Acid phosphatase activity of small intestine of mice after exposure to different doses of gamma rays

Summary Effect of whole-body radiation at 3 different dose levels on the activity of acid phosphatase was studied in the small intestine of Swiss albino mice. In all the 3 exposure groups the enzyme activity increased significantly at 24 h after irradiation; the time at which the maximum histological damage was seen. With the beginning of recovery the enzyme tended to decrease and gradually approached control values.     

Effect of carbon particles on the recovery of bone marrow stem cells after irradiation in LPS-resistant C3H/HeJ mice

Effect of RES-blockade on bone marrow cells was studied serially after irradiation in LPS-resistant mice. Injection of carbon particles reduced damage and accelerated recovery of marrow hemopoietic stem cells, indicating that LPS-resistant mice can react normally to RES-blockade.     

Cellular damage and recovery of the early developing mouse eye following low dose irradiation. I. X-rays on day 8 of gestation

Summary The eye region of mouse embryos, irradiated with 90 rad X-rays on day 8 of gestation, was examined 24 h later for cellular damage. Besides the overall developmental retardation, the radiation insult decreased the proliferation rate and altered the mitotic phase ratio. Due to the limited extension of necrotic zones, a reduced number of dead cells was found in the irradiated optic vesicles.Supported by the Swiss National Foundation for Scientific Research. The technical assistance of Mrs E. Frei is gratefully acknowledged.     

Effect of carbon particles on the recovery of bone marrow stem cells after irradiation in LPS-resistant C3H/HeJ mice

Summary Effect of RES-blockade on bone marrow cells was studied serially after irradiation in LPS-resistant mice. Injection of carbon particles reduced damage and accelerated recovery of marrow hemopoietic stem cells, indicating that LPS-resistant mice can react normally to RES-blockade.This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Education, Science and Culture, Japan.     

100 years of radiobiology: Implications for biomedicine and future perspectives

The development of radiobiology from the very early detection of the biological action of X-rays to the knowledge of today is described in sections on radiation chemistry and biochemistry, mutation and cancer induction, and embryonic damage, as well as the dependence of radiation response on radiation quality and temporal dose distribution (repair) and the interaction with other factors. For medicine radiobiology serves as a basis for radiotherapy and radiological protection. The effect of very low doses, and their possible biopositive effect (hormesis and adaptive response), is also discussed, as are the health hazard of radon, health risks after the Chernobyl accident, and space radiobiology. The radiobiology of the future will be concerned with biomolecular and genetic implications, problems of damage and repair, and connected problems like hormesis.     

Biochemical aspects of radiation biology

In order to analyze the mechanisms of biological radiation effects, the events after radiation energy absorption in irradiated organisms have to be studied by physico-chemical and biochemical methods. The radiation effects in vitro on biomolecules, especially DNA, are described, as well as their alterations in irradiated cells. Whereas in vitro, in aqueous solution, predominantly OH radicals are effective and lead to damage in single moieties of the DNA, in vivo the direct absorption of radiation energy leads to 'locally multiply-damaged sites', which produce DNA double-strand breaks and locally denatured regions. DNA damage will be repaired in irradiated cells. Error free repair leads to the original nucleotide sequence in the genome by excision or by recombination. "Error prone repair"(mutagenic repair), leads to mutation. However, the biochemistry of these processes, regulated by a number of genes, is poorly understood. In addition, more complex reactions, such as gene amplification and transposition of mobile gene elements, are responsible for mutation or malignant transformation.     

