Office of Biological and Environmental Research

DOE Lowdose Radiation Program Workshop III

Abstract

Title: Induction of Genomic Instability In vivo by Low Doses of 137Cs Gamma Rays.

Authors: Kanokporn Rithidech1, Sanford R. Simon1, Carl W. Anderson2, and Elbert B. Whorton3.

Institutions: 1Pathology Department, SUNY @ Stony Brook, 2Biology Department, BNL, 3Molecular Epidemiology Research Program, University of Texas Medical Branch.

Genomic instability may be defined as a persistent increase in genetic lesions in the progeny of exposed cells for several cell generations following irradiation. It has been hypothesized that genomic instability is a key event in the development of cancer; nevertheless, the mechanisms involved in induction of genomic instability are poorly understood. Moreover, information is lacking on the in vivo induction of genomic instability by radiation at doses below the levels traditionally requiring human radiation protection, i.e., less than or equal to 10 cGy. This study is designed to investigate whether these very low doses of ionizing radiation induce genomic instability and to examine the mechanisms leading to genomic instability that occur in response to low doses of ionizing radiation.

Four groups of male BALB/cByJ mice (20 in each group) were exposed to 0, 5, 10, and 100 cGy of ¹³⁷Cs g rays, respectively. The frequency and type of metaphase chromosome aberrations in bone marrow cells of exposed mice collected at different times following irradiation, i.e. 1 hr, 4 hr, 1 and 6 months, following irradiation will be evaluated by multicolor fluorescence in situ hybridization (FISH) of mouse chromosomes 1, 2, and 3. All other chromatid-type aberrations and gross structural abnormalities involving all other chromosomes will be determined on the same metaphase cells used to score stable chromosomal aberrations involving painted chromosomes. The extent and type of chromatid damage in metaphase cells collected at 1 hr after irradiation will provide a measure of the sensitivity of cells to radiation. A difference in the rate of decline of chromatid break frequencies at 4 hr after irradiation reflects the capacity of cells to repair radiation-induced DNA double strand breaks (DSBs). Levels of kinase activity of DNA-PKcs (the enzyme involved in the repair of DSBs) at 1 and 4 hr following irradiation, in parallel with the extent of activation of two important transcription factors (NF-kB and AP-1) will be measured. This would permit us to evaluate whether levels of DNA-PKcs activity and transcription factor activation influence the extent of initial chromosomal damage, which, in turn, lead to the induction of genomic instability. Results from this study should aid substantially in understanding potential mechanisms for radiation-induced genomic instability. Research funded by the Low Dose Radiation Research Program, Biological and Environmental Research (BER), U.S. Department of Energy, grant # DE-FG02-02ER63311.

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