) The broad purpose of this application is to better characterize and understand mechanisms involved in the phenomenon of heritable genomic instability induced in low passage cultured normal human cells following exposure to high atomic number high energy (HZE) particles such as iron nuclei and other high LET charged particles. The focus of the proposed studies is on the high frequency delayed chromosomal instability that the applicant and others have seen after exposure to such high LET radiations. To better characterize the phenomenon, the applicant has designed specific aims to (1) carefully determine dose-response relationships for initiation of instability and follow accumulation of any stable or complex aberrations, (2) follow the development of instability in the progeny of individual cells to see if, and how, the heritable property arises and segregates in the lineage, (3) determine whether the heritable chromosomal instability trait behaves in a dominant or recessive manner by measuring the development or lack of development of this property in hybrids formed by fusing irradiated and unirradiated cells, and (4) examine the possible correlation between the development of chromosomal versus mutational instabilities, at least at the HPRT locus. With regard to mechanisms, he would examine the possibility that (5) the development of instability is related to an induced alteration in the ability of cells to cope with oxygen related free radical damage by comparing such development under an oxygen tension reduced from 20 to 2 percent, as is more typical of the levels in normal human tissues; all previous studies on the phenomenon have been carried out in air, i.e., approximately 20 percent oxygen. He would also compare time versus number of cell doublings required for the expression of chromosomal instabilities. Lastly, he would test the hypothesis that traversal of the cytoplasm of a cell and not the nucleus with one or more high LET particles is sufficient to induce chromosomal instability. Knowledge concerning radiation induced chromosomal instability is potentially very important for understanding why radiation, especially high LET radiation, is a """"""""complete carcinogen"""""""". The induction of an instability would allow the multi-step oncogenic process involving otherwise low frequency mutations and chromosomal rearrangements to proceed with an overall probability consistent with observed cancer induction frequencies after radiation exposure.
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