Non-targeted and Delayed Effects of Exposure to Ionizing Radiation: II. Radiation-Induced Genomic Instability and Bystander Effects In Vivo, Clastogenic Factors and Transgenerational Effects

Abstract Morgan, W. F. Non-targeted and Delayed Effects of Exposure to Ionizing Radiation: II. Radiation-Induced Genomic Instability and Bystander Effects In Vivo, Clastogenic Factors and Transgenerational Effects. Radiat. Res. 159, 581–596 (2003). The goal of this review is to summarize the evidence for non-targeted and delayed effects of exposure to ionizing radiation in vivo. Currently, human health risks associated with radiation exposures are based primarily on the assumption that the detrimental effects of radiation occur in irradiated cells. Over the years a number of non-targeted effects of radiation exposure in vivo have been described that challenge this concept. These include radiation-induced genomic instability, bystander effects, clastogenic factors produced in plasma from irradiated individuals that can cause chromosomal damage when cultured with nonirradiated cells, and transgenerational effects of parental irradiation that can manifest in the progeny. These effects pose new challenges to evaluating the risk(s) associated with radiation exposure and understanding radiation-induced carcinogenesis.

[1]  M. Harms-Ringdahl,et al.  Chromosomal instability in human lymphocytes after low dose rate gamma-irradiation and delayed mitogen stimulation. , 1998, International journal of radiation biology.

[2]  M. Jobling,et al.  Mutation processes at human minisatellites , 1995, Electrophoresis.

[3]  E. Petit,et al.  Children of Chernobyl Cleanup Workers do not Show Elevated Rates of Mutations in Minisatellite Alleles , 2001, Radiation research.

[4]  K. Goh.  Total-body irradiation and human chromosomes: cytogenetic studies of the peripheral blood and bone marrow leukocytes seven years after total-body irradiation. , 1968, Radiation research.

[5]  J. Tucker,et al.  The persistence of aberrations in mice induced by gamma radiation as measured by chromosome painting. , 1996, Mutation research.

[6]  M. Mann,et al.  Directed Proteomic Analysis of the Human Nucleolus , 2002, Current Biology.

[7]  R. Kuick,et al.  Genetic analysis of children of atomic bomb survivors. , 1996, Environmental health perspectives.

[8]  E. Wright,et al.  Chromosomal instability in unirradiated cells induced in vivo by a bystander effect of ionizing radiation. , 2000, Cancer research.

[9]  Y. Dubrova,et al.  Nuclear Weapons Tests and Human Germline Mutation Rate , 2002, Science.

[10]  R. Ullrich,et al.  Radiation-induced chromosomal instability in BALB/c and C57BL/6 mice: the difference is as clear as black and white. , 1997, Radiation research.

[11]  K. Dohi,et al.  Dose-response of a radiation induction of a germline mutation at a hypervariable mouse minisatellite locus. , 1995, International journal of radiation biology.

[12]  Y. Yoshimoto.  Cancer risk among children of atomic bomb survivors. A review of RERF epidemiologic studies , 1991, JAMA.

[13]  R. Lynch,et al.  Inhibition by superoxide dismutase of methemoglobin formation from oxyhemoglobin. , 1976, The Journal of biological chemistry.

[14]  Y E Dubrova,et al.  Minisatellite mutation frequency in human sperm following radiotherapy. , 2000, Mutation research.

[15]  Y. Dubrova,et al.  Elevated minisatellite mutation rate in the post-chernobyl families from ukraine. , 2002, American journal of human genetics.

[16]  G. Moment.  Recovery and abscopal effects after inhibitory X-irradiation in earthworm regeneration. , 1972, The Journal of experimental zoology.

[17]  N. Kamada,et al.  Chromosome aberrations in normal leukocytes induced by the plasma of exposed individuals. , 1977, Hiroshima journal of medical sciences.

[18]  E. Wright.  Inherited and inducible chromosomal instability: a fragile bridge between genome integrity mechanisms and tumourigenesis , 1999, The Journal of pathology.

