Comparison of radiobiological endpoints in cells from CXB RI mice
Date
2008
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Abstract
Recombinant inbred (RI) mouse strains have been used both for trait cosegregation studies and genetic linkage analysis. They are created by using a breeding scheme that consists of a cross between two inbred mouse strains (progenitor strains) followed by at least 20 generations of brother-sister inbreeding. Thus, RI strains are inbred (homozygous at every locus) and derive roughly half their genome from each of the two progenitor strains. The CXB RI strain set consists of 13 RI strains derived from matings of BALB/c (C) and C57BL/6(B) mice. The CXB progenitor strains, BALB/c and C57BL/6, differ in their susceptibility to radiation-induced mammary tumors with BALB/c being susceptible and C57BL/6 being resistant. In part, the susceptibility difference can be explained by a polymorphism in the Prkdc gene which encodes the catalytic subunit of DNA-dependent protein kinase. However, other, as yet unknown, loci may be involved. The CXB RI strain set provides a useful tool to unravel the events that lead to radiation-induced mammary tumorigenesis and to understand the interrelationships of cellular radiobiological endpoints to one-another. We have generated fibroblast strains from each of the CXB RI strains and from the progenitor strains. The fibroblast strains were assayed for a number of radiobiological endpoints including clonogenic survival following acute and low dose-rate exposures, γ-H2AX focus formation and clearance following acute and low dose-rate exposures, and G2 chromosomal aberrations. In addition, we genotyped the strains for a polymorphism in the gene encoding the catalytic subunit of the DNA-dependent protein kinase, Prkdc. We then determined the correlations of different endpoints between the RI strains. As expected, clonogenic survival at low dose rates and following acute exposures were positively correlated. γ-H2AX focus formation at low dose rate correlated well with survival endpoints, particularly clonogenic survival under low dose rate irradiation and the surviving fraction at 2 Gy acute exposures. These three endpoints are all significantly associated with the Prkdc genotype with radiosensitive strains having the BALB/c genotype. The data we have collected provides a baseline description of cellular radio sensitivity in CXB fibroblasts. The approach used in this dissertation can be used to correlate these cellular radiobiological endpoints with susceptibility to clinically significant adverse outcomes from cancer radiotherapy, such as normal tissue injury and radiation-induced second cancers.
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Subject
CXB RI
endpoints
radiobiological
recombinant inbreeding
molecular biology
genetics
cellular biology