ISSN 0006 3509, Biophysics, 2011, Vol. 56, No. 3, pp. 577–583. © Pleiades Publishing, Inc., 2011. Original Russian Text © I.I. Pelevina, G.G. Afanas’ev, A.V. Aleshchenko, M.M. Antoshchina,V.Ya. Gotlib, A.A. Konradov, O.V. Kudryashova, E.Yu. Lizunova, A.N. Osipov, N.I. Ryabchenko, A.M. Serebryanyi, 2011, published in Radiatsionnaya Biologiya. Radioekologiya, 2011, Vol. 51, No. 1, pp. 154–161. RADIOBIOLOGY AND RADIOECOLOGY
The Molecular and Cellular Consequences of the Chernobyl Accident I. I. Pelevinaa, G. G. Afanas’eva,†, A. V. Aleshchenkob, M. M. Antoshchinac, V. Ya. Gotliba, A. A. Konradovb,†, O. V. Kudryashovaa, E. Yu. Lizunovaa, A. N. Osipova, N. I. Ryabchenkoc, and A. M. Serebryanyib a Institute of Chemical Physics, Russian Academy of Sciences, Moscow, 119991 Russia b Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, 119334 Russia c Medical Radiological Research Center, Russian Academy of Medical Sciences, Obninsk, 249036 Russia E mail: [email protected] Received July 5, 2010
Abstract—In this paper the results of research at 5–10 and 24 years after the Chernobyl accident are summa rized. These results include the investigation of genomic instability, formation of the adaptive response, genome damage, and oxidative status. The studies were performed on cells in culture, mice, children and adults who lived in the contaminated areas, and liquidators of the consequences of the Chernobyl accident. Inhibition of cell proliferative activity, late cell death, and the increase in micronucleus and giant cell fre quency were observed after the exposure of cells in culture in the accident zone followed by their culturing in laboratory conditions. In the progeny of the exposed cells, the effect of enhanced radiosensitivity was detected. Thus, it can be assumed that exposure of parental cells in culture in the area of the accident induced genomic instability that resulted in the development of various abnormalities in progeny cells. At the organ ism level, the Chernobyl zone exposure of mice caused an increase in radiosensitivity; as well, a decrease in the endotheliocyte density in the cerebral cortex and other brain tissues was observed. In the blood lympho cytes of children stimulated by PHA, a more than two times increase in micronucleus cell frequency was detected. A reduced number of individuals with significant adaptive response was found in both the juvenile and adult groups. In all investigated populations, an increased number of individuals with enhanced radi osensitivity were observed in response to low dose radiation exposure. At 24 years after the accident liquida tors were subjected to examinations, which revealed an increased frequency of cells with micronuclei and chromosome type aberrations in blood lymphocytes, an elevated level of DNA double strand breaks, and a reduced level of reactive oxygen species compared to those of the control group. This means that the genomic instability that was accumulated by the residents of the contaminated regions and liquidators as a result of the accident leads to damage of the genetic apparatus, an increase in radiosensitivity, and hypoxia as late conse quences that all are risk factors and increase the probability of the development of tumor and non tumor dis eases. The development of the above mentioned pathological processes may occur in the distant future.
