Hierarchical and cybernetic nature of biologic systems and their relevance to homeostatic adaptation to low-level exposures to oxidative stress-inducing agents.

During evolution in an aerobic environment, multicellular organisms survived by adaptive responses to both the endogenous oxidative metabolism in the cells of the organism and the chemicals and low-level radiation to which they had been exposed. The defense repertoire exists at all levels of the biological hierarchy--from the molecular and biochemical level to the cellular and tissue level to the organ and organ system level. Cells contain preventive antioxidants to suppress oxidative damage to membranes. Cells also contain proteins and DNA; built-in redundancies for damaged molecules and organelles; tightly coupled redox systems; pools of reductants; antioxidants; DNA repair mechanisms and sensitive sensor molecules such as nuclear factor kappa beta; and signal transduction mechanisms affecting both transcription and post-translational modification of proteins needed to cope with oxidative stress. The biologic consequences of the low-level radiation that exceeds the background level of oxidative damage could be necrosis or apoptosis, cell proliferation, or cell differentiation. These effects are triggered by oxidative stress-induced signal transduction mechanisms--an epigenetic, not genotoxic, process. If the end points of cell proliferation, differentiation, or cell death are not seen at frequencies above background levels in an organism, it is unlikely that low-level radiation would play a role in the multistep processes of chronic diseases such as cancer. The mechanism linked to homeostatic regulation of proliferation and adaptive functions in a multicellular organism could provide protection of any one cell receiving deposited energy by the radiation tract through the sharing of reductants and by triggering apoptosis of target stem cells. Examples of the role of gap junctional intercellular communication in the adaptive response of cells and the bystander effect illustrate how the interaction of cells can modulate the effect of radiation on the single cell.