Cell kinetics and radiation pathology

Conclusion Radiation pathology is a general term describing the damage that occurs in tissues after irradiation. After the very low doses, received by the normal working population, no major pathology is seen. There is a hazard of cancer induction if DNA damage that has been inflicted in an individual cell is repaired in such a way that the DNA remains intact but rearranged. This radiation carcinogenesis is however a low risk compared with many chemical carcinogens in the environment and in cancer chemotherapy.The treatment of cancer by radiation is now commonly accepted as one of the most effective forms of treatment. It can kill tumour cells effectively, but the dose that can be given is limited by the normal tissues that are inevitably included in the beam. Cell function is maintained for some time even after very large doses. However normal tissues show a loss of function and structure because the proliferating subcompartment of each tissue is depleted as the radiation injured cells fail to divide and die. The time at which the cell deficit is detected varies from hours in some tissues to months or years in others. It depends upon the normal rate of cell turnover. The apparent sensitivity of each tissue therefore depends upon the time at which the assessment is made. Lung and kidney would appear very resistant at 1–3 months post irradiation, but would seem very radiosensitive at 6–12 months as their latent damage is expressed.The ultimate expression of radiation pathology is the death of the whole animal as the essential organ function fails. The time of this death is only comprehensible if the time sequence and the proliferation kinetics of the target cells are taken into account. It must be recognised that it is initial damage to the clonogenic cells, not to the differentiated cells per se that is important.     

Regulation of the cell cycle following DNA damage in normal and Ataxia telangiectasia cells

A proportion of the population is exposed to acute doses of ionizing radiation through medical treatment or occupational accidents, with little knowledge of the immedate effects. At the cellular level, ionizing radiation leads to the activation of a genetic program which enables the cell to increase its chances of survival and to minimize detrimental manifestations of radiation damage. Cytotoxic stress due to ionizing radiation causes genetic instability, alterations in the cell cycle, apoptosis, or necrosis. Alterations in the G1, S and G2 phases of the cell cycle coincide with improved survival and genome stability. The main cellular factors which are activated by DNA damage and interfere with the cell cycle controls are: p53, delaying the transition through the G1-S boundary; p21^WAF1/CIPI, preventing the entrance into S-phase; proliferating cell nuclear antigen (PCNA) and replication protein A (RPA), blocking DNA replication; and the p53 variant protein p53as together with the retinoblastoma protein (Rb), with less defined functions during the G2 phase of the cell cycle. By comparing a variety of radioresistant cell lines derived from radiosensitive ataxia talangiectasia cells with the parental cells, some essential mechanisms that allow cells to gain radioresistance have been identified. The results so far emphasise the importance of an adequate delay in the transition from G2 to M and the inhibition of DNA replication in the regulation of the cell cycle after exposure to ionizing radiation.     

The impact of cyclin-dependent kinase 5 depletion on poly(ADP-ribose) polymerase activity and responses to radiation

Cyclin-dependent kinase 5 (Cdk5) has been identified as a determinant of sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Here, the consequences of its depletion on cell survival, PARP activity, the recruitment of base excision repair (BER) proteins to DNA damage sites, and overall DNA single-strand break (SSB) repair were investigated using isogenic HeLa stably depleted (KD) and Control cell lines. Synthetic lethality achieved by disrupting PARP activity in Cdk5-deficient cells was confirmed, and the Cdk5^KD cells were also found to be sensitive to the killing effects of ionizing radiation (IR) but not methyl methanesulfonate or neocarzinostatin. The recruitment profiles of GFP-PARP-1 and XRCC1-YFP to sites of micro-irradiated Cdk5^KD cells were slower and reached lower maximum values, while the profile of GFP-PCNA recruitment was faster and attained higher maximum values compared to Control cells. Higher basal, IR, and hydrogen peroxide-induced polymer levels were observed in Cdk5^KD compared to Control cells. Recruitment of GFP-PARP-1 in which serines 782, 785, and 786, potential Cdk5 phosphorylation targets, were mutated to alanines in micro-irradiated Control cells was also reduced. We hypothesize that Cdk5-dependent PARP-1 phosphorylation on one or more of these serines results in an attenuation of its ribosylating activity facilitating persistence at DNA damage sites. Despite these deficiencies, Cdk5^KD cells are able to effectively repair SSBs probably via the long patch BER pathway, suggesting that the enhanced radiation sensitivity of Cdk5^KD cells is due to a role of Cdk5 in other pathways or the altered polymer levels.     

