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Office of Biological and Environmental Research

DOE Lowdose Radiation Program Workshop IV

Abstract

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Title: Full 24-color Painting Of Human Chromosomes Reveals Differences In The Spectra of Cytogenetic Damage Produced by ¹³⁷Cs Y rays, ²³⁸Pu a Particles and ⁵⁶Fe Ions.

Authors: Michael N. Cornforth, PI; Bradford D. Loucas, Co-PI

High LET exposures cause more chromosome damage per unit dose than do low
LET exposures. Because most chromosome aberrations are exchanges that require the interaction of breaks located in close spatial and temporal proximity, changes in
ionization density and/or track structure for a given dose of radiation are expected to
influence the frequency of exchanges, particularly the relative contribution of complex
exchanges, which require the interaction of three or more chromosome breaks. It is in this context that the spectrum of cytogenetic damage seen following irradiation
with high LET radiation (particularly HZE particles) is of relevance to manned space
exploration. Such information is also of importance as it relates to predictions of
biophysical models of radiation action, including those upon which low-dose
extrapolations are based.

Unstimulated (G0) human lymphocytes were irradiated with accelerated Fe ions with energies ranging from 0.5 to 5.0 GeV/n, and to 662 keV ¹³⁷Cs y rays; human fibroblasts were exposed to 3.5 MeV a particles from ²³⁸Pu. mFISH was used to study the frequency of chromosome exchanges at the first postirradiation mitosis, so as to distinguish simple from complex exchanges.

High LET exposures from ²³⁸Pu a particles and ⁵⁶Fe Ions produced far more
complex exchanges per unit dose compared to low LET exposures from ¹³⁷Cs y rays, an 18-fold increase in the case of ⁵⁶Fe ions following 1 Gy. Such relatively low-fluence HZE exposures occasionally resulted in spectacularly complex exchanges, in one case involving (at least) 28 chromosomes and over 60 breaks. The relative contribution of complex versus simple aberrations was such that the dose responses for the three types of radiation could be easily distinguished from one another as a function of dose, suggesting that this approach may provide a robust cytogenetic “signature” of prior exposure that is reflective of LET and/or track structure.

There is some evidence that densely ionizing radiations are capable of producing
breaks that are qualitatively different (i.e., more difficult to rejoin) than those produced
by their sparsely ionizing counterparts. In that case one might expect high LET
exposures to cause an excess of unrejoined breaks. Interestingly, of the total breakpoints detectable by mFISH, the fraction that remained unrejoined—in the form of either a terminal deletion or incomplete exchange—was found to be nearly identical for ¹³⁷Cs Y rays and ²³⁸Pu a particles. ⁵⁶Fe Ions did cause a increase in the relative frequency of unrejoined breaks, although the effect was not nearly large enough to account for the high relative biological effectiveness of this HZE radiation. We interpret this result to imply that the vast majority of DNA dsbs from high LET radiation are not qualitatively different than those produced by low LET radiation, at least not in terms of a cell’s ability to rejoin them.

On the other hand, Fe ions also induced a small number of bizarre complex
exchanges that we believe represent true hybrid “chromosome-chromatid-type” damage interactions (as opposed to chromatid-isochromatid interactions commonly seen following exposure during S or G₂phases of the cell cycle.) If this interpretation is correct, it would imply that HZE particles are capable producing lesions in DNA which are probably not dsbs, but some other form of DNA damage whose manifestation as chromosome aberrations requires passage into S phase. Although these novel rearrangements were relatively rare, that we have never observed them following exposure to gamma rays or alpha particles argues in favor of HZE particles being capable of producing a type of damage that is qualitatively different than that produced by other types of ionizing radiation.

Research was supported by the Office of Science (BER), U.S. Department of Energy, Grant No. DE-FG03-02ER63442 and the National Aeronautical and Space Administration Office of Biological and Physical Research (NASA/OBPR).