Radiation-Induced Genomic Instability in the Offspring of Irradiated Parents

Conference paper
Part of the NATO Science for Peace and Security Series book series (NAPSC)

So far, mutation induction in the germline of directly exposed parents has been regarded as the main component of the genetic risk of ionising radiation. However, recent data on the delayed effects of exposure to ionising radiation challenge for the existing paradigm. The results of some publications imply that exposure to ionising radiation results in elevated mutation rates detectable not only in the directly irradiated cells, but also in their non-irradiated progeny. Here I review the data on transgenerational instability showing that radiation-induced instability in the germline of irradiated parents manifests in their offspring, affecting their mutation rates and some other characteristics. This paper summarises the data on increased cancer incidence and elevated mutation rates in the germline and somatic tissues of the offspring of irradiated parents. The possible mechanisms of transgenerational instability are discussed.


Mutation Rate Somatic Tissue Transgenerational Effect Fission Neutron Paternal Exposure 
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  1. Anway, M. D., A. S. Cupp, M. Uzumcu, and M. K. Skinner, Epigenetic transgenerational actions of endocrine disruptors and male fertility, Science, 308, 1466–469 (2005).CrossRefGoogle Scholar
  2. Bakkenist, C. J. and M. B. Kastan, Initiating cellular stress response, Cell, 118, 9–17 (2004).CrossRefGoogle Scholar
  3. Barber, R. and Y. E. Dubrova, The offspring of irradiated parents, are they stable? Mutat. Res., 598, 50–60 (2006).Google Scholar
  4. Barber, R. C., L. Miccoli, P. P. W. van Buul, K. L. Burr, A. van Duyn-Goedhart, J. F. Angulo and Y. E. Dubrova, Germline mutation rates at tandem repeat loci in DNA-repair deficient mice, Mutat. Res., 554, 287–295 (2004).Google Scholar
  5. Barber, R. C., P. Hickenbotham, T. Hatch, D. Kelly, N. Topchiy, G. Almeida, G. G. D. Jones, G.E. Johnson, J.M. Parry, K. Rothkamm, and Y.E. Dubrova, Radiation-induced transgenerational alterations in genome stability and DNA damage, Oncogene, 25, 7336–7342 (2006).CrossRefGoogle Scholar
  6. Barber, R., M. A. Plumb, E. Boulton, I. Roux, and Y. E. Dubrova, Elevated mutation rates in the germ line of first- and second-generation offspring of irradiated male mice, Proc. Natl. Acad. Sci. USA, 99, 6877–882 (2002).CrossRefGoogle Scholar
  7. Bartkova, J., Z. Horejsi, K. Koed, A. Kramer, F. Tort, K. Zieger, P. Guldberg, M. Sehested, J. M. Nesland, C. Lukas, T. Orntoft, J. Lukas, and J. Bartek, DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis, Nature, 434, 864–870 (2005).CrossRefGoogle Scholar
  8. Barton, T. S., B. Robaire, and B. F. Hales, Epigenetic programming in the preimplantation rat embryo is disrupted by chronic paternal cyclophosphamide exposure, Proc. Natl. Acad. Sci. USA, 102, 7865–870 (2005).CrossRefGoogle Scholar
  9. Baulch, J. E., O. G. Raabe, and L. M. Wiley, Heritable effects of paternal irradiation in mice on signaling protein kinase activities in F3 offspring, Mutagenesis, 16, 17–23 (2001).CrossRefGoogle Scholar
  10. Bois, P., J. Williamson, J. Brown, Y.E. Dubrova, and A.J. Jeffreys, A novel unstable mouse VNTR family expanded from SINE B1 element, Genomics, 49, 122–128, (1998).CrossRefGoogle Scholar
