Nonmonotonous Changes in Metabolic Parameters of Tissues and Cells under Action of Ionizing Radiation on Animal

A nonmonotonous relationship between changes of metabolic parameters of tissues and cells of animal and radiation dose were discussed. Under acute irradiation of animals the nonmonotonous dose-response curve for metabolic parameters of tissues and cells were found. The nonmonotonous dose-response curves of metabolic and functional tissues and cells parameters were also revealed upon chronic irradiation of animals at a low dose-rate. The nonmonotonous shape of dose-response curves may be explained on the basis of nonmonotonous kind of the time-course of metabolic response after irradiation. Living cells were supposed to possess a fundamental property in response to action of different stress agents by nonmonotonous changes of cell metabolism. This response was damping in time oscillation of the value of metabolic parameters around the normal level. Amplitudes and periods of oscillations in these changes of metabolic parameters could be observed. In case of chronic irradiation at a low dose-rate the metabolic and functional parameters showed some modified oscillation during irradiation. The nonmonotonous type of changes in metabolic and functional parameters of tissue and cell by chronic low dose-rate irradiation threw some new light on the peculiarities of biological effects of chronic irradiation.     

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.     

Methodological aspects of the problem of nonmonotonic dose-effect dependence

Considered are the methodological bases of two radiobiological theories—target theory and structural-metabolic theory. The target theory states the existence in the cell of a biologically significant structure (sensitive volume) and the monotonic “dose-effect“ dependence. In the structural-metabolic theory at the molecular level the unity of structure and metabolism is postulated. Discussed is the role of homeostatic mechanisms in the nonmonotonicity of the “time-effect” dependence. The nonmonotonicity of the “dose-effect” dependence for metabolic and functional parameters of cells and tissues is stipulated by the non-monotonicity in time of the metabolic and functional response to the action of ionizing radiation.     

Effects of single gamma-irradiation on the activity of ornithine decarboxylase in the thymus and pulmonary tissue]

In studying the dose (0.1-6 Gy) and time (2 h to 180 days) dependence of ornithine decarboxylase activity, it was found that deviations from the control were more pronounced in the thymus than in the pulmonary tissue. The radiation effect was a function of dose and time after irradiation. A nonmonotonous type of the dose-response curve was observed 7 days after irradiation: the radiation effect with a low dose (0.1 Gy) was opposite to that with sublethal doses (1-6 Gy).     

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.     

Ionizing Radiation Impairs T Cell Activation by Affecting Metabolic Reprogramming

Ionizing radiation has a variety of acute and long-lasting adverse effects on the immune system. Whereas measureable effects of radiation on immune cell cytotoxicity and population change have been well studied in human and animal models, little is known about the functional alterations of the surviving immune cells after ionizing radiation. The objective of this study was to delineate the effects of radiation on T cell function by studying the alterations of T cell receptor activation and metabolic changes in activated T cells isolated from previously irradiated animals. Using a global metabolomics profiling approach, for the first time we demonstrate that ionizing radiation impairs metabolic reprogramming of T cell activation, which leads to substantial decreases in the efficiency of key metabolic processes required for activation, such as glucose uptake, glycolysis, and energy metabolism. In-depth understanding of how radiation impacts T cell function highlighting modulation of metabolism during activation is not only a novel approach to investigate the pivotal processes in the shift of T cell homeostasis after radiation, it also may lead to new targets for therapeutic manipulation in the combination of radiotherapy and immune therapy. Given that appreciable effects were observed with as low as 10 cGy, our results also have implications for low dose environmental exposures.     

Quantitative regularities of development of endogenous infection in irradiated organism (survey of literature)

Statistical analysis of data from the literature and the author's own experimental results was carried out in order to reveal functional dependence between the dose of irradiation and the development of endogenous infection in an irradiated organism. Direct linear dependence was established between the dose of irradiation and the severity of endogenous infection at doses causing death from the "bone-marrow" syndrome in acute radiation sickness. In the case of death from the "intestinal" syndrome, inverse linear dependence can be observed between the dose of irradiation and the culture yield of microbes from internal organs. In this case, the pathological effect on the organism is due to bacterial endotoxins formed during disintegration of microbial cells in the organism. Endogenous infection and endotoxinaemia essentially aggravate the course of acute radiation disease. The importance of endogenous infection in death of the organism is neutralized after irradiation in doses causing death "under the ray".     

