The goal of this core is to better define the risks of low level exposure to physical and chemical agents which damage DNA and to develop methods for reducing these risks. This core also functions as a resource within the Center in the area of genetic toxicology. Collaborations exist with the Occupational Health Core in developing biomarkers for effects of genotoxic agents to be used in epidemiological studies. These studies include markers of susceptibility (especially in minorities) to lung cancer in smokers, P53 and K-ras mutations in lung cancers, and variations in pharmacokinetics in the mutagenic effects of vinyl chloride in exposed workers. An overall theme of the research is the elucidation of genetic factors in environmental health. A training grant from NCI funds six predoctoral and six postdoctoral fellows, and an additional three students and five postdoctoral fellows are funded by other mechanisms. Three courses (graduate courses in cellular and molecular radiobiology, and an introductory course in cancer biology, as well as a radiation biology course for clinicians) are taught by members of this core. Members also contribute to a course in Principles of Toxicology. Faculty from this core have also acted on thesis-advisor committees for students in the other programs. Research and training are focused primarily in the areas of carcinogenesis and genetic toxicology. One area of interest is to understand the role of genome-wide instability in carcinogenesis. Studies have been carried out demonstrating the existence of """"""""coincident mutations"""""""", i.e. increased mutant frequency at a second locus in cells selected at the first locus, suggesting a general up-regulation of mutation rates in those cells. Microsatellite and minisatellite mutations are also increased in such cells. In cells surviving radiation, genomic instability is seen sometimes for up to 50 generations. The mutational spectrum of these late mutations was found to differ from that of direct x-ray induced mutations. Future goals are to more completely analyze these late-arising mutations and to test the hypothesis that oxidative metabolism may be up-regulated in a sub-set of cells which have elevated spontaneous mutation rates. The cdc2 expression was also found to be down-regulated following X-irradiation. This may explain the G2 delay. Factors in the host animal were found to be important in increasing the frequency of chromosome rearrangements and alterations in microsatellite and minisatellite mutations in tumor cells. Subsets of cancer patients treated with chemotherapeutic agents or radiotherapy also seem to have persistently elevated mutation frequencies. It was demonstrated that mutations in the p53 gene rendered cells hypermutable to X-rays. Cells lacking wild type p53 function are more resistant to X-rays. Different genes appear to have different sensitivities to mutation at different points in the cell cycle. Future studies will focus on the effects of transcription rates on mutability, effects of homologous sequences on recombination rates, involvement of inducible repair in the response of human cells to ionizing radiation, and the mechanism of cell cycle perturbations after genotoxic insult. Studies are also ongoing on the mechanism by which genotoxic effects are caused by a particle, particularly on neighboring cells which may not themselves have received any radiation (""""""""bystander effect""""""""). Another area of research is in the mechanism of recombinational repair in yeast and mammalian cells. Site-directed techniques (one of which is patented) are used to demonstrate that most gene conversion results from mismatch repair rather than gap repair. Transcription rates have little effects on these processes in yeast. In mammalian cells, transcription (which up-regulated repair) reduces UV-induced recombination. Systems to study mismatches in vivo have been developed.
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