We propose to investigate and test the mechanistically-based hypothesis that densely-ionizing radiations such as neutrons or alpha particles produce a measurable, stable, characteristic chromosomal marker of past exposure. The suggested marker is the ratio of induced inter- to intra- chromosomal aberrations - the F value. Experimental and theoretical evidence suggests that this F value will be significantly different for densely-ionizing radiations, compared to that produced by either gamma rays or chemical carcinogens. We suggest that, if the biomarker is reproducible, in practical situations a past exposure to very low doses of densely-ionizing radiation could be reliably reconstructed, using FISH technology to measure the F value. We propose firstly to perform in-vitro based FISH experiments to check directly the hypothesis in 2 normal human cell lines (assayed at 1st mitosis) for both stable and unstable aberrations, at our Radiological Research Accelerator Facility. Second, we will measure F values for stable aberrations in 9th- to 12th- generation progeny of cells exposed to neutrons and gamma rays, to test the hypothesis that the F value for stable aberrations will not change as a function of progeny generation. Third, we will measure F values in 1st, and 9th- to 12th-generation human cells that were exposed to the tobacco-specific nitrosamine, NNK, testing the hypothesis that F values for chemically-induced chromosomal aberrations are significantly larger than those produced by densely-ionizing radiations. Assayed at first mitosis, many of the exchange-type aberrations produced by chemicals such as NNK are likely to be of the chromatid type. However, at subsequent mitoses, the surviving symmetric chromatid exchange-type aberrations are likely to appear as translocations or pericentric inversions, and it is these that will be scored. Finally, we shall develop the modeling of F values to incorporate the fact that chromosomal domains may not freely overlap with one another.
Showing the most recent 10 out of 16 publications
