Chromosome damage in human cells by γ rays, α particles and heavy ions: track interactions in basic dose-response relationships

Abstract

We irradiated normal human lymphocytes and fibroblasts with (137)Cs γ rays, 3.5 MeV α particles and 1 GeV/amu (56)Fe ions and measured the subsequent formation of chromosome-type aberrations by mFISH at the first mitosis following irradiation. This was done for the purposes of characterizing the shape of dose-response relationships and determining the frequency distribution of various aberration types with respect to the parameters of dose, radiation quality and cell type. Salient results and conclusions include the following. For low-LET γ rays, lymphocytes showed a more robust dose response for overall damage and a higher degree of upward curvature compared to fibroblasts. For both sources of high-LET radiation, and for both cell types, the response for simple and complex exchanges was linear with dose. Independent of all three parameters considered, the most likely damage outcome was the formation of a simple exchange event involving two breaks. However, in terms of the breakpoints making up exchange events, the majority of damage registered following HZE particle irradiation was due to complex aberrations involving multiple chromosomes. This adds a decidedly nonlinear component to the overall breakpoint response, giving it a significant degree of positive curvature, which we interpret as being due to interaction between ionizations of the primary HZE particle track and long-range δ rays produced by other nearby tracks. While such track interaction had been previously theorized, to the best of our knowledge, it has never been demonstrated experimentally.

FIG. 1

Total chromosome breakpoints per cell. The minimum number of chromosome breaks required to produce each aberration is determined from the number of color junctions or open breaks that are required to produce the mFISH pattern observed. These are totaled and expressed here as the mean number of breakpoints per cell. The error bars represent standard deviations assuming a Poisson distribution. Lines represent least squared fits to the data (see Table 2 for parameters). (●) γ-irradiated fibroblasts, (▲) γ-irradiated lymphocytes, (◆) ⁵⁶Fe ion-irradiated lymphocytes and (▼) α-particle irradiated fibroblasts.

FIG. 2

Simple and complex exchanges. Panels A–C: exchanges per cell. Panels D–E: breakpoints per cell. The error bars represent standard deviations assuming a Poisson distribution. Lines represent least squared fits to the data (see Table 3 for parameters). Solid symbols and lines: simple exchanges; open symbols and dashed lines: complex exchanges. (●, ○) γ-irradiated fibroblasts; (▲, △) γ-irradiated lymphocytes; (◆,◇) ⁵⁶Fe ion-irradiated lymphocytes and (▼, ▽) α-particle irradiated fibroblasts.

FIG. 3

Frequency distributions of breakpoints per cell. In each panel, small graphs to the left of the main plot show the frequency of undamaged cells. Panels A–D represent breakpoint distributions for isoeffective doses (see text). Panels E and F show distributions for the unirradiated controls.

FIG. 4

Frequency distributions of breakpoints versus chromosome aberrations per cell. This figure compares the frequency of breakpoints in cells with specific numbers of aberrations. NB: a cell with a single simple exchange (2 breakpoints) will be recorded at 2 breakpoints, 1 aberration. A cell with two simple exchanges will be recorded at 4 breakpoints, 2 aberrations and so forth. Panels A–D correspond to panels A–D on Fig. 3. Panels E and F represent the highest doses delivered to lymphocytes and do not correspond to the iso-effective doses plotted in Fig. 3. The frequency axes on these panels are also plotted on a different scale.

FIG. 5

Frequency distributions of chromosome aberration size. Sizes of chromosome aberrations in terms of breakpoints are plotted as frequencies relative to the total number of aberrations. Points for each dose are offset around a specific size to allow greater clarity. The error bars represent standard deviations assuming a Poisson distribution. Panel A: γ-irradiated fibroblasts, (△) 0.9 Gy, (○) 1.8 Gy and (▽) 3.6 Gy. Panel B: γ-irradiated lymphocytes, (△) 1 Gy, (○) 2 Gy and (▽) 4 Gy. Panel C: α-irradiated fibroblasts, (□) 0.1 Gy, (△) 0.2 Gy, (▽) 0.4 Gy and (○) 0.6 Gy. Panel D: Fe ion-irradiated lymphocytes, (□) 0.2 Gy, (△) 0.4 Gy, (○) 0.7 Gy, (▽), 1.0 Gy and (◇) 1.5 Gy.

FIG. 6

Diagram of available comparisons between fibroblasts and lymphocytes exposed to low-LET ¹³⁷Cs γ rays and high-LET radiations from either ²³⁸Pu α particles or ⁵⁶Fe heavy ions. The four comparisons are numbered to correspond to the appropriate subsections of the Discussion section.