  11. Breger, K. S., L. Smith, M. S. Turker and M. J. Thayer, Ionizing radiation induces frequent translocations with delayed replication and condensation, Cancer Res., 64, 8231–238 (2004).CrossRefGoogle Scholar
  12. Brilliant, M. H., Y. Gondo, and E. M. Eicher, Direct molecular identification of the mouse pink-eyed unstable mutation by genome scanning, Science, 252, 566–569 (1991).CrossRefGoogle Scholar
  13. Cattanach, B. M., D. Papworth, G. Patrick, D. T. Goodhead, T. Hacker, L. Cobb, and E. Whitehill, Investigation of lung tumour induction in C3H/HeH mice, with and without tumour promotion with urethane, following paternal X-irradiation, Mutat. Res., 403, 1–12 (1998).Google Scholar
  14. Cattanach, B. M., G. Patrick, D. Papworth, D. T. Goodhead, T. Hacker, L. Cobb, and Whitehill, E., Investigation of lung tumour induction in BALB/cJ mice following paternal X-irradiation, Int. J. Radiat. Biol., 67, 607–615 (1995).CrossRefGoogle Scholar
  15. Derijck, A. A. H. A., G. W. van der Heijden, M. Giele, M. E. Philippens, C. C. A. W. van Bavel CC, and P. de Boer, dH2AX signalling during sperm chromatin remodelling in the mouse zygote, DNA Repair, 5, 959–971 (2006).Google Scholar
  16. Dubrova, Y. E., A. J. Jeffreys, and A. M. Malashenko, Mouse minisatellite mutations induced by ionizing-radiation, Nat. Genet., 5, 92–94 (1993).CrossRefGoogle Scholar
  17. Dubrova, Y. E., M. Plumb, B. Gutierrez, E. Boulton, and A. J. Jeffreys, Genome stability - Transgenerational mutation by radiation, Nature, 405, 37–37 (2000).CrossRefGoogle Scholar
  18. Dubrova, Y. E., M. Plumb, J. Brown, E. Boulton, D. Goodhead, and A. J. Jeffreys, Induction of minisatellite mutations in the mouse germline by low-dose chronic exposure to gamma-radiation and fission neutrons, Mutat. Res., 453, 17–24 (2000).Google Scholar
  19. Dubrova, Y. E., M. Plumb, J. Brown, J. Fennelly, P. Bois, D. Goodhead, and A. J. Jeffreys, Stage specificity, dose response, and doubling dose for mouse minisatellite germ-line mutation induced by acute radiation, Proc. Natl. Acad. Sci. USA, 95, 6251–255 (1998).CrossRefGoogle Scholar
  20. Dubrova, Y. E., Radiation-induced mutation at tandem repeat DNA loci in the mouse germline: spectra and doubling doses, Radiat. Res., 163, 200–207 (2005).CrossRefGoogle Scholar
  21. Dubrova, Y. E., Radiation-induced transgenerational instability, Oncogene, 22, 7087–7093 (2003).CrossRefGoogle Scholar
  22. Fenech, M., N. Holland, W.P. Chang, E. Zieger, and S. Bonassi, The HUman MicroNucleus Project–An international collaborative study on the use of the micronucleus technique for measuring DNA damage in humans, Mutat. Res., 428, 271–283 (1999).Google Scholar
  23. Fomenko, L. A., G. V. Vasil’eva, and V. G. Bezlepkin, Micronucleus frequency is increased in bone marrow erythrocytes from offspring of male mice exposed to chronic low-dose gamma irradiation, Biol. Bull., 28, 419–423 (2001).Google Scholar
  24. Friedberg, E. C., G. C. Walker, W. Siede, R. D. Wood, R. A. Schultz, and T. Ellenberger, DNA Repair and Mutagenesis (ASM Press, Washington, 2006).Google Scholar
  25. Gardner, M. J., M. P. Snee, A. J. Hall, C. A. Powell, S. Downes, and J. D. Terrell, Results of case-control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria, Br. Med. J., 300, 423–429 (1990).CrossRefGoogle Scholar
