Effect of low doses of low-intensity ionizing radiation on the DNA structure and functions

Chronic effects of low doses of low intensity ionizing radiation (IR) on biological objects have now become of great social significance. This has given a considerable impetus to research into biological effects and mechanisms of such exposures both in Russia and abroad. This paper provides an overview of physicochemical and molecular bases of the IR influence at small doses and the ways of cell protection from the radiation damage, as well as the analysis of characteristic features and differences in the effects of radiation at small and high doses. We consider the DNA radiation damage both in cell cultures and in vivo, as well as processes and results of their repair. Particular attention is paid to the changes in the basic paradigms of radiation biological effects of small doses.     

Mathematical analysis of genetic effects of low doses of ionizing radiation

The comparative study of effects of low doses of radiation on peripheral blood lymphocytes of persons occupationally exposed to radiation and non-exposed ones was carried out. The main attention was paid to radio-adaptive response forming under consistent exposure to low (0.05 Gy) and damaging (2 Gy) doses of gamma-irradiation. Noticeable heterogeneity in capacity for adaptive response forming in occupational group was revealed. The mathematical model adequate to experimental material was constructed using Kohonen neuronets.     

Cytogenetic effects in children exposed to low doses of ionizing radiation

The obtained data indicate that frequencies of different types of cytogenetic anomalies in investigated children groups living in radionuclide contaminated territories and children irradiated in utero have complicated patterns. The frequency of chromosomal anomalies in the investigated groups of children exceeds the average population level. At the same time, no statistically significant differences in frequencies of various types aberrations between groups of children were revealed.     

Early effects of low doses of ionizing radiation on the fetal cerebral cortex in rats

Pregnant rats were exposed to gamma radiation from a 137Cs irradiator on gestational Day 15. Fetuses that received 0.25, 0.5, 0.75, or 1.0 Gy were examined 24 h after irradiation for changes in the cells of the cerebral mantle of the developing brain. The extent of changes following 0.5 Gy was studied at 3, 6, 12, or 24 h after exposure. Cortical thickness of the cerebral mantle was not significantly altered. The number of pyknotic cells, number of macrophages, nuclear area, and number of mitotic cells were altered in a dose-related way. The number of pyknotic cells was significantly increased at all doses. A positive correlation between the number of pyknotic cells and the number of macrophages developed with time. At 3 h after irradiation about 60% of pyknotic cells were found in the subventricular zone and about 25% in the intermediate zone and cortical plate. The number of such cells in the upper layers of the cortex steadily increased up to 24 h, at which time about 70% of pyknotic cells were in these two layers. The relationship of the movement of pyknotic cells to migration of postmitotic neuroblasts is discussed.     

Carcinogenesis in laboratory mice after low doses of ionizing radiation

Experimental data on the incidence of solid tumors from various long-term mouse studies performed at the Casaccia laboratories over several years were reconsidered, limiting the analysis to the results available for doses equal to or less than 17 cGy of neutrons and 32 cGy of X rays since these dose limits are reasonably close to the generally accepted low-dose levels for high- and low-LET radiation (i.e. D(high-LET) < 5 cGy and D(low-LET) < 20 cGy, respectively). The following long-term experiments with BC3F1 mice were reviewed: (a) females treated with single doses of 1.5 MeV neutrons or 250 kVp X rays, (b) males treated with fractionated doses of fission neutrons, and (c) mice of both sexes irradiated in utero 17.5 days post coitus with single doses of fission neutrons or X rays. An experiment with CBA mice of both sexes treated with single doses of fission neutrons was also included in this study. Analysis was done on animals at risk; thus all incidences of tumor-bearing animals were expressed as the percentage excess incidence with respect to the controls. Ovarian tumors and other solid neoplasms were considered. The percentage frequencies and mean survival times of tumor-free mice were also recalculated. The results indicate the existence of a region at low doses where the final incidence of solid neoplasms is indistinguishable from the background incidence. These data reinforce the idea that at low doses the effectiveness of ionizing radiation in inducing solid neoplasms in laboratory mice is very low.     

