Bystander Effects and Adaptive Responses Modulate In Vitro and In Vivo Biological Responses to Low Dose Ionizing Radiation

We have utilized cellular and molecular approaches to characterize biological effects that are induced in normal mammalian cells and tissues exposed to low doses/low fluences of ionizing radiations that differ in their quality (i.e. linear energy transfer; LET). In human cells exposed to particulate radiations with high, but not low, LET character, the induced stressful effects were not only confined to the cells that have been directly targeted by the radiation, but involved a number of non-targeted and delayed effects. Chromosomal damage and oxidative changes in proteins and lipids were detected in cells exposed to alpha and high charge and high energy (HZE) particles and in their neighboring bystanders. Signaling events mediated via inflammatory cytokines and/or intercellular channels that comprise gap junctions were critical for the expression of the induced non-targeted effects. With relevance to health risks, the stressful changes in bystander cells were propagated to their progeny. In contrast, induced DNA repair and antioxidant defense mechanisms often attenuated the basal level of DNA damage and oxidative stress to below the spontaneous rate in tissues of animals and in cultured rodent and human cells exposed to low dose/low dose-rate gamma rays, a low LET radiation. Together, our data suggest that low dose radiation-induced signaling events act to alter the linearity of the dose-response relation that is predicted by biophysical arguments. They show that the nature of the altered responses strongly depend on radiation quality.