Title

Cellular responses to simultaneous irradiation with alpha particles and X-rays

Examination board

Alexandros Georgakilas, National Technical University of Athens, Greece (opponent)
Bo Stenerlöw, Dept. of Immunology, Genetics and Pathology, Uppsala University
Ulrich Theopold, Dept. of Molecular Biosciences, Wenner-Gren Instiute, Stockholm University
Irena Gudowska, Dept. of Physics, Stockholm University
Arne Lindqvist, Dept. of Cell and Molecular Biology, Karolinska Institute
Kristina Jonas, Dept. of Molecular Biosciences, Wenner-Gren Instiute, Stockholm University (Chairman

Abstract

Mixed radiation fields, where different ionizing particles act together, are very important in radiobiology and in radiation protection. Mixed beams are not only the most common form of radiation exposure, but the prediction of their biological effect is also full of uncertainties. Currently, prediction of the biological damage of exposure to mixed radiation fields is based on the default assumption of simple additivity between the effects of all the radiation in the field. This assumption has been proven to be incorrect. Indeed, the simultaneous effect of different radiation qualities has been shown to be greater than additive, namely synergistic. This implicates that, for instance, the predicted cancer risk for astronauts, that remain a prolonged time in space, is currently underestimated as well as the risk of developing secondary cancer for radiotherapy patients.

This thesis aims at understanding the mechanisms behind the cellular response to simultaneous exposure to alpha particles and X-rays (that is referred as mixed beam).

Paper I describes the cell killing and the mutagenic effect of mixed beam exposure in human lymphoblastoid wild type and in cells with impaired capacity to repair oxidative DNA damage .We found that oxidative DNA damage plays an important role in the lethal, synergistic effect of mixed beams.

Paper II and III investigates whether mixed beams exposure leads to an augmented DNA double strand breaks (DSB) induction or to an altered response of the cellular DSB repair machinery. We found that mixed irradiation resulted in synergistic induction of DSB, and that those lesions were repaired with slow kinetics.

Paper IV focuses on the effect of mixed beams at the level of DNA damage in normal cells. Induction and repair of DNA lesions such as DSB, single strand breaks and apurinic sites was quantified using the alkaline comet assay. We found that alpha particles and X-rays interacted in inducing DNA damage. Moreover, although mixed beam exposure resulted in strong activation of the DNA damage response, it resulted in delayed repair.

Although more research is needed to fully elucidate the mechanisms behind the detected synergistic effects, our results strongly suggest that an overwhelmed DNA-repair system causes delay in repair of damage.

Keywords: Radiation, DNA damage, mutations, alpha particles, X-rays, mixed beam.