Our project has critically addressed the relevance of the laboratory mammal experimental results by identifying the mechanisms leading to radiation induced mutations which, should they occur in a human population, would result in a deleterious phenotype, as well as a direct assay of the human genome. As the comparative characterizations of the mouse and human genomes continue we may anticipate an identification of homologous chromosomal regions and homologous genes which are prone to the effects of radiation and would result in transmitted germ cell mutations with phenotypic effects.
An adequate understanding of the genetic risk associated with radiation exposure as well as the mechanisms of mutation induction are essential for an informed action to protect mankind from the harmful effects of radiation. To this end our present proposal will address the strategy of risk estimation based on experimental data in animals and determine factors important in the mechanisms of mutation induction by radiation exposure to germ cells. Researchers specializing in germ cell genetics and radiation mutagenesis from five leading European laboratories (GSF-Neuherberg, Leiden University, MRC-Radiobiology Unit, Utrecht University and TNO-Medical Biological Laboratory) will participate in a coordinated research effort to improve risk extrapolation procedures as well as to determine the influences of DNA damage repair and cell killing on the levels of mutation induction by radiation. Further, molecular techniques will assess DNA damage to the genome as well as characterize the DNA changes associated with radiation induced mutations to elucidate the mechanisms of mutation induction by radiation in mammalian germ cells. The major aims of our research proposal are outlined below:
1) Experiments will determine the validity of assumptions required in estimating human radiation genetic risk based on animal data. 2) Methods to sensitize as well as synchronize the spermatogonial stem cells of mice will be applied to determine correlated effects on DNA damage, cell death, as well as mutation and translocation yields. 3) Molecular analyses of radiation-induced damage of the mouse genome as well as of radiation-induced mutations will be carried out to characterize the nature of induced DNA lesions ultimately resulting in mutation. 4) Studies to test the biological relevance of transgenic mouse systems in determining the mutagenic effects of radiation will be conducted. Experimental design of the various projects including choice of species and genetic endpoint examined as well as genetic and chemical manipulations of germ cell populations to alter radio-sensitivities have been coordinated. Results obtained will lead to a better understanding of the problem of cross species extrapolations as well as the interactive roles of DNA damage induction, cell death and DNA damage repair in radiation mutagenesis.
Funding SchemeCSC - Cost-sharing contracts
B9 5ST Birmingham
2300 RA Leiden
3508 TD Utrecht