[19]  I. Emerit,et al.  Transferable clastogenic activity in plasma from persons exposed as salvage personnel of the Chernobyl reactor , 2005, Journal of Cancer Research and Clinical Oncology.

[20]  L. M. Cobb,et al.  Investigation of lung tumour induction in BALB/cJ mice following paternal X-irradiation. , 1995, International journal of radiation biology.

[21]  M. Plumb,et al.  Genetic instability in radiation-induced leukaemias: mouse models. , 1998, International journal of radiation biology.

[22]  K. Goh,et al.  Breaks in normal human chromosomes: are they induced by a transferable substance in the plasma of persons exposed to total-body irradiation? , 1968, Radiation research.

[23]  J. Coggle,et al.  Lung tumour induction in mice after uniform and non-uniform external thoracic X-irradiation. , 1985, International journal of radiation biology and related studies in physics, chemistry, and medicine.

[24]  G Vergnaud,et al.  Further evidence for elevated human minisatellite mutation rate in Belarus eight years after the Chernobyl accident. , 1997, Mutation research.

[25]  A. Jeffreys,et al.  Induction of minisatellite mutations in the mouse germline by low-dose chronic exposure to gamma-radiation and fission neutrons. , 2000, Mutation research.

[26]  O. Ponzio,et al.  Plasma from patients exposed to ischemia reperfusion contains clastogenic factors and stimulates the chemiluminescence response of normal leukocytes. , 1995, Free radical biology & medicine.

[27]  M. Nobler.  The abscopal effect in malignant lymphoma and its relationship to lymphocyte circulation. , 1969, Radiology.

[28]  M. Kodaira,et al.  Effects of radiation on children , 1996, Nature.

[29]  C. Streffer,et al.  Analysis of structural and numerical chromosomal anomalies at the first, second, and third mitosis after irradiation of one-cell mouse embryos with X-rays or neutrons. , 1988, International journal of radiation biology.

[30]  J. Souto.  Tumour Development in the Rat induced by Blood of Irradiated Animals , 1962, Nature.

[31]  A. Craft,et al.  Geographical distribution of preconceptional radiation doses to fathers employed at the Sellafield nuclear installation, West Cumbria. , 1993, BMJ.

[32]  John R Yates,et al.  The hMre11/hRad50 Protein Complex and Nijmegen Breakage Syndrome: Linkage of Double-Strand Break Repair to the Cellular DNA Damage Response , 1998, Cell.

[33]  M. Cohen,et al.  A diffusable clastogenic factor in ataxia telangiectasia. , 1980, Cytogenetics and cell genetics.

[34]  貞本 誠治.  Radiation induction of germline mutation at a hypervariable mouse minisatellite locus , 1994 .

[35]  C. Streffer,et al.  Lethal and teratogenic effects in two successive generations of the HLG mouse strain after radiation exposure of zygotes -- association with genomic instability? , 1999, Mutation research.

[36]  J Buard,et al.  Spontaneous and induced minisatellite instability , 1997, Electrophoresis.

[37]  J. Montour.  Abscopal radiation damage to chick thymus and bursa of Fabricius. , 1971, Acta radiologica: therapy, physics, biology.

[38]  B. Källén,et al.  Outcome of reproduction in women irradiated for skin hemangioma in infancy. , 1998, Radiation research.

[39]  C. Whitehouse,et al.  Chromosome aberrations in radiation workers with internal deposits of plutonium. , 1998, Radiation research.

[40]  J D Harrison,et al.  Lack of Detectable Transmissible Chromosomal Instability after In Vivo or In Vitro Exposure of Mouse Bone Marrow Cells to 224Ra Alpha Particles , 2001, Radiation research.

[41]  R. Okayasu,et al.  A deficiency in DNA repair and DNA-PKcs expression in the radiosensitive BALB/c mouse. , 2000, Cancer research.

[42]  L. Parker,et al.  Leukaemia and non‐Hodgkin's lymphoma in children of male Sellafield radiation workers , 2002, International journal of cancer.

[43]  J. A. Watson,et al.  Abscopal and Direct Effects on Calcium Mobilization, Alkaline Phosphatase Levels, and Dentin Formation following X-Irradiation of either the Rat Incisor or the Thyroid-Parathyroid Region , 1966, Journal of dental research.