Effects of pre- and post-irradiation glucan treatment on pluripotent stem cells,granulocyte, macrophage and erythroid progenitor cells,and hemopoietic stromal cells

Summary Glucan, a beta-1, 3 polyglucose, was administered to mice either 1 h before or 1 h after a 650 rad exposure to cobalt-60 radiation. Compared to radiation controls, glucan-treated mice consistantly exhibited a more rapid recovery of pluripotent stem cells and committed granulocyte, macrophage, and erythroid progenitor cells. This may partially explain the mechanism by which glucan also enhances survival in otherwise lethally irradiated mice.     

What mechanisms/processes underlie radiation-induced genomic instability?

Radiation-induced genomic instability is a modification of the cell genome found in the progeny of irradiated somatic and germ cells but that is not confined on the initial radiation-induced damage and may occur de novo many generations after irradiation. Genomic instability in the germ line does not follow Mendelian segregation and may have unpredictable outcomes in every succeeding generation. This phenomenon, for which there is extensive experimental data and some evidence in human populations exposed to ionising radiation, is not taken into account in health risk assessments. It poses an unknown morbidity/mortality burden. Based on experimental data derived over the last 20?years (up to January 2012) six mechanistic explanations for the phenomenon have been proposed in the peer-reviewed literature. This article compares these hypotheses with the empirical data to test their fitness to explain the phenomenon. As a conclusion, the most convincing explanation of radiation-induced genomic instability attributes it to an irreversible regulatory change in the dynamic interaction network of the cellular gene products, as a response to non-specific molecular damage, thus entailing the rejection of the machine metaphor for the cell in favour of one appropriate to a complex dissipative dynamic system, such as a whirlpool. It is concluded that in order to evaluate the likely morbidity/mortality associated with radiation-induced genomic instability, it will be necessary to study the damage to processes by radiation rather than damage to molecules.     

Biological effectiveness of solar UV radiation in humans

Solar UVB radiation is prejudicial to the health of humans in a number of ways. Erythema and photodermatoses are acute reactions of the skin; keratitis and conjunctivitis are acute reactions of the eye. Various types of skin cancer, accelerated aging of the skin, and cataract formation in the crystalline lens are reactions that appear with great latency. UV radiation can also cause damage to the immune system and DNA. For the period 1981–1991, an increase in erythemal effective UVB radiation of +(7±4)% per decade was measured in a non-pulluted high mountain area (Jungfraujoch, 3576m a.s.l., Switzerland). This increase is related to a decrease in stratospheric ozone. The effects on human health are discussed. A 10% ozone reduction increases non-melanoma skin cancer by 26% and cataract by 6 to 8%.     

Modification of radiation-induced spleen weight changes in mice by 2-mercaptopropionylglycine

It was found that the MPG partially protects the spleen against weight loss due to radiation, and exaggerates the compensatory reaction in the tissue during recovery. It is also concluded that MPG protects the stem cells in the spleen, which helps to restore the peripheral blood by extramedullary erythropoiesis.     

Modification of radiation-induced spleen weight changes in mice by 2-mercaptopropionylglycine

Summary It was found that the MPG partially protects the spleen against weight loss due to radiation, and exaggerates the compensatory reaction in the tissue during recovery. It is also concluded that MPG protects the stem cells in the spleen, which helps to restore the peripheral blood by extramedullary erythropoiesis.     

