Cellular exposure to DNA damaging agents like ionizing radiation can result in direct (targeted) damage to the genetic material and a number of non-targeted indirect effects that can manifest in the progeny of a damaged cell. Both targeted and non-targeted effects can result in DNA mutations, gene amplifications, chromosomal rearrangements, carcinogenesis, and even cell death. The paradigm for understanding how induced damage results in these cellular endpoints dictates that cellular responses to the induced damage, e.g., DNA repair, and cell cycle arrest fix the damage and thereby seal the fate of the irradiated cell. However, non-targeted effects cannot be accounted for by this paradigm. This presentation will focus on delayed genetic effects occurring in the progeny of cells after exposure to ionizing radiation. We will describe how the cellular micro-environment can perpetuate instability in clonally expanded populations of cells surviving irradiation. The emphasis will be on gene expression analysis, the persistently elevated levels of reactive oxygen species and the role of mitochondrial dysfunction that characterize many of our chromosomally unstable clones. These results will be discussed in terms of non-targeted bystander like effects where by cells that themselves were not irradiated exhibit many of the same detrimental effects as irradiated cells. In addition, other non-targeted effects associated with radiation exposure including clastogenic factors, the death inducing effect, hereditary effects, and abscopal effects of radiation and how these might impact on human disease will be discussed.

This work was supported by the Biological and Environmental Research Program (BER), U.S. Department of Energy.