[44]  N. Kamada,et al.  Chromosome aberrations in B lymphocytes of atomic bomb survivors. , 1979, Blood.

[45]  C. Whitehouse,et al.  No Evidence for Chromosomal Instability in Radiation Workers with In Vivo Exposure to Plutonium , 2001, Radiation research.

[46]  J. Baulch,et al.  Heritable effects of paternal irradiation in mice on signaling protein kinase activities in F3 offspring. , 2001, Mutagenesis.

[47]  R. Ullrich,et al.  Strain-dependent susceptibility to radiation-induced mammary cancer is a result of differences in epithelial cell sensitivity to transformation. , 1996, Radiation research.

[48]  W. M. COURT BROWN.  Radiation carcinogenesis. , 1963, The Practitioner.

[49]  J. Baulch,et al.  Impaired cell proliferation in mice that persists across at least two generations after paternal irradiation. , 1997, Radiation research.

[50]  Y. Yoshimoto.  Cancer Risk Among Children of Atomic Bomb Survivors: A Review of RERF Epidemiologic Studies , 1990 .

[51]  R. Kominami,et al.  Untargeted mutation of the maternally derived mouse hypervariable minisatellite allele in F1 mice born to irradiated spermatozoa. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[52]  M. Kadhim,et al.  Radiation-induced chromosomal instability in human fibroblasts: temporal effects and the influence of radiation quality. , 1998, International journal of radiation biology.

[53]  K. Tanaka,et al.  Comet assay to assess the non-target effect of neutron-radiation in human peripheral blood. , 2001, Journal of radiation research.

[54]  H S Weinberg,et al.  Very high mutation rate in offspring of Chernobyl accident liquidators , 2001, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[55]  M. Ohtaki,et al.  Persistent Induction of Somatic Reversions of the Pink-Eyed Unstable Mutation in F1 Mice Born to Fathers Irradiated at the Spermatozoa Stage , 2002, Radiation research.

[56]  R. McClellan,et al.  The induction of liver tumors by 239Pu citrate or 239PuO2 particles in the Chinese hamster. , 1983, Radiation research.

[57]  A. Jeffreys,et al.  Mouse minisatellite mutations induced by ionizing radiation , 1993, Nature Genetics.

[58]  L. Abramsson-Zetterberg,et al.  Absence of genomic instability in mice following prenatal low dose-rate gamma-irradiation. , 2000, International journal of radiation biology.

[59]  A. Jeffreys,et al.  Radiation-induced germline instability at minisatellite loci. , 1998, International journal of radiation biology.

[60]  H. Kato,et al.  Malignant tumors during the first 2 decades of life in the offspring of atomic bomb survivors. , 1990, American journal of human genetics.

[61]  A J Hall,et al.  Results of case-control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria. , 1990, BMJ.

[62]  William F. Morgan,et al.  A Murine Model of Nijmegen Breakage Syndrome , 2002, Current Biology.

[63]  O. Raabe,et al.  A chimera embryo assay reveals a decrease in embryonic cellular proliferation induced by sperm from X-irradiated male mice. , 1989, Radiation research.

[64]  I. Emerit,et al.  Chromosome breakage factor in the plasma of two Bloom's syndrome patients , 2004, Human Genetics.

[65]  D. Goodhead,et al.  Evidence of genetic instability in 3 Gy X-ray-induced mouse leukaemias and 3 Gy X-irradiated haemopoietic stem cells , 2001, International journal of radiation biology.

[66]  I. Emerit,et al.  Clastogenic factors in the plasma of Chernobyl accident recovery workers: anticlastogenic effect of Ginkgo biloba extract. , 1995, Radiation research.

[67]  I. Emerit,et al.  Clastogenic factors in the plasma of children exposed at Chernobyl. , 1997, Mutation research.

[68]  I. Emerit.  [58] Clastogenic factors: Detection and assay , 1990 .