Biochemical aspects of radiation biology

Summary In order to analyze the mechanisms of biological radiation effects, the events after radiation energy absorption in irradiated organisms have to be studied by physico-chemical and biochemical methods. The radiation effects in vitro on biomolecules, especially DNA, are described, as well as their alterations in irradiated cells. Whereas in vitro, in aqueous solution, predominantly OH radicals are effective and lead to damage in single moieties of the DNA, in vivo the direct absorption of radiation energy leads to locally multiply-damaged sites, which produce DNA double-strand breaks and locally denatured regions. DNA damage will be repaired in irradiated cells. Error free repair leads to the original nucleotide sequence in the genome by excision or by recombination. Error prone repair (mutagenic repair), leads to mutation. However, the biochemistry of these processes, regulated by a number of genes, is poorly understood. In addition, more complex reactions, such as gene amplification and transposition of mobile gene elements, are responsible for mutation or malignant transformation.     

Selective protection of cells against X-irradiation. Isoproterenol protects only those cells that possess beta-adrenoreceptors

In mixed culture of Chinese hamster fibroblasts, clone 431, and transformed murine L fibroblasts, clone B-82, isoproterenol was found to protect only 431 cells against ionizing radiation. It was shown that 431 cells, in contrast to B-82 cells, possess beta-adrenoreceptors, and the radioprotective effect of isoproterenol can be realized only if this agent interacts with beta-adrenoreceptors coupled with the cAMP system. Since malignization often causes the disappearance of beta-adrenergic and other hormone receptors, the combined culturing and irradiation of the cells studied can be regarded as a model of the growth of malignant cells (B-82) among normal tissue cells (431 cells) under conditions of radiation therapy. A possibility of selective protection against radiation damage of normal tissue cells, with retention of the former radiosensitivity of tumor cells, is discussed.     

3H-thymidine incorporation (DNA synthesis) and radiotoxicity in the ovary of the Japanese quail before and during follicle formation

No evidence was found for ribosomal DNA amplification in the oocytes of the Japanese quail, before or during folliculogenesis. DNA synthesis in the somatic cells, involved in follicle formation, starts at the medullar side of the basement membrane. The localized sterilization of the quail ovary after administration of 3H-thymidine (3H-TdR) seems to be due to radiation-induced lesions in the follicle forming somatic cells, rather than to direct radiation damage of the oocyte.     

Implication of the VRK1 chromatin kinase in the signaling responses to DNA damage: a therapeutic target?

DNA damage causes a local distortion of chromatin that triggers the sequential processes that participate in specific DNA repair mechanisms. This initiation of the repair response requires the involvement of a protein whose activity can be regulated by histones. Kinases are candidates to regulate and coordinate the connection between a locally altered chromatin and the response initiating signals that lead to identification of the type of lesion and the sequential steps required in specific DNA damage responses (DDR). This initiating kinase must be located in chromatin, and be activated independently of the type of DNA damage. We review the contribution of the Ser-Thr vaccinia-related kinase 1 (VRK1) chromatin kinase as a new player in the signaling of DNA damage responses, at chromatin and cellular levels, and its potential as a new therapeutic target in oncology. VRK1 is involved in the regulation of histone modifications, such as histone phosphorylation and acetylation, and in the formation of γH2AX, NBS1 and 53BP1 foci induced in DDR. Induction of DNA damage by chemotherapy or radiation is a mainstay of cancer treatment. Therefore, novel treatments can be targeted to proteins implicated in the regulation of DDR, rather than by directly causing DNA damage.     

Zum Wirkungsmechanismus des chemischen Strahlenschutzes

Summary Possible mechanisms for the action of radiation damage inhibiting substances, especially 1-hydrazinophtalazine, are discussed. From experiments, designed for simulation of radiated aqueous systems, it can be concluded that this inhibiting action is caused by the special redox-kinetic behaviour of the compound towards strong oxidizing agents.     

Effects of hypergravity on rat fertility,pregnancy, parturition and survival

Summary Persistent centrifugation (at 1.18×g to 1.47×g) of pregnant rats reduced the number of deliveries and the survival time of the newborns. The extent of the damage increased with increasing distance from the axis. Male fertility was reduced.