  26. Garwicz, S., H. Anderson, J. H. Olsen, H. Dollner, H. Hertz, G. Jonmundsson, F. Langmark, M. Lanning, T. Moller, R. Sankila, and H. Tulinius, Second malignant neoplasms after cancer in childhood and adolescence: a population-based case-control study in the 5 Nordic countries, Int. J. Cancer, 88, 672–678 (2000).CrossRefGoogle Scholar
  27. Gibbs, M., A. Collick, R. G. Kelly, and A. J. Jeffreys, A tetranucleotide repeat mouse minisatellite displaying substantial somatic instability during early preimplantation development, Genomics, 17, 121–128 (1993).CrossRefGoogle Scholar
  28. Gondo, Y., J. M. Gardner, Y. Nakatsu, D. Durham-Pierre, and S. A. Deveau, C. Kuper and M. H. Brilliant. High-frequency genetic reversion mediated by a DNA duplication: the mouse pink-eyed unstable mutation, Proc. Natl. Acad. Sci. USA, 90, 297–301 (1993).CrossRefGoogle Scholar
  29. Goodhead, D. T., Spatial and temporal distribution of energy, Health Phys., 55, 231–240 (1988).CrossRefGoogle Scholar
  30. Gorgoulis, V. G., L. V. Vassiliou, P. Karakaidos, P. Zacharatos, A. Kotsinas, T. Liloglou, M. Venere, R. A. Ditullio, Jr., N. G. Kastrinakis, B. Levy, D. Kletsas, A. Yoneta, M. Herlyn, C. Kittas, and T. D. Halazonetis, Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions, Nature, 434, 907–913 (2005).CrossRefGoogle Scholar
  31. Hales, B. F., K. Crosman, and B. Robaire, Increased postimplantation loss and malformations among the F2 progeny of male rats chronically treated with cyclophosphamide, Teratology, 45, 671–678 (1992).CrossRefGoogle Scholar
  32. Harrouk, W., A. Codrington, R. Vinson, B. Robaire, and B. F. Hales, Paternal exposure to cyclophosphamide induces DNA damage and alters the expression of DNA repair genes in the rat preimplantation embryo, Mutat. Res., 461, 229–241 (2000).Google Scholar
  33. Holliday, R., The inheritance of epigenetic defects, Science, 238, 163–170 (1987).CrossRefGoogle Scholar
  34. Hoyes, K. P., B. I. Lord, C. McCann, J. H. Hendry, and I. D. Morris, Transgenerational effects of preconception paternal contamination with (55) Fe, Radiat. Res., 156, 488–494 (2001).CrossRefGoogle Scholar
  35. Huang, L., A. R. Snyder, and W. F. Morgan, Radiation-induced genomic instability and its implications for radiation carcinogenesis, Oncogene, 22, 5848–854 (2003).CrossRefGoogle Scholar
  36. Jackson, A. L. and L. A. Loeb, The contribution of endogenous sources of DNA damage to the multiple mutations in cancer, Mutat. Res., 477, 7–21 (2001).Google Scholar
  37. Jones, P. A. and S. B. Baylin, The fundamental role of epigenetic events in cancer, Nat. Rev. Genet., 3, 415–428 (2002).CrossRefGoogle Scholar
  38. Kassie, F., W. Parzefall, and S. Knasmuller, Single cell gel electrophoresis assay: a new technique for human biomonitoring studies, Mutat. Res., 463, 13–31 (2000).CrossRefGoogle Scholar
  39. Kelly, R., G. Bulfield, A. Collick, M. Gibbs and A. J. Jeffreys, Characterization of a highly unstable mouse minisatellite locus: evidence for somatic mutation during early development, Genomics, 5, 844–856 (1989).CrossRefGoogle Scholar
  40. Kropacova, K., L. Slovinska, and E. Misurova, Cytogenetic changes in the liver of progeny of irradiated male rats, J. Radiat. Res., 43, 125–133 (2002).CrossRefGoogle Scholar