[69]  E. Wright,et al.  Long-term in vivo transmission of alpha-particle-induced chromosomal instability in murine haemopoietic cells. , 1996, International journal of radiation biology.

[70]  W. Coleman,et al.  The role of genomic instability in human carcinogenesis. , 1999, Anticancer research.

[71]  A. Jeffreys,et al.  Monitoring spontaneous and induced human mutation by RAPD-PCR: a response to Weinberg et al. (2001) , 2001, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[72]  M. Lyon,et al.  Induction of congenital malformations in the offspring of male mice treated with X-rays at pre-meiotic and post-meiotic stages. , 1984, Mutation research.

[73]  Matthias Platzer,et al.  Nibrin, a Novel DNA Double-Strand Break Repair Protein, Is Mutated in Nijmegen Breakage Syndrome , 1998, Cell.

[74]  W. Piegorsch,et al.  Developmental response of zygotes exposed to similar mutagens. , 1991, Mutation research.

[75]  M. Sherman,et al.  A Preliminary Report , 1953 .

[76]  I. Emerit,et al.  Formation of a clastogenic factor by asbestos-treated rat pleural mesothelial cells , 1991, Agents and Actions.

[77]  K. Kinzler,et al.  Genetic instabilities in human cancers , 1998, Nature.

[78]  A. Jeffreys,et al.  Human minisatellite mutation rate after the Chernobyl accident , 1996, Nature.

[79]  P. U. Devi,et al.  Induction of chromosomal instability in mouse hemopoietic cells by fetal irradiation. , 2000, Mutation research.

[80]  M. Lyon,et al.  Induction of congenital anomalies in offspring of female mice exposed to varying doses of X-rays. , 1982, Mutation research.

[81]  R. McClellan,et al.  Effect of 239PuO2 particle number and size on the frequency and distribution of chromosome aberrations in the liver of the Chinese hamster. , 1974, Radiation research.

[82]  B. Lehnert,et al.  Radiation-induced effects in unirradiated cells: a review and implications in cancer. , 2002, International journal of oncology.

[83]  D. J. Brenner,et al.  The Bystander Effect in Radiation Oncogenesis: II. A Quantitative Model , 2001, Radiation research.

[84]  G. Faguet,et al.  Radiation-induced clastogenic plasma factors. , 1984, Cancer genetics and cytogenetics.

[85]  J. Bertho,et al.  Human thymic stromal cell irradiation reduces intra-thymic T cell precursor proliferation: evidence for a soluble mediator. , 1998, International journal of radiation biology.

[86]  I. Emerit,et al.  Transferable clastogenic activity in plasma from patients with Fanconi anemia , 1995, Human Genetics.

[87]  I. Emerit,et al.  Clastogenic factors in plasma of HIV-1 infected patients activate HIV-1 replication in vitro: inhibition by superoxide dismutase. , 1997, Free radical biology & medicine.

[88]  Yuri E. Dubrova,et al.  Genome stability: Transgenerational mutation by radiation , 2000, Nature.

[89]  D. Lloyd,et al.  The clastogenic effect of irradiated human plasma. , 1985, International journal of radiation biology and related studies in physics, chemistry, and medicine.

[90]  T Kageoka,et al.  Search for mutations affecting protein structure in children of atomic bomb survivors: preliminary report. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[91]  M. Barcellos-Hoff,et al.  Extracellular Signaling through the Microenvironment: A Hypothesis Relating Carcinogenesis, Bystander Effects, and Genomic Instability , 2001, Radiation research.

[92]  C. Streffer,et al.  Prenatal death and malformations after irradiation of mouse zygotes with neutrons or X-rays. , 1988, Teratology.

[93]  E. Major,et al.  Hypothesis: "Rogue cell"-type chromosomal damage in lymphocytes is associated with infection with the JC human polyoma virus and has implications for oncopenesis. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[94]  Carmel Mothersill,et al.  Radiation-Induced Bystander Effects: Past History and Future Directions , 2001, Radiation research.

[95]  R. Ullrich,et al.  Radiation-induced instability and its relation to radiation carcinogenesis. , 1998, International journal of radiation biology.