Keywords: blood lymphocyte, liquidators of the Chernobyl accident consequences, genome instability, cell death, genome damage, reactive oxygen species, late consequences DOI: 10.1134/S0006350911030237
The Chernobyl accident opened a new era of radio The effects of low dose radiation differ from that of biology where much attention has been given to stud high dose exposure. According to the classical model ies of the effects of low dose radiation. Experimental of radiation effects, the response of discrete cell targets is very individual and depends on the number of non research on isolated cells, animals, and lymphocytes repaired and incorrectly DNA lesions. In the modern of individuals who were exposed to irradiation, such as concept, response processes may occur at a distance liquidators or the residents of the contaminated zones, that is greater than the cell size; these responses are played an important role in achieving a better under controlled by cell signaling pathways and a direct hit is standing of post accident effects. These studies enable not a compulsory for cell damage. As a result of this one to gain knowledge of the early and late conse concept change a new approach to the understanding quences of low dose radiation exposure and possible and assessment of the effects of radiation has arisen. mechanisms of their development that allows solving According to this approach, epigenetic abnormalities the problem of the formation and development of the may be the most important event, as it leads to the consequences of the Chernobyl accident. conversion of normal cells into malignant ones with out direct mutations. In non exposed cells, changes in † Deceased. the gene expression, DNA repair, chromosome aber
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Table 1. Cell survival (clonogenic ability) in the progeny of main phenomena that lead to a number of various cells exposed in the 10 kilometer zone around the Cherno consequences [11]. byl Nuclear Power Plant (0.096 Gy total irradiation dose) In this work, the results of many years of research Number In the Chernobyl (at 5–10 years and 24 years after the Chernobyl acci of generations after Control accident zone dent) are summarized. These are data on the cellular initial exposure and cytogenetic manifestations of genomic instability, 6 0.21 0.14* and the formation of the adaptive response, as well as genome damage (the micronucleus test, metaphase 12 0.17 0.06* analysis of chromosome aberrations, and comet assay 18 0.31 0.25 analysis of the number of DNA breaks). All tests were 21 0.36 0.15* carried out either in areas that were contaminated as a 24 0.36 0.15* result of the Chernobyl accident, such as the Cherno byl Nuclear Power Plant near the nuclear reactor, on * The statistically significant difference between the con χ2 the border with the “Red Forest,” or in the Bryansk trol and irradiated populations of cells ( criterion). region (Klintsy, Vyshkov, and Novozybkov areas) or by using biological samples from liquidators of the Cher nobyl accident [12, 13]. The studies were performed Table 2. The number of giant cells (per 1000 cells analyzed) in the progeny of cells exposed in the 10 kilometer zone using mammalian and human cells in culture, the around the Chernobyl Nuclear Power Plant blood lymphocytes of children and adults, and, at the organism level, those of small laboratory animals that Number Time of exposure – total dose were exposed to the environmental conditions of the of generations Control industrial disaster. after initial 1 days – 0.024 Gy 6 days – 0.144 Gy exposure In cells of a tissue culture that were exposed to irra diation in the accident area for 1, 4, or 6 days, then 46270– cultivated under normal laboratory conditions for 650136*– many cell cycle passages, and then subjected to anal 96280– yses of the consequences of genomic instability, inhi bition of cell proliferative activity in a period of six to 14 60 85 – seven generations after cell culture exposure in the 16 49 62 127* Chernobyl zone was observed, as the control level of 24 63 50 154* cell proliferation was achieved only by the eighth gen eration (control cultures were maintained under simi * The statistically significant difference between the control and irradiated populations of cells (χ2 criterion). lar ecological and other conditions in areas that were not contaminated with radionuclides). The number of cells in the control increased by approximately seven rations, mutations, cell death, and radiation induced and a half times, whereas after the above mentioned genome instability occur. The genes that regulate radi exposure the value of the growth factor was two times osensitivity are widely studied in epidemiological smaller. It may be assumed that such inhibition of the proliferative activity in the progeny of the exposed research and risk management as markers of the genetic cells is caused by the