Failla Lecture

Sunday, October 16, 2005 5:00 PM-6:00 PM Room No. 605/607

(SS004) Radiation Mutagenesis: Size Matters.

Waldren, Charles1,2, 1 Radiation Effects Research Foundation (RERF), Hiroshima/Nagasaki, Japan2 Environmental and Radiologic Health Sciences (ERHS), Fort Collins, CO, USA

ABSTRACT- Mutation, defined by HJ Muller and other radiation biologists as any potentially heritable change in the genome, underlies and drives genetic diseases including cancer so that studies of mutagenesis shed light on carcinogenesis. We thus set out in the early 1970ís to develop a mammalian cell system that could sensitively and accurately measure all of the kinds of mutations caused by various agents, especially radiation, which cytogenetic evidence indicated were likely so large as to escape detection in many gene assays. The methodology we devised employs a hybrid cell line formed by fusing a Chinese hamster J1 cell with a human cell. The most used hybrid for mutation studies (the AL hybrid) contains a standard set of CHO-J1 chromosomes and a single, intact, stable human chromosome 11. Cell surface antigens encoded by genes on chromosome 11 provide convenient, quantitative selectable markers that allow quantification of both gene and chromosomal mutations. Dissociation in this hybrid construct of mutation and survival increases mutation sensitivity so that effects of mutagens and antimutagens can be measured at low, relevant doses. Chromosome 11 markers also permit accurate and simple definition of mutant spectra and chromosomal instability. This assay has provided improved estimates of the in vitro genotoxicity of single agents including chemicals, ultraviolet light, diagnostic ultrasound, and of complex mixtures like cigarette smoke condensate, vaccines and pyrolytic products of cooked meats and to reveal that the so-called non-mutagenic carcinogens arsenic and asbestos were in fact mutagens in mammalian cells. Our focus has, however, always been on genotoxic actions of ionizing radiations of various quality (X- and gamma rays, neutrons, high alpha particles, high energy iron nuclei iron, etc) delivered via different exposure regimens including low dose rates, fractionations, and targeted to specific cellular sites, without and with radio-protectors. We have also investigated relationships of DNA repair to mutagenesis and studied such non-targeted effects as bystander phenomenon (cell-cell and media-mediated), adaptive response and heritable chromosomal instability. Following on work of Japanese colleagues we are, with their help, characterizing the genotoxicity of new kinds of radicals [long-lived radicals (LLR) also called slow release radicals (SLR)] that they had showed to be increased in irradiated cells and mutagenic but not lethal. All of our these findings have been possible because the kinds of mutations generated by ionizing radiation, from very small to very large, are detected by the AL assay. We believe the insights thus provided, many of which have come from our splendid collaborators and all from support of several agencies, especially NASA and NIH-NCI, will continue to shed light on levels and mechanisms of radiation-induced pathology arising from environmental, work-related or therapeutic exposure, and may have implications for risk estimates in exposed human populations.

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2005 RRS