A MONTE-CARLO MARKOV-CHAIN MODEL FOR THE ASSOCIATION OF DATA FOR CHROMOSOME-ABERRATIONS AND FORMATION OF MICRONUCLEI

The micronucleus assay is a convenient, in situ method for observing cell damage resulting from exposure to clastogenic agents and has been widely used as a dosimeter of human exposure to radiation or chemicals. It also is a complement to the classic clonogenic cell survival assay in that it can be used to examine radiation damage vs dose as a function of cell type or radiation quality. Digitized imaging densitometry was conducted on CHO cells that have undergone one division and in which further cytokinesis was blocked to collect data on the distributions of percentage total cellular DNA per micronucleus and frequency of micronuclei per cell after gamma irradiation in G(1) phase. Theoretical counterparts to both classes of distributions were generated by a Monte Carlo double-strand breakage (DSB) simulation to the CHO genome, followed by simulated repair of this initial damage using a Markov chain algorithm that assumes linear restitutions of single DSBs complete with quadratic, incomplete exchanges among pairs of DSBs. Micronuclei were presumed to consist of single acentric fragments (including fused acentric pairs). The empirical distributions, when compared to their fitted theoretical counterparts, suggest, inter alia, that: (1) a slight dependence of micronucleus size on dose exists, with a trend toward higher density in the 2-4% genome range, at the expense of the 0-2% range, with increasing dose; (2) the probability of exchange incompleteness is at least 20%; and (3) the dispersions of the micronucleus frequency distributions are progressively lower than their (essentially constant) counterparts with increasing dose. Suggested is a cooperative increase in the number of fragments per micronucleus with increasing dose. Beyond these specific results, however, it is clear that furthering the understanding of the connection between DNA aberrations and formation of micronuclei would further link these two large bodies of data.