By NCF Medical Committee
Copyright 2014

From Spring 2014 Forum

In 1992, scientists first described radiation-induced chromosomal instability. Formally, this refers to the induction of chromosomal rearrangements in the progeny of irradiated cells. The chromosomal instability was observed in cells that had undergone multiple cell division cycles after ionizing radiation exposure. What this demonstrated scientifically was that of delayed cytogenetic damage which has since been confirmed by many research investigators. This suggests that ionizing radiation can elicit a memory in an irradiated cell that can manifest as cytogenetic changes weeks, even months, after cellular irradiation.

At the time that these chromosomal alterations are observed, the radiation-induced DNA lesions are presumably long gone, either as a consequence of DNA repair processes or by dilution during successive cell division cycles. It has been suggested that the memory of ionizing radiation must include the delayed induction of genetic lesions in the progeny of an irradiated cell. Radiation-induced chromosomal instability has been described both in-vivo in both animal studies and in exposed human populations. There has been intense scientific interest in this area of research.

The conventional understanding of the mechanisms of radiation-induced chromosomal instability is further complicated by convincing scientific evidence demonstrating that chromosomal instability can be observed in the progeny of cells that were not irradiated and thus not subjected to energy-deposition events. Using alpha-particles, scientists showed chromosomal instability in significantly greater numbers of clonogenic survivors than could possibly have been hit by radiation. Extending these initial observations, other researchers described chromosomal instability in cells that were protected from radiation exposure by a metal grid, while cells around them had been lethally irradiated and were, thus, non-viable. These non-targeted surviving cells were likely subject to signals from irradiated cell-to-cell communications or factors that were produced by an irradiated cell and being available to interact with a non-targeted cell by exposure in the culture medium or possibly a combination of the above. Of particular interest is that radiation-induced chromosomal instability in-vivo also appears to have a significant non-targeted component that might also involve the transmission of soluble signaling factors.

To possibly explain the transfer of a signal from a targeted cell to a non-targeted cell that can induce chromosomal rearrangements, these signals must be soluble, relatively long lived, and capable of reaching the nucleus of the non-targeted cell as well as inducing DNA strand breaks. As far back as the 1950's, this has been described in-vivo in humans occupationally, therapeutically, or accidentally exposed to ionizing radiation. Blood plasma isolated from these irradiated individuals can induce chromosomal breakage when mixed and co-cultured with peripheral blood lymphocytes from non-irradiated individuals. These clastogenic factors indicate that soluble factors can be induced in irradiated humans and these can cause cytogenetic damage in normal healthy lymphocytes.

References:

1. Chromosomal Alterations: Methods, Results and Importance in Human Health; Gunter Obe, Vijayalaxmi - Editors; Springer-Verlag Publishers, 2007
2. Transmission of chromosomal instability after plutonium alpha-particle irradiation; Kadhim MA, Macdonald DA, Goodhead DT, Lorimore SA, Marsden SJ, Wright EG; Nature, 1992 Feb 20;355(6362):738-40.
3. Non-targeted and delayed effects of exposure to ionizing radiation: I. Radiation-induced genomic instability and bystander effects in vitro; Morgan WF; Radiat Res. 2003 May;159(5):567-80.
4. 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; Morgan WF; Radiat Res. 2003 May;159(5):581-96.
5. Genetic instability in radiation-induced leukaemias: mouse models; Plumb M, Cleary H, Wright E; Int J Radiat Biol. 1998 Dec;74(6):711-20.
6. In vivo chromosomal instability and transmissible aberrations in the progeny of haemopoietic stem cells induced by high- and low-LET radiations; Watson GE, Pocock DA, Papworth D, Lorimore SA, Wright EG; Int J Radiat Biol. 2001 Apr;77(4):409-17.
7. Chromosomal instability in unirradiated cells induced in vivo by a bystander effect of ionizing radiation; Watson GE, Lorimore SA, Macdonald DA, Wright EG; Cancer Res. 2000 Oct 15;60(20):5608-11.
8. Chromosomal instability in acute myelocytic leukemia and myelodysplastic syndrome patients among atomic bomb survivors; Nakanishi M, Tanaka K, Shintani T, Takahashi T, Kamada N; J Radiat Res. 1999 Jun;40(2):159-67.
9. Chromosomal instability in in vivo radiation exposed subjects; Salomaa S, Holmberg K, Lindholm C, Mustonen R, Tekkel M, Veidebaum T, Lambert B; Int J Radiat Biol. 1998 Dec;74(6):771-9.
10. Chromosomal instability in the descendants of unirradiated surviving cells after alpha-particle irradiation; Lorimore SA, Kadhim MA, Pocock DA, Papworth D, Stevens DL, Goodhead DT, Wright EG; Proc Natl Acad Sci U S A. 1998 May 12;95(10):5730-3.
11. Chromosome aberrations in lymphocytes and clastogenic factors in plasma detected in Belarus children 10 years after Chernobyl accident; Gemignani F, Ballardin M, Maggiani F, Rossi AM, Antonelli A, Barale R; Mutat Res. 1999 Dec 13;446(2):245-53.
12. Chromosome damage induced by plasma of x-rayed patients: an indirect effect of x-ray; Hollowell JG Jr, Littlefield LG; Proc Soc Exp Biol Med. 1968 Oct;129(1):240-4.
13. Chromosomal aberrations induced by plasma from irradiated patients: an indirect effect of X radiation. Further observations and studies of a control population; Littlefield LG, Hollowell JG Jr, Pool WH Jr; Radiology. 1969 Oct;93(4):879-86.
14. Breaks in normal human chromosomes: are they induced by a transferable substance in the plasma of persons exposed to total-body irradiation; Goh K, Sumner H; Radiat Res. 1968 Jul;35(1):171-81.
15. Chromosome aberrations in normal leukocytes induced by the plasma of exposed individual; Pant GS, Kamada N; Hiroshima J Med Sci. 1977 Sep;26(2-3):149-54.
16. Changes in sternal marrow following roentgen-ray therapy to the spleen in chronic granulocytic leukemia; Parsons WB Jr, Watkins CH, Pease GL, Childs DS Jr; Cancer. 1954 Jan;7(1):179-89.