induction of genomic instability sensitivity of individuals and populations [1, 2]. and, consequently, an elevated level of cell death in the In the last 15 years, the non targeted effects of low parental culture. This assumption is supported by the dose radiation, such as genomic instability (GI), the fact that the clonogenic ability of cells exposed in the adaptive response (AR), the bystander effect, horme 10 kilometer zone around the Chernobyl Nuclear sis, and, at the organism level, the clastogenic effect, Power Plant is lower than that of non treated cells in have been described [3–10]. the period of 24 generations (Table 1). A very similar situation was observed when the number of giant cells It can be assumed that the problem of the late con was studied as their number increased by more than sequences of the Chernobyl accident is mainly about a two times in the exposed population and does not deep understanding of the effects and mechanisms of decreased in the period of 16–24 generations the actions caused by low dose radiation. It is (Table 2). extremely important that in response to low dose radi Radiosensetivity increase is another important ation GI is induced, which may promote other conse phenomenon that can be classified as a manifestation quences in response to external effects, stress, and of genomic instability; it is detected in the progeny of irradiation in the case of additional load. Therefore, cells exposed in the accident zone. Additional irradia one might suppose that GI induced by low dose radia tion treatment at a 3 Gy dose affects cell survival or the tion in cells of liquidators and residents of the contam clonogenic ability of the progeny of the exposed cells, inated areas of the Chernobyl accident is one of the which becomes significantly lower than that of the
BIOPHYSICS Vol. 56 No. 3 2011 THE MOLECULAR AND CELLULAR CONSEQUENCES OF THE CHERNOBYL 579 control cells (Table 3); at the same time the frequency Table 3. Cell survival (clonogenic ability) in the progeny of cells of cells with micronuclei (MN), as well as giant cells, exposed in the 10 kilometer zone around the Chernobyl had a statistically significant increase in the period of 9 Nuclear Power Plant followed by an additional acute radiation to 12 generations (Table 4). treatment at a dose of 3 Gy These results also suggest that prolonged irradia Number Time of exposure – total dose tion of cells in the radiation contaminated areas has of genera no effect on the induction of the adaptive response, tions after 2 days – 0.048 Gy 4 days – 0.096 Gy which is characterized by an increase of radioresis initial tance, as irradiation of these cells results only in an exposure 3 Gy 0.048 Gy + 3 Gy 3 Gy 0.096 Gy + 3 Gy increase in their radiosensitivity (Tables 3 and 4). 60.16– 0.210.14 A separate series of experiments was performed on 12 0.10 0.03 0.17 0.06 fibroblasts in culture obtained from the embryos of mice that were mated in areas that were contaminated 18 0.26 0.17 0.31 – after the accident. Cytogenetic analysis revealed a sta 21 0.30 0.16 0.36 0.15 tistically significant increase of the number of cells 24 0.27 0.16 0.36 0.15 containing chromosome aberrations, viz., 24.5% compared to 1–3% in the control population. Together with cells containing single chromosome aberrations, cells with multiple aberrations were found Table 4. Micronucleus (MN) and giant cell frequency in and their percentage reached 8% of the total number the progeny of cells exposed for 4 days in the 10 kilometer of metaphase aberrations; moreover, different types of zone around the Chernobyl Nuclear Power Plant (0.096 Gy aberrations were detected, such as fragments and total irradiation dose) and then additionally treated with translocations that were absent in the control. acute radiation at a dose of 3 Gy Therefore, tissue culture cell exposure in the Parameter Generation In the Cher Chernobyl accident area resulted in the induction of (per 1000 cells number after Control nobyl acci GI; in the progeny of exposed cells this leads to inhi analyzed) initial exposure dent zone bition of cell proliferation, cell death, an increase of The number 3109185* micronucleus cell frequency and the amount of giant of cells with MN cells, the loss of AR, and the elevation of cell radiosen 9 106 127* sitivity to additional exposure. 