Manifestation of radiation effects in cold environment: data review and modeling

The peculiarities of radiation response in animals at low environmental temperatures are analyzed in the context of radiation safety of the Arctic/Northern wildlife. The paper includes a data review on radiation effects in cold environments based on international and Russian publications since 1948, which forms a supplement to the EPIC and FREDERICA data collections. In homoiothermic and heterothermic animals, imbalances in thermoregulation caused by ionizing radiation are discussed, which increase energy loss of animals, and decrease their fitness to the Arctic/Northern climate. In poikilothermic animals, both radiation damage and recovery are temperature dependant, their rates being slow in the cold environment. At low temperatures, radiation damage of biological tissues is conserved in hidden form; when the temperature of poikilothermic animal rises to a normal level, radiation injury is developed rapidly similar to acute dose response. Additionally, a mathematical model is described, demonstrating the combined effects of chronic radiation exposures and seasonal temperature variations on a fish population. Computer simulations show that at the same level of irradiation, the overall radiation damage to Arctic/Northern poikilothermic fish is higher than that to the fish from warm climate. Considering the peculiarities of radiation effects in the cold climate, the Arctic/Northern fauna might be expected to be more vulnerable to chronic radiation stress compared to temperate fauna. In the case of acute radiation exposure during winter periods, hibernation of heterothermic and cooling of poikilothermic animals may provide temporary protection from acute radiation effects.     

The effect of ionizing radiation with low dose rate on the state of electron transfer chain of enterocyte mitochondria of rat small intestine

The influence of ionizing radiation with low absorbed dose rate (55 mGy x min(-1)) in 1, 12 and 24 hours after irradiation in doses of 0.1; 0.5 and 1.0 Gy on functional state of the electron transfer chain of the rat small intestine mitochondria was investigated by assessment of the oxygen consumption rate. The uncoupling of oxidation and phosphorylation, a decrease of phosphorylation rate and inhibition of ATP hydrolysis reactions were established in mitochondria in dependence on the irradiation dose and time interval after irradiation. The functional peculiarities of the oxidation-phosphorylation coupling sites of the mitochondrial electron transfer chain were detected.     

Functional changes in the rat distal colon after whole-body irradiation: dose-response and temporal relationships

The aim of this study was to determine the acute radiation response of the rat distal colon by in vivo and in vitro measurements of the functions of the colon over a range of radiation doses. Rats received a whole-body irradiation of 2 to 12 Gy and were studied from 1 to 7 days after exposure. In vivo water and electrolyte absorption was measured by insertion of an agarose cylinder in the colon of anesthetized rats. In vitro transepithelial electrical parameters (potential difference, short-circuit current, transepithelial conductance) were measured in Ussing chambers in basal and agonist-stimulated conditions. In vivo and in vitro functional studies were completed by standard histological analyses. The majority of functional modifications appeared at 4 days after exposure. At this time, a dose-dependent decrease in absorption of water and sodium/chloride ions in the colon was noted. In contrast, a twofold increase in potassium secretion was observed for every radiation dose studied. The response to secretagogues was attenuated at doses >8 Gy. Modifications of basal transepithelial electrical parameters together with marked histological alterations were observed at 4 days with the higher doses (>/=10 Gy). In conclusion, these results show that functions of the colon are affected by irradiation and may contribute to diarrhea induced by ionizing radiation.     

Exploring the link between ceramide and ionizing radiation

The aim of radiotherapy is to eradicate cancer cells with ionizing radiation; tumor cell death following irradiation can be induced by several signaling pathways, most of which are triggered as a consequence of DNA damage, the primary and major relevant cell response to radiation. Several lines of evidence demonstrated that ceramide, a crucial sensor and/or effector of different signalling pathways promoting cell cycle arrest, death and differentiation, is directly involved in the molecular mechanisms underlying cellular response to irradiation. Most of the studies strongly support a direct relationship between ceramide accumulation and radiation-induced cell death, mainly apoptosis; for this reason, defining the contribution of the multiple metabolic pathways leading to ceramide formation and the causes of its dysregulated metabolism represent the main goal in order to elucidate the ceramide-mediated signaling in radiotherapy. In this review, we summarize the current knowledge concerning the different routes leading to ceramide accumulation in radiation-induced cell response with particular regard to the role of the enzymes involved in both ceramide neogenesis and catabolism. Emphasis is placed on sphingolipid breakdown as mechanism of ceramide generation activated following cell irradiation; the functional relevance of this pathway, and the role of glycosphingolipid glycohydrolases as direct targets of ionizing radiation are also discussed. These new findings add a further attractive point of investigation to better define the complex interplay between sphingolipid metabolism and radiation therapy.     

Neoplastic transformation in vitro by low doses of ionizing radiation: role of adaptive response and bystander effects

The shape of the dose-response curve for cancer induction by low doses of ionizing radiation is of critical importance to the assessment of cancer risk at such doses. Epidemiologic analyses are limited by sensitivity to doses typically greater than 50-100 mGy for low LET radiation. Laboratory studies allow for the examination of lower doses using cancer-relevant endpoints. One such endpoint is neoplastic transformation in vitro. It is known that this endpoint is responsive to both adaptive response and bystander effects. The relative balance of these processes is likely to play an important role in determining the shape of the dose-response curve at low doses. A factor that may influence this balance is cell density at time of irradiation. The findings reported in this paper indicate that the transformation suppressive effect of low doses previously seen following irradiation of sub-confluent cultures, and attributed to an adaptive response, is reduced for irradiated confluent cultures. However, even under these conditions designed to optimize the role of bystander effects the data do not fit a linear no-threshold model and are still consistent with the notion of a threshold dose for neoplastic transformation in vitro by low LET radiation.     

