) For genomic instability to be of importance in radiation biology, it has to be induced in vivo in epithelial cells that are at risk for radiation-induced cancer. Genomic instability could provide a great marker for cancer risk if cells with high radiation-induced cancer rates are also sensitive to the induction of genomic instability. This application will use an in vivo/in vitro approach to determine the relationship between cancer risk and genomic instability and will help understand the role of cytogenetic damage as a potential mechanisms for induction and repair of genomic instability. This application will address three hypotheses: (1) Genomic instability is related to the amount or type of initial chromosome damage. (2) Genomic instability can be induced in vivo in respiratory epithelial cells and is directly related to cell sensitivity for the induction of cancer. (3) Lesions which are responsible for genomic instability are lost as a function of time after the radiation exposure. Wistar rats will be exposed to graded doses of both low LET X-rays and HZE particles (10000 MeV/Amu). The high energy iron particles are similar to those encountered in space flight and will be generated by the Alternating Gradient Synchrotron (AGS) at Brookhaven National Laboratory. Cells from regions of the respiratory tract that are known to be sensitive to the induction of cancer from high LET particles, deep lung epithelial cells; areas where no radiation-induced cancers have been observed, tracheal epithelial cells; and cells known to show genomic instability, bone marrow, will be isolated and evaluated for genomic instability using cytogenetic end-points. The frequency of micronuclei provides an indicator of the relative biological effect (RBE) for initial cytogenetic damage as a function of radiation type. The induction of chromatid type aberrations after several cell generations in tissue culture will be evaluated as an indicator of radiation-induced genomic instability. In cell types and populations that show genomic instability, the relationship between stable chromosome aberrations and the induction of genomic instability will be evaluated using fluorescence in situ hybridization techniques (FISH). The repair of the lesions responsible for the induction of genomic instability will be evaluated by serial sacrifice of animals exposed to both high and low LET radiation and the culture of the cells over extended periods of time. This protocol will address the stated hypotheses and provide radiobiological understanding of the relationships that exist between cell types, clastogenic change, genomic instability, and cancer risk from exposure in vivo to low doses of HZE particles.
| Brooks, Antone L; Lei, Xingye C; Rithidech, Kanokporn (2003) Changes in biomarkers from space radiation may reflect dose not risk. Adv Space Res 31:1505-12 |
| Barcellos-Hoff, M H; Brooks, A L (2001) Extracellular signaling through the microenvironment: a hypothesis relating carcinogenesis, bystander effects, and genomic instability. Radiat Res 156:618-27 |
