the exact nature of the defect resulting from exposure to radiation requires further study.     

Non-targeted bystander effects induced by ionizing radiation

Radiation-induced bystander effects refer to those responses occurring in cells that were not subject to energy deposition events following ionizing radiation. These bystander cells may have been neighbors of irradiated cells, or physically separated but subject to soluble secreted signals from irradiated cells. Bystander effects have been observed in vitro and in vivo and for various radiation qualities. In tribute to an old friend and colleague, Anthony V. Carrano, who would have said "well what are the critical questions that should be addressed, and so what?", we review the evidence for non-targeted radiation-induced bystander effects with emphasis on prevailing questions in this rapidly developing research field, and the potential significance of bystander effects in evaluating the detrimental health effects of radiation exposure.     

The effect of dose rate on radiation-induced neoplastic transformation in vitro by low doses of low-LET radiation

The dependence of the incidence of radiation-induced cancer on the dose rate of the radiation exposure is a question of considerable importance to the estimation of risk of cancer induction by low-dose-rate radiation. Currently a dose and dose-rate effectiveness factor (DDREF) is used to convert high-dose-rate risk estimates to low dose rates. In this study, the end point of neoplastic transformation in vitro has been used to explore this question. It has been shown previously that for low doses of low-LET radiation delivered at high dose rates, there is a suppression of neoplastic transformation frequency at doses less than around 100 mGy. In the present study, dose-response curves up to a total dose of 1000 mGy have been generated for photons from (125)I decay (approximately 30 keV) delivered at doses rates of 0.19, 0.47, 0.91 and 1.9 mGy/min. The results indicate that at dose rates of 1.9 and 0.91 mGy/min the slope of the induction curve is about 1.5 times less than that measured at high dose rate in previous studies with a similar quality of radiation (28 kVp mammographic energy X rays). In the dose region of 0 to 100 mGy, the data were equally well fitted by a threshold or linear no-threshold model. At dose rates of 0.19 and 0.47 mGy/min there was no induction of transformation even at doses up to 1000 mGy, and there was evidence for a possible suppressive effect. These results show that for this in vitro end point the DDREF is very dependent on dose rate and at very low doses and dose rates approaches infinity. The relative risks for the in vitro data compare well with those from epidemiological studies of breast cancer induction by low- and high-dose-rate radiation.     

Combined action of ultrasound and ionizing radiation on yeast cells

Summary This communication reports the observation of synergistic relationships between ultrasound and gamma-irradiation of stationary phase cultures ofSaccharomyces cerevisiae of different strains. The gamma-ray dose was applied before or after the sound. The extent of synergism depended upon the sequence of application; it was smaller for (US +-ray)-exposure in comparison with (-ray + US)-treatment. The combined action of both modalities had smaller or no synergistic effect for mutant (rad51) yeast cells incapable of recovery. On this basis, it was concluded that possible mechanisms for ultrasound radiosensitization of yeast cells may involve the reduced capacity of cells to recover damages resulted from the combined action and/or the enhanced expression of lethal damage.     

Sensitivity to low-dose/low-LET ionizing radiation in mammalian cells harboring mutations in succinate dehydrogenase subunit C is governed by mitochondria-derived reactive oxygen species

It has been hypothesized that ionizing radiation-induced disruptions in mitochondrial O? metabolism lead to persistent heritable increases in steady-state levels of intracellular superoxide (O?(?U+2212)) and hydrogen peroxide (H?O?) that contribute to the biological effects of radiation. Hamster fibroblasts (B9 cells) expressing a mutation in the gene coding for the mitochondrial electron transport chain protein succinate dehydrogenase subunit C (SDHC) demonstrate increases in steady-state levels of O??- and H?O?. When B9 cells were exposed to low-dose/low-LET radiation (5-50 cGy), they displayed significantly increased clonogenic cell killing compared with parental cells. Clones derived from B9 cells overexpressing a wild-type human SDHC (T4, T8) demonstrated significantly increased surviving fractions after exposure to 5-50 cGy relative to B9 vector controls. In addition, pretreatment with polyethylene glycol-conjugated CuZn superoxide dismutase and catalase as well as adenoviral-mediated overexpression of MnSOD and/or mitochondria-targeted catalase resulted in significantly increased survival of B9 cells exposed to 10 cGy ionizing radiation relative to vector controls. Adenoviral-mediated overexpression of either MnSOD or mitochondria-targeted catalase alone was equally as effective as when both were combined. These results show that mammalian cells over expressing mutations in SDHC demonstrate low-dose/low-LET radiation sensitization that is mediated by increased levels of O??- and H?O?. These results also support the hypothesis that mitochondrial O??- and H?O? originating from SDH are capable of playing a role in low-dose ionizing radiation-induced biological responses.     

Non-parametric estimation of thresholds for radiation effects in vertebrate species under chronic low-LET exposures

Databases on effects of chronic low-LET radiation exposure were analyzed by non-parametric statistical methods, to estimate the threshold dose rates above which radiation effects can be expected in vertebrate organisms. Data were grouped under three umbrella endpoints: effects on morbidity, reproduction, and life shortening. The data sets were compiled on a simple ‘yes’ or ‘no’ basis. Each data set included dose rates at which effects were reported without further details about the size or peculiarity of the effects. In total, the data sets include 84 values for endpoint “morbidity”, 77 values for reproduction, and 41 values for life shortening. The dose rates in each set were ranked from low to higher values. The threshold TDR5 for radiation effects of a given umbrella type was estimated as a dose rate below which only a small percentage (5%) of data reported statistically significant radiation effects. The statistical treatment of the data sets was performed using non-parametric order statistics, and the bootstrap method. The resulting thresholds estimated by the order statistics are for morbidity effects 8.1 × 10⁻⁴ Gy day⁻¹ (2.0 × 10⁻⁴–1.0 × 10⁻³), reproduction effects 6.0 × 10⁻⁴ Gy day⁻¹ (4.0 × 10⁻⁴–1.5 × 10⁻³), and life shortening 3.0 × 10⁻³ Gy day⁻¹ (1.0 × 10⁻³–6.0 × 10⁻³), respectively. The bootstrap method gave slightly lower values: 2.1 × 10⁻⁴ Gy day⁻¹ (1.4 × 10⁻⁴–3.2 × 10⁻⁴) (morbidity), 4.1 × 10⁻⁴ Gy day⁻¹ (3.0 × 10⁻⁴–5.7 × 10⁻⁴) (reproduction), and 1.1 × 10⁻³ Gy day⁻¹ (7.9 × 10⁻⁴–1.3 × 10⁻³) (life shortening), respectively. The generic threshold dose rate (based on all umbrella types of effects) was estimated at 1.0 × 10⁻³ Gy day⁻¹.