[96]  L. Strong,et al.  Genetic disease in offspring of long-term survivors of childhood and adolescent cancer. , 1998, American journal of human genetics.

[97]  J. Neel.  Reappraisal of studies concerning the genetic effects of the radiation of humans, mice, and Drosophila , 1998, Environmental and molecular mutagenesis.

[98]  K. Tanaka,et al.  Chromosomal instability in acute myelocytic leukemia and myelodysplastic syndrome patients among atomic bomb survivors. , 1999, Journal of radiation research.

[99]  C. Whitehouse,et al.  Sequential chromosome aberration analysis following radiotherapy - no evidence for enhanced genomic instability. , 2000, Mutation research.

[100]  B. Djordjevic.  Bystander effects: a concept in need of clarification. , 2000, BioEssays : news and reviews in molecular, cellular and developmental biology.

[101]  D. Scott.  THE EFFECT OF IRRADIATED PLASMA ON NORMAL HUMAN CHROMOSOMES AND ITS RELEVANCE TO THE LONG‐LIVED LYMPHOCYTE HYPOTHESIS , 1969 .

[102]  I. Emerit,et al.  Clastogenic Factors as Biomarkers of Oxidative Stress in Chronic Hepatitis C , 2000, Digestion.

[103]  G. M. Taylor.  Cancer in the offspring of survivors of childhood leukaemia and non-Hodgkin lymphomas. , 1996, British Journal of Cancer.

[104]  R. Barale,et al.  Chromosome aberrations in lymphocytes and clastogenic factors in plasma detected in Belarus children 10 years after Chernobyl accident. , 1999, Mutation research.

[105]  D. Childs,et al.  Changes in sternal marrow following roentgen‐ray therapy to the spleen in chronic granulocytic leukemia , 1954, Cancer.

[106]  I. Emerit,et al.  Clastogenic inosine nucleotide as components of the chromosome breakage factor in scleroderma patients. , 1990, Archives of biochemistry and biophysics.

[107]  M. Kadhim,et al.  Genetic factors influencing alpha-particle-induced chromosomal instability. , 1997, International journal of radiation biology.

[108]  K. Hiyama,et al.  Lack of effects of atomic bomb radiation on genetic instability of tandem-repetitive elements in human germ cells. , 1995, American journal of human genetics.

[109]  Lyons Mf,et al.  Induction of congenital malformations in the offspring of male mice treated with X-rays at pre-meiotic and post-meiotic stages. , 1984 .

[110]  J. Hendry,et al.  Transgenerational Effects of Preconception Paternal Contamination with 55Fe , 2001, Radiation research.

[111]  K Sankaranarayanan,et al.  Cancer predisposition, radiosensitivity and the risk of radiation-induced cancers. I. Background. , 1995, Radiation research.

[112]  M. Grigorova,et al.  Induction and persistence of chromosomal exchanges in mouse bone marrow cells following whole-body exposure to X-rays. , 1999, International journal of radiation biology.

[113]  R. Ullrich,et al.  Induction of lung tumors in RFM mice after localized exposures to X rays or neutrons. , 1979, Radiation research.

[114]  A. Riches,et al.  Genomic instability in haematopoietic cells of F1 generation mice of irradiated male parents. , 1997, Mutagenesis.

[115]  M. Cornforth.  Radiation-Induced Damage and the Formation of Chromosomal Aberrations , 1998 .

[116]  S. C. Darby,et al.  Paternal exposure not to blame , 1994, Nature.

[117]  C. Streffer,et al.  Lethal and teratogenic effects after exposure to X-rays at various times of early murine gestation. , 1990, Teratology.

[118]  Littlefield Lg,et al.  Chromosomal aberrations induced by plasma from irradiated patients: an indirect effect of X radiation. Further observations and studies of a control population. , 1969 .

[119]  D. Nelson,et al.  Lifetime Persistence and Clonality of Chromosome Aberrations in the Peripheral Blood of Mice Acutely Exposed to Ionizing Radiation , 2000, Radiation research.

[120]  K. Tanaka,et al.  Microsatellite instability in acute myelocytic leukaemia developed from A-bomb survivors , 2001, International journal of radiation biology.