12 101 123* Consequently, the question arises as to whether the 15 94 105 radiation exposure itself can cause these kinds of 21 96 92 effects. To answer this question, model experiments The number 3107167* were performed using various cell lines that were of giant cells treated with irradiation at doses of 10–40 cGy and 995109* dose rate values close to that of the Chernobyl exper 12 94 99 iments [13, 14]. It was found that the distant progeny 15 90 88 of the exposed cells are characterized by loss of repro 21 84 86 ductive ability and an increased frequency of cells with MN. Thus, it can be suggested that the above men 27 87 83 tioned effects, which were obtained during the expo * The statistically significant difference between the control and sure of cells in tissue culture in the radiation contam irradiated populations of cells (χ2 criterion). inated 10 kilometer zone around the Chernobyl nuclear reactor, are mainly caused by prolonged expo sure to low dose radiation. additional irradiation at a 9 Gy dose and 2 days post At the organism level, similar effects were found in exposure in the contaminated zones was found to mice that were irradiated in the contaminated zones of result in a dramatic increase of death of animals that the accident at different time intervals using all round reached 100% after 9 days. The extent of the increase multi cell containers coupled with a dosimeter at each in radiosensitivity seems to depend significantly on the unit cell. Animals were initially exposed to chronic time interval between the end of exposure and an addi radiation at doses of 0.024–0.336 Gy for 1 to 14 days tional acute irradiation. For example, in the case of a followed by their transportation to Moscow; they then 2 day time interval, an increase of animal death was were subjected to an additional treatment at doses of 3, noted within the period of the development of the 5, 7, and 9 Gy after 2, 7, and 30 days after initial expo marrowy syndrome, whereas in the case of the 30 day sure. Control animals were kept under similar ecolog time interval a notable increase in death of animals was ical and other conditions in areas that were not con registered within the time frame that is characterized taminated with radionuclides. Survival studies on ani by the development of the gastrointestinal syndrome. mals were carried out for 30 days (Fig. 1). An These data show that the action of prolonged expo
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100 8 5 Gy (a) 1 (a) 7 2 Average = 343 3 6 50 7 Gy Average = 502 5 Average = 218 9 Gy 4 3 0 2 6 10 14 18 2622 30 Number of occurrences 2 3 Gy 100 1 (b) 5 Gy 0 150 200 250 300 350 400 450 500 550 600 Number of survivd animals 50 8 7 Gy (b) 1 9 Gy 7 2 Average = 317 3 6 Average = 204 0 2 6 10 14 18 2622 30 5 Time after initial exposure, days 4 Fig. 1. Survival of mice within a 30 day period after acute Average = 443 irradiation at different doses. a, control; b, initial exposure 3
in the Chernobyl accident zone (0.336 Gy total irradiation Number of occurrences dose). 2
1 sure, together with several other factors in the contam inated areas, resulted in elevated radiosensitivity at the 0 organism level of mice [15]. 150 200 250 300 350 400 450 500 550 In a separate series of experiments, animals Average number of cells per 1 square mm of slice exposed in the accident zone were tested for the den Fig. 2. The distribution of endotheliocytes in the cerebrum sity of endotheliocytes in various parts of the cerebrum of 14 month old mice that were (a) either non irradiated using the fluorescent hystochemical method (Fig. 2). or (b) exposed in the accident zone (2 Gy total irradiation In these experiments the animals were subjected to dose) and examined 12 month after treatment. 1, Cortex, prolonged radiation treatment at the 2 Gy dose, which 2, septum, 3, corpus callosum. was achieved by their exposure in the accident zone for 1 month. At one year after the exposure the density of endotheliocytes in various parts of the cerebrum was that lived in the radiation contaminated as a result of found to be decreased [15]. the accident (Vyshkov, Klintsy, and Novozybkov, Thus, experiments on animals, as well as at the cel where the contamination density reaches up to 2 lular level, demonstrated elevated radiosensitivity and 40 Cu/km ) and also liquidators of the Chernobyl postponed death of endotheliocytes in the cerebrum of accident consequences. The analyses were carried out mice. The effect of late death of endotheliocytes in the using the micronucleus test with the use of a cytokine cerebrum may indicate the possible development of sis block induced by cytochalasin B. hypoxic conditions and cerebrovascular disorders caused by the exposure in the accident zone. Interestingly, it has been demonstrated that the ability of lymphocytes to be stimulated with PHA is The frequency of damaged cells, their radiosensi tivity (after irradiation at the 1 Gy dose), and the substantially decreased in the case of children from induction of adaptive response were examined after Novozybkov and adult individuals from Vyshkov; the irradiation at a low (adaptive) dose of 0.05 Gy and a frequency of PHA stimulated cells was 1.5–2 times 5 h post treatment with high (challenged) dose. The lower. Moreover, no statistically significant difference experiments were performed on blood lymphocytes was found in the level of aberrant lymphocytes of (PHA) that were obtained from children and adults adults compared to that of Moscow citizens [11].
