) Ever since x-rays were shown to induce mutations in Drosophila more than 70 years ago, prevailing dogma considered the genotoxic effects of ionizing radiation as being due mostly to direct damage to the nucleus. While suggestive evidence that extracellular/extranuclear that extracellular/extranuclear targets may play a role in such damage has surfaced recently, direct proof of this not been available. With the availability of a precision charged particle microbeam, we showed recently, and for the first time, that irradiation of cellular cytoplasm with either a single or an exact number of alpha-particles results in gene mutations in the nucleus and that reactive oxygen species mediate the process. Furthermore, we have preliminary evidence indicating that irradiation of a fixed proportion of randomly selected mammalian cells with a lethal dose of 20 alpha-particles each enhanced the background mutant yield of neighboring, non-irradiated cells by 3 fold The overall goals of this application are 1) To determine the mutagenic response of neighboring, non-irradiated human-hamster hybrid mutagenic response of neighboring, non-irradiated human-hamster hybrid (AL) cells (bystanders) after a fixed proportion of the cultures are irradiated with an exact number of alpha-particle traversals either through the nucleus or cytoplasm; 2) To examine the mechanism(s) for the bystander mutagenic response in mammalian cells. To address these goals, a series of 6 testable hypotheses are proposed to be examined by 11 well-defined specific aims. By using a more sensitive assay system which allows the detection of mutants on marker genes located on a non-essential chromosome, quantification of mutagenic effects of alpha-particles will be studied. Using specific probes for marker genes mapped to human chromosome 11, the molecular changes that result in cellular mutations at the S1 locus as a result of bystander mutagenic response will be examined.
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