  41. Limoli, C. L., B. Ponnaiya, J. J. Corcoran, E. Giedzinski, M. I. Kaplan, A. Hartmann, and W. F. Morgan, Genomic instability induced by high and low LET ionizing radiation, Adv. Space. Res., 25, 2107–117 (2000).CrossRefGoogle Scholar
  42. Little, J. B., Radiation carcinogenesis, Carcinogenesis, 21, 397–404 (2000).CrossRefGoogle Scholar
  43. Loeb, L. A., K. R. Loeb, and J. P. Anderson, Multiple mutations and cancer, Proc. Natl. Acad. Sci. USA, 100, 776–781 (2003).CrossRefGoogle Scholar
  44. Lord, B. I., L. B. Woolford, L. Wang, D. McDonald, S. A. Lorimore, V. A. Stones, E. Wright, G. and D. Scott, Induction of lympho-haemopoietic malignancy: impact of preconception paternal irradiation, Int. J. Radiat. Biol., 74, 721–728 (1998).Google Scholar
  45. Lord, B. I., L. B. Woolford, L. Wang, V. A. Stones, D. McDonald, S. A. Lorimore, D. Papworth, E. G. Wright, and D. Scott, Tumour induction by methyl-nitroso-urea following preconceptional paternal contamination with plutonium-239, Br. J. Cancer, 78, 301–311 (1998).Google Scholar
  46. Lorimore, S. A., P. J. Coates, and E. G. Wright, Radiation-induced genomic instability and bystander effects: inter-related nontargeted effects of exposure to ionizing radiation, Oncogene, 22, 7058–7069 (2003).CrossRefGoogle Scholar
  47. Luke, G. A., A. C. Riches, and P. E. Bryant, Genomic instability in haematopoietic cells of F1 generation mice of irradiated male parents, Mutagenesis, 12, 147–152 (1997).CrossRefGoogle Scholar
  48. Luning, K. G., H. Frolen, and A. Nilsson, Genetic effects of 239Pu salt injections in male mice, Mutat. Res., 34, 539–542 (1976).Google Scholar
  49. Matsuda, Y. and I. Tobari, Repair capacity of fertilized mouse eggs for X-ray damage induced in sperm and mature oocytes, Mutat. Res., 210, 35–47 (1989).Google Scholar
  50. Mohrenweiser, H. W., D. M. Wilson, and I. M. Jones, Challenges and complexities in estimating both the functional impact and the disease risk associated with the extensive genetic variation in human DNA repair genes, Mutat. Res., 526, 93–125 (2003).Google Scholar
  51. Morgan, W. F., Non-targeted and delayed effects of exposure to ionizing radiation: I. Radiation-induced genomic instability and bystander effects in vitro, Radiat. Res., 159, 567–580 (2003a).CrossRefGoogle Scholar
  52. 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 (2003b).CrossRefGoogle Scholar
  53. Mothersill, C. E., K. J. O’Malley, D. M. Murphy, C. B. Seymour, S. A. Lorimore, and E. G. Wright, Identification and characterization of three subtypes of radiation response in normal human urothelial cultures exposed to ionizing radiation, Carcinogenesis, 20, 2273–278 (1999).CrossRefGoogle Scholar
  54. Niwa, O. and R. Kominami, Untargeted mutation of the maternally derived mouse hypervariable minisatellite allele in F1 mice born to irradiated spermatozoa, Proc. Natl. Acad. Sci. USA, 98, 1705–710 (2001).CrossRefGoogle Scholar
  55. Nomura, T., H. Nakajima, H. Ryo, L.Y. Li, Y. Fukudome, S. Adachi, H. Gotoh, and H. Tanaka, Transgenerational transmission of radiation- and chemically induced tumors and congenital anomalies in mice: studies of their possible relationship to induced chromosomal and molecular changes, Cytogenet. Genome Res., 104, 252–260 (2004).CrossRefGoogle Scholar