Reduced oxygen enhancement ratio at low doses of ionizing radiation

A decreased oxygen enhancement ratio (OER) at lower radiation doses has been previously reported (B. Palcic, J. W. Brosing, and L. D. Skarsgard, Br. J. Cancer 46, 980-984 (1984]. The question remained whether or not this effect is due to a possible oxygen contamination at low doses, which was not the case at high doses. To ensure a sufficient degree of hypoxia prior to the start of irradiation, Chinese hamster cells (CHO) were made hypoxic by gas exchange combined with metabolic consumption of oxygen at 37 degrees C. At the same time oxygen levels in cell suspension were measured using a Clark electrode. It was found that under experimental conditions used in this laboratory for hypoxic irradiations, the oxygen levels before the start of irradiation are always below the levels which could give any significant enhancement to radiation inactivation by X rays. Full survival curves were determined in the dose range 0-30 Gy using the conventional survival assay and in the dose range 0-3 Gy using the low dose survival assay. The results confirmed the earlier finding that the OER decreases at low doses. It is therefore believed that the dose-dependent OER is a true radiobiological phenomenon and not an artifact of the experimental method used in the low dose survival assay.     

Characteristic cytogenetic effects of small doses of ionizing radiation

A study was made of the frequency of chromosome aberrations in human lymphocyte culture after gamma-irradiation (60Co) with doses ranging from 0.05 to 1.0 Gy at dose--rates of 0,005, 0.05 and 0.5 Gy/min. The frequency of structural changes in chromosomes at low doses was higher than it was expected in the case of extrapolating the effect produced by high to low doses of radiation; within the dose range from 0.1 to 0.5 Gy a plateau was registered for aberrations of the exchange type (dicentrics and rings). The abnormal character of the dose dependence of the yield of chromosome aberrations persisted with all three dose - rates under study.     

Response of hippocampal pacemaker-like neurons to low doses of ionizing radiation

Spontaneous discharges of hippocampal pacemaker-like neurons are induced by X- and gamma-rays doses lower than 0.8 cGy. The effect is direct and connected with the activation of an endogenous mechanism of unit activity generation.     

DNA damage responses at low radiation doses

Increased cell killing after exposure to low acute doses of X rays (0-0.5 Gy) has been demonstrated in cells of a number of human tumor cell lines. The mechanisms underlying this effect have been assumed to be related to a threshold dose above which DNA repair efficiency or fidelity increases. We have used cells of two radioresistant human tumor cell lines, one that shows increased sensitivity to low radiation doses (T98G) and one that does not (U373), to investigate the DNA damage response at low doses in detail and to establish whether there is a discontinuous dose response or threshold in activation of any important mediators of this response. In the two cell lines studied, we found a sensitive, linear dose response in early signaling and transduction pathways between doses of 0.1 and 2 Gy with no evidence of a threshold dose. We demonstrate that ATM-dependent signaling events to downstream targets including TP53, CHK1 and CHK2 occur after doses as low as 0.2 Gy and that these events promote an effective damage response. Using chemical inhibition of specific DNA repair enzymes, we show that inhibition of DNA-PK-dependent end joining has relatively little effect at low (<1 Gy) doses in hyper-radiosensitive cells and that at these doses the influence of RAD51-mediated repair events may increase, based on high levels of RAD51/BRCA2 repair foci. These data do not support a threshold model for activation of DNA repair in hyper-radiosensitive cells but do suggest that the balance of repair enzyme activity may change at low doses.     

Non-monotonous dose-response relationship in the region of low doses of ionizing radiation

The statement about nonmonotony of dose-effect curves as a result of nonmonotony of the time-effect relationship including the field of low doses is discussed. The living cells possess a fundamental property to response to action of different stress agents by oscillatory--nonmonotonous--hanges of metabolism. The systems keeping up homeostasis by direct and feed-back regulation return metabolism to norm. In the fixed temporary point a dose-effect dependence may take the nonmonotonous character e.g. reverse dose-response relationship. The changes of the oscillation parameters suggested the inclusion of the different pathway for homeostasis keeping. Radiation hormesis does not focused on the metabolic and functional nonmonotonous response. Radiation stimulation is considered as consequence of the peculiarity of the homeostasis maintenance pathways in the certain interval of the low doses of ionizing radiation.