Genomic instability in non-targeted bystander mammalian cells

抄録

The radiobiological effects of low doses of ionizing radiation are subject to modulations by various parameters including bystander effects, adaptive response, genomic instability and genetic susceptibility of the exposed individuals. Although the inter-relationship between bystander effects and adaptive responses have recently been discussed in the context of low dose effect, the correlation between genomic instability and non-targeted bystander cells are far from clear. Using the Columbia University microbeam, we selectively irradiated an exact fraction of cells in a population of either human fibroblasts or human-hamster hybrid (A_L) cells with a lethal dose of alpha particles. The non-hit, bystander cells were followed over a range of time periods up to 40 days to ascertain both the incidence of mutagenesis at the CD59 locus and chromosomal aberrations using M-FISH. A progressive increase in mutagenesis as well as chromosomal rearrangements characterized by deletions, duplications, insertions, para- and peri- centric inversions, and reciprocal and nonreciprocal translocations involving human chromosome 11 were detected. Furthermore, in the presence of chemical inhibitors of gap junctions and cyclooxygenase-2, the induced genomic instability was significantly suppressed. These data indicate that genomic instability can be induced in both directly irradiated as well as in bystander cells generations after the original radiation exposure, at similar levels, independently of initial cell-cell contact.