  56. Nomura, T., Parental exposure to x rays and chemicals induces heritable tumours and anomalies in mice, Nature, 296, 575–577 (1982).CrossRefGoogle Scholar
  57. Nomura, T., Transgenerational carcinogenesis: induction and transmission of genetic alterations and mechanisms of carcinogenesis, Mutat. Res., 544, 425–432 (2003).CrossRefGoogle Scholar
  58. Nomura, T., X-ray-induced germ-line mutation leading to tumors. Its manifestation in mice given urethane post-natally, Mutat. Res., 121, 59–65 (1983).CrossRefGoogle Scholar
  59. Pils, S., W-U. Muller, and C. Streffer, Lethal and teratogenic effects in two successive generations of the HLG mouse strain after radiation exposure of zygotes - association with genomic instability?, Mutat. Res., 429, 85–92 (1999).Google Scholar
  60. Ponnaiya, B., M. N. Cornforth, and R. L. Ullrich, Radiation-induced chromosomal instability in BALB/c and C57BL/6 mice: the difference is as clear as black and white, Radiat. Res., 147, 121–125 (1997).CrossRefGoogle Scholar
  61. Rakyan, V. K., J. Preis, H. D. Morgan, and E. Whitelaw, The marks, mechanisms and memory of epigenetic states in mammals, Biochem. J., 356, 1–10 (2001).CrossRefGoogle Scholar
  62. Rassoulzadegan, M., V. Grandjean, P. Gounon, S. Vincent, I. Gillot, and F. Cuzin, RNA-mediated non-Mendelian inheritance of an epigenetic change in the mouse, Nature, 241, 469–474 (2006).CrossRefGoogle Scholar
  63. Reik, W. and J. Walter, Genomic imprinting: parental influence on the genome, Nat. Rev. Genet., 2, 21–32 (2001).CrossRefGoogle Scholar
  64. Roderick, T. H., The response of twenty-seven inbred strains of mice to daily doses of whole body X-irradiation, Radiat. Res., 20, 631–639 (1963).CrossRefGoogle Scholar
  65. Roemer, I., W. Reik, W. Dean, and J. Klose, Epigenetic inheritance in the mouse, Current Biol., 7, 277–280 (1997).CrossRefGoogle Scholar
  66. Rousseaux, S., C. Caron, J. Govin, C. Lestrat, A. K. Faure, and S. Khochbin, Establishment of male-specific epigenetic information, Gene, 345, 139–153 (2005).CrossRefGoogle Scholar
  67. Sancar, A., L. A. Lindsey-Boltz, K. Unsal-Kacman, and S. Linn, Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints, Annu. Rev. Biochem., 73, 39–85 (2004).CrossRefGoogle Scholar
  68. Sanova, S., S. Balentova, L. Slovinska, and E. Misurova, Effects of preconception gamma irradiation on the development of rat brain, Neurotoxicol. Teratol., 2005, 27, 145–151 (2005).CrossRefGoogle Scholar
  69. Shimada, A. and A. Shima, Transgenerational genomic instability as revealed by a somatic mutation assay using the medaka fish, Mutat. Res., 552, 119–124 (2004).Google Scholar
  70. Shimada, A., H. Eguchi, S. Yoshinaga, and A. Shima, Dose-rate effect on transgenerational mutation frequencies in spermatogonial stem cells of the medaka fish, Radiat. Res., 163, 112–114 (2005).CrossRefGoogle Scholar
  71. Shimura, T., M. Inoue, M. Taga, K. Shiraishi, N. Uematsu, N. Takei, Z-M. Yuan, T. Shinohara, and O. Niwa, p53-dependent S-phase damage checkpoint and pronuclear cross talk in mouse zygotes with X-irradiated sperm, Mol. Cell. Biol., 22, 2220–228 (2002).CrossRefGoogle Scholar
  72. Shiraishi, K., T. Shimura, M. Taga, N. Uematsu, Y. Gondo, M. Ohtaki, R. Kominami, and O. Niwa, Persistent induction of somatic reversions of the pink-eyed unstable mutation in F1 mice born to fathers irradiated at the spermatozoa stage, Radiat. Res., 157, 661–667 (2002).CrossRefGoogle Scholar