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16 50 14 12 40 10
30 8 6 Number of individuals, % 20 4 2 Number of individuals, % 10 0 Moscow Klintsy Liquida tors 0 Moscow Klintsy Vyshkov Liquida Fig. 4. The percentage of individuals with significant increase of radiosensitivity after adaptive radiation among tors liquidators, residents of contaminated Klintsy area, and citizens of Moscow. Fig. 3. The percentage of individuals with an adaptive response among citizens of Moscow, residents of the con taminated territories of Bryansk region (Klintsy and Vysh populations of people, various critical systems of dam kov areas), and liquidators. age, etc. AR is an increase in resistance to high (challenged) However, very high individual variability of the doses of radiation in cells that were previously treated studied parameters was observed in some adults from with low (adaptive) doses. The study of AR revealed a the radiation contaminated areas; in addition, some reduced frequency of individuals with a significant liquidators were found to have a very high frequency of adaptive response (5.2%, compared to 19.8% in the damaged lymphocytes. The frequency of damaged control) in the examined groups of liquidators, adult lymphocytes of children that lived in the contami residents (Fig. 3) of the areas that were contaminated nated areas varies within the range of 7–65 per 1000 as a result of the Chernobyl accident, and also chil cells in comparison with 1–37 in the control popula dren. A similar dependence was found in residents of tion. On average, the frequency of lymphocytes with the Techa riverbank territories [16]. MN is more than two times higher in the population of irradiated children (23.0 ± 1.0 per 1000 cells) com Another effect was found simultaneously: this is the pared to that of the control (10.0 ± 0.6 per 1000 cells). phenomenon of increased radiosensitivity among liq uidators and all groups of adult residents of the radia No increase of radioresistance was observed in both tion contaminated territories after exposure to low the liquidator group and the population of residents of dose radiation (Fig. 4). This phenomenon appears to the contaminated zones in response to irradiation at be highly important for the human population and the dose of 1 Gy, i.e., no induction of AR was caused most probably depends on the initial number of dam by the continuing action of radiation in these regions aged cells, ecological factors, defects in DNA repair [11]. On the other hand, a statistically significant systems, the state of humoral and cellular immunity, increase of radioresistance was observed in South Ural individual features of an organism, and the presence of area residents (the Techa riverbank territories) where somatic diseases [18, 19]. The role of clastogenic fac 50 years has passed since radioactive waste release; in tors in the formation of the phenomenon of elevated this region chronic radiation exposure leads to the radiosensitivity should not also be excluded. Clastoge induction of AR [16, 17]. Apparently, these differences nic factors are found in animal and human blood in the AR induction in the residents of the radiation serum exposed to low dose radiation; they cause cell contaminated zone can be associated with a number of death, chromosome aberrations, and mutations (for various factors, such as a different spectrum of con example, when blood serum of irradiated individuals is taminants in the environment (mostly strontium in the added to cells in tissue culture) as initially described in Ural area and cesium in the Chernobyl zone), various [20]. However, very high individual variability in the periods of monitoring the accident consequences and ability to form clastogenic factors has been noted [21]. the action of radiation as a result of contamination, It is possible that one of the features of the existence of differences in ecological conditions and the examined human and other organisms on the territories affected