[121]  J. Baulch,et al.  Germline drift in chimeric male mice possessing an F2 component with a paternal F0 radiation history. , 2002, Mutagenesis.

[122]  M. Plumb,et al.  Elevated mutation rates in the germ line of first- and second-generation offspring of irradiated male mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[123]  R. Ullrich.  Effects of split doses of x rays or neutrons on lung tumor formation in RFM mice. , 1980, Radiation research.

[124]  M. Plumb,et al.  Susceptibility to radiation-induced leukaemia/lymphoma is genetically separable from sensitivity to radiation-induced genomic instability. , 2001, International journal of radiation biology.

[125]  J. Hollowell,et al.  Chromosome Damage Induced by Plasma of X-Rayed Patients , 1968, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[126]  J. Little,et al.  In vivo enhancement of genomic instability in minisatellite sequences of mouse C3H/10T1/2 cells transformed in vitro by X-rays. , 1994, Cancer research.

[127]  P. Nowell.  The clonal evolution of tumor cell populations. , 1976, Science.

[128]  R. Okayasu,et al.  Elevated breast cancer risk in irradiated BALB/c mice associates with unique functional polymorphism of the Prkdc (DNA-dependent protein kinase catalytic subunit) gene. , 2001, Cancer research.

[129]  E. W. Hahn,et al.  Abscopal delay of embryonic development after prefertilization x-irradiation. , 1973, Radiation research.

[130]  Y E Dubrova,et al.  Stage specificity, dose response, and doubling dose for mouse minisatellite germ-line mutation induced by acute radiation. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[131]  E. Wright,et al.  Induction of lympho-haemopoietic malignancy: impact of preconception paternal irradiation. , 1998, International journal of radiation biology.

[132]  B. Bridges.  Radiation and Germline Mutation at Repeat Sequences: Are We in the Middle of a Paradigm Shift? , 2001, Radiation research.

[133]  T. Nomura.  Parental exposure to X rays and chemicals induces heritable tumours and anomalies in mice. , 1982, Nature.

[134]  C. Streffer,et al.  Analysis of structural and numerical chromosomal aberrations at the first and second mitosis after X irradiation of two-cell mouse embryos. , 1989, Radiation research.

[135]  I. Emerit.  Reactive oxygen species, chromosome mutation, and cancer: possible role of clastogenic factors in carcinogenesis. , 1994, Free radical biology & medicine.

[136]  I. Emerit,et al.  Chromosomal breakage in Crohn's disease: Anticlastogenic effect of D-penicillamine and L-cysteine , 2004, Human Genetics.

[137]  E. Wright,et al.  In vivo chromosomal instability and transmissible aberrations in the progeny of haemopoietic stem cells induced by high- and low-LET radiations , 2001, International journal of radiation biology.

[138]  R. Fry.  Mice, myths, and men , 1994 .

[139]  C. Muirhead,et al.  Cancer in the offspring of radiation workers: a record linkage study , 1997, BMJ.

[140]  T. Veidebaum,et al.  Chromosomal instability in in vivo radiation exposed subjects. , 1998, International journal of radiation biology.

[141]  J. Van Dyk,et al.  Partial volume rat lung irradiation: an evaluation of early DNA damage. , 1998, International journal of radiation oncology, biology, physics.

[142]  T. Nomura,et al.  X-ray-induced germ-line mutation leading to tumors. Its manifestation in mice given urethane post-natally. , 1983, Mutation research.

[143]  D A Pierce,et al.  Radiation-Related Cancer Risks at Low Doses among Atomic Bomb Survivors , 2000, Radiation research.

[144]  W. Morgan,et al.  Radiation-induced genomic instability and its implications for radiation carcinogenesis , 2003, Oncogene.

[145]  E. Wright,et al.  Inflammatory-type responses after exposure to ionizing radiation in vivo: a mechanism for radiation-induced bystander effects? , 2001, Oncogene.

[146]  R. Ullrich,et al.  Radiation-induced cytogenetic instability in vivo. , 1999, Radiation research.