  73. Sigurdson, A. J. and I. M. Jones, Second cancers after radiotherapy: any evidence for radiation-induced genomic instability?, Oncogene, 22, 7018–7027 (2003).CrossRefGoogle Scholar
  74. Slovinska, L., A. Elbertova, and E. Misurova, Transmission of genome damage from irradiated male rats to their progeny, Mutat. Res., 559, 29–37 (2004).Google Scholar
  75. Turusov, V. S., T. V. Nikonova, and Yu. D. Parfenov, Increased multiplicity of lung adenomas in five generations of mice treated with benz(a) pyrene when pregnant, Cancer Lett., 55, 227–231 (1990).CrossRefGoogle Scholar
  76. UNSCEAR, Hereditary Effects of Radiation (United Nations, New York, 2001).Google Scholar
  77. UNSCEAR, Sources and Effects of Ionizing Radiation. Annex I. Epidemiological evaluation of radiation-induced cancer. Vol. 2. (United Nations, New York, 2000).Google Scholar
  78. Vance, M. M., J. E. Baulch, O. G. Raabe, L. M. Wiley and J. W. Overstreet, Cellular reprogramming in the F3 mouse with paternal F0 radiation history, Int. J. Radiat. Biol., 78, 513–526 (2002).CrossRefGoogle Scholar
  79. Vilarino-Guell, C., A. G. Smith, and Y. E. Dubrova, Germline mutation induction at mouse repeat DNA loci by chemical mutagens, Mutat. Res., 526, 63–73 (2003).Google Scholar
  80. Vorobtsova, I. E., Irradiation of male rats increases the chromosomal sensitivity of progeny to genotoxic agents, Mutagenesis, 15, 33–38 (2000).CrossRefGoogle Scholar
  81. Vorobtsova, I. E., L. M. Aliyakparova, and V. N. Anisimov, Promotion of skin tumors by 12-O-tetradecanoylphorbol-13-acetate in two generations of descendants of male mice exposed to X-ray irradiation, Mutat. Res., 287, 207–216 (1993).Google Scholar
  82. Watson, G. E., S. A. Lorimore, S. M. Clutton, M. A. Kadhim, and E. G. Wright, Genetic factors influencing alpha-particle-induced chromosomal instability, Int. J. Radiat. Biol., 71, 497–503 (1997).CrossRefGoogle Scholar
  83. Wiley, L. M., J. E. Baulch, O. G. Raabe, and T. Straume, Impaired cell proliferation in mice that persists across at least two generations after paternal irradiation, Radiat. Res., 148, 145–151 (1997).CrossRefGoogle Scholar
  84. Yauk, C. L., Y. E. Dubrova, G. R. Grant, and A. J. Jeffreys, A novel single molecule analysis of spontaneous and radiation-induced mutation at a mouse tandem repeat locus, Mutat. Res., 500, 147–156 (2002).Google Scholar
  85. Yu, Y., R. Okayasu, M. M. Weil, A. Silver, M. McCarthy, R. Zabriskie, S. Long, R. Cox, and R. L. Ullrich, Elevated breast cancer risk in irradiated BALB/c mice associates with unique functional polymorphism of the Prkdc (DNA-dependent protein kinase catalytic subunit) gene, Cancer Res., 61, 1820–824 (2001).Google Scholar
  86. Goldberg, Z. Clinical implications of radiation-induced genomic instability, Oncogene, 22, 7011–7017 (2003).CrossRefGoogle Scholar
  87. Zhang, S., E. S. Ramsay, and B. A. Mock, Cdkn2a, the cyclin-dependent kinase inhibitor encoding p16INK4a and p19ARF, is a candidate for the plasmacytoma susceptibility locus, Pctr1, Proc. Natl. Acad. Sci. USA, 95, 2429–434 (1998).CrossRefGoogle Scholar

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© Springer 2007

Authors and Affiliations

  1. 1.Department of GeneticsUniversity of LeicesterUK

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