Some effects of radiation hormesis for bacterial and yeast cells

A comparative study of chronic and acute action of ionizing radiation on the processes of aging and dying off of bacterial and yeast cells was carried out. It was ascertained that chronic action of ionizing radiation, 2-10,000 times exceeded the natural background, resulted in slowing down of aging and dying off of both pro- and eukaryotic cells. A single acute irradiation of yeast also resulted in the retardation of dying off of the yeast cells surviving after irradiation. The data is presented demonstrating a great increase in the survival of yeast cells under their repeated irradiation after recovery from potentially lethal radiation.     

Issues and epidemiological evidence regarding radiation-induced thyroid cancer.

The available information on the induction of thyroid cancer in humans by ionizing radiation is summarized and weaknesses or gaps in assessing risk are identified. Issues to be addressed include: average estimates of thyroid cancer risk from external irradiation, the effects of age on thyroid cancer induction, shape of the dose-response curve for acute irradiation, magnitude of risk at low doses, effects of dose fractionation or dose protraction, the relative effectiveness of iodine-131 (131I) in inducing thyroid cancer compared to external radiation, the temporal course of radiogenic thyroid cancer risk, mortality caused by thyroid cancer, host-susceptibility factors for radiogenic thyroid cancer, and biological factors in risk. It is concluded that the most important needs are to obtain more information on thyroid cancer risks following low-level or highly fractionated radiation exposures and following 131I exposure in children.     

Activation of the DNA repair system in tissues of mice subjected to chronic gamma irradiation

Mice exposed to gamma-quanta during 47 and 82 days at a dose-rate of 1.3 mGy/h and cumulative doses of 1.45 and 2.54 Gy, respectively, were subsequently subjected to a single acute irradiation with a dose of 20 Gy. Repair of DNA damages induced by the acute exposure was shown to proceed in the brain, pulmonary and splenic tissues of chronically exposed mice more readily than in the tissues of mice not subjected to chronic irradiation. The data obtained indicate that the induced adaptive response activates DNA repair in tissues of mice exposed to long-term low-level radiation.     

DNA double-strand breaks in human lymphocytes after single irradiation by low doses of pulsed X-rays: non-linear dose-response relationship

Effects of ionizing radiation registered in cells after low dose irradiation are still poorly understood. A pulsed mode of irradiation is even more problematic in terms of predicting the radiation-induced response in cells. Thus, the aim of this paper was to study and analyze the effects of dose and frequency of pulsed X-rays on the frequency of radiation-induced DNA double-strand breaks and their repair kinetics in human peripheral blood lymphocytes in vitro. Analysis of radiation-induced gammaH2AX and 53BP1 repair foci was used to assess the DNA damage in these cells. The dose-response curve of radiation-induced foci of both proteins has shown deviations from linearity to a higher effect in the 12-32 mGy dose range and a lower effect at 72 mGy. The dose-response curve was linear at doses higher than 100 mGy. The number of radiation-induced gammaH2AX and 53BP1 foci depended on the frequency of X-ray pulses: the highest effect was registered at 13 pulses per second. Moreover, slower repair kinetics was observed for those foci induced by very low doses with a nonlinear dose-response relationship.     

The Cosmic Silence experiment: on the putative adaptive role of environmental ionizing radiation

Previously we reported that yeast and Chinese hamster V79 cells cultured under reduced levels of background environmental ionizing radiation show enhanced susceptibility to damage caused by acute doses of genotoxic agents. Reduction of environmental radiation dose rate was achieved by setting up an underground laboratory at Laboratori Nazionali del Gran Sasso, central Italy. We now report on the extension of our studies to a human cell line. Human lymphoblastoid TK6 cells were maintained under identical in vitro culture conditions for six continuous months, at different environmental ionizing radiation levels. Compared to “reference” environmental radiation conditions, we found that cells cultured in the underground laboratories were more sensitive to acute exposures to radiation, as measured both at the level of DNA damage and oxidative metabolism. Our results are compatible with the hypothesis that ultra-low dose rate ionizing radiation, i.e. environmental radiation, may act as a conditioning agent in the radiation-induced adaptive response.     

Phospholipid metabolism in the organs of gamma-irradiated rats

The phospholipid content and incorporation of L-3H-serine and 2-14C-glycerol into phospholipids of the liver, intestine and spleen were studied 48 hr after irradiation of rats with a dose of 8 Gy. The changes in the phospholipid content of the irradiated rat organs were induced by those in the individual phospholipids in the exposed body tissues. This is assumed to be a result of the adaptive reactions of the organism to the damaging effect of ionizing radiation.