Abstract
Radiation-induced genomic instability (RIGI) encompasses a variety of effects such as delayed reproductive death, which occurs in the progeny of irradiated cells multiple generations after the initial insult. Whereas the biological effectiveness in irradiated cells has been shown to vary with the LET of the radiation, the LET dependence of the manifestation of RIGI is incompletely characterized. To address this, we have investigated the delayed effects arising in the progeny of normal human diploid fibroblasts surviving exposure to low-LET gamma-rays (0.2 keV/μm) or high-LET heavy ions (16.2-1610 keV/μm). First, we examined delayed loss of clonogenicity as an endpoint of delayed reproductive death, and found that carbon ions (18.3 MeV/amu, 108 keV/μm) were most effective at reducing the clonogenic survival both in primary and secondary colonies. Second, to gain insight into potential cellular mechanisms underpinning the dose- and LET-dependent delayed loss of clonogenicity, morphological changes induced in primary colonies were assessed. It was found that while the yield of differentiated cells having reduced capacity to further proliferate was increased in a dose- and LET-dependent fashion, the incidence of giant or multinucleated cells was much less frequent. Collectively, our results suggest that accelerated differentiation may be a major defensive response in the descendants of irradiated fibroblasts to minimize further expansion of aberrant cells, and may account for LET-dependent delayed loss of clonogenicity,