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Table 5. Characteristics of the blood lymphocytes of liquidators compared to those of healthy individuals (mean ± SE) Number Average Initial Initial Concentration of aberrations per 100 cells number of DNA Examined frequency frequency of of ROS, arb. double strand populations of cells with cells with MN units per 1 mil chromosome breaks, arb. aberrations, % chromatid type (per 1000 cells) lion cells type units Liquidator 1.381 ± 0.368 (21) 0.341 ± 0.129** 1.463 ± 0.265 16.17 ± 1.16 14.42 ± 1.60** 0.405 ± 0.039** (21) (21) (47) (21) (21) Control 1.490 ± 0.181 (42) 0.022 ± 0.022 1.489 ± 0.180 12.03 ± 0.73 7.93 ± 1.10 0.581 ± 0.048 A (42) (42) (57) (19) (12) Comments. The number of examined individuals in each case is presented in brackets. **p < 0.01 as analyzed by the Students t test or χ2 crite rion with Yates correction factor. A indicates the results of metaphase analysis of chromosome aberrations of non irradiated popula tion performed in 2006–2009 that were used as a control. by nuclear catastrophes is the appearance of individu quency of cells with chromosome type aberrations in als that have high sensitivity to extreme factors after the group of liquidators was characterized by a statisti low dose exposure to chemical and physical agents. cally significant increase (0.341 ± 0.129 compared to The phenomenon of an increase of radiosensitivity in 0.022 ± 0.022 in the control group). It should be men response to low dose irradiation can be regarded as a tioned that one person with a level of chromatid type manifestation of genomic instability. aberrations that was 10 times higher than that of other At later periods, 24 years after the Chernobyl people was found in the group of tested individuals Nuclear Power Plant accident liquidators were sub who performed deactivation and clean up and dealt jected to examination of damage to their genetic appa with the consequences of the Chernobyl accident. ratus (the frequency of cells with MN and chromo The frequency of lymphocytes with MN varied some aberrations and also the level of DNA double within a wide range, from 2 to 52 per 1000 cells ana strand breaks) and oxidative status (reactive oxygen lyzed in the experiment, and it was found to be inde species content, ROS). pendent of radiation exposure dose. The distribution The average frequency of blood lymphocytes with of the tested liquidators according to their frequency chromosome aberrations of liquidators of the Cherno of cells with MN is presented in Fig. 5. The average byl accident was found to be similar to that of the con number of frequency of MN cells is 16.17 ± 1.16 per trol individuals as judged by metaphase analysis 1000 cells, which is statistically different from the fre (Table 5). These chromosome aberrations were pre quency of cells with MN in the control (12.03 ± 0.73) dominantly of the chromatid type; however, the fre (Table 5). For comparison, the average value of MN cell frequency in citizens of Moscow is about 16.58 ± 1.09. 16 However, for some individuals the frequency of cells with MN of reached 50 (Fig. 5). Such a high fre 14 quency value of cells with MN appears to be correlated 12 with the characteristics of the individual organism. In general terms, the distribution of cells with MN can be 10 described by a normal Gaussian function (p = 0.30). In addition, the level of DNA damage in both the 8 liquidator and control groups was tested using the 6 DNA comet assay. It was found that the level of DNA double strand breaks was significantly higher in the 4 blood lymphocytes of the individuals who dealt with Number of occurrences the Chernobyl accident consequences. 2 The decrease of the density of endotheliocytes in 0 the cerebrum (cerebrum cortex) of mice suggests the 0 5 10 15 20 25 30 35 40 45 50 55 60 possible development of hypoxia and the ischemic Number of cells with MN per 1000 analyzed cells syndrome in their organism; thus the oxidative status was determined in the blood lymphocytes of liquida tors and the residents of contaminated regions. Detec Fig. 5. The distribution of the frequency of lymphocytes with a micronucleus in the population of liquidators. The tion was carried out using the non fluorescent com solid line represents the normal theoretical distribution pound 5 (6) chloromethyl 2',7' dichlorodihydroflu calculated using the same values of mean and distribution. orescein diacetate (DCF, Invitrogen), which easily
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