Identification of mechanisms responsible for low dose radioprotective responses in vivo
This project was a renewal of our previous Low Dose Radiation Research Program grant. In the previous grant we used the very sensitive pKZ1 chromosomal inversion assay in vivo to study the effect of very low doses of X-radiation. Using this assay we studied doses ranging from single whole body doses of 1 μGy up to 2 Gy X-rays and confirmed a 3 phase dose-response with an increase in inversions in the 5-10 μGy range, a decrease below sham-treated in the 1-10 mGy dose range and an increase in inversions for greater than 100 mGy. The same results were observed in both spleen and prostate. All doses below 10 mGy and as low as 1 μGy were capable of protecting from high dose radiation induced inversions and were therefore conditioning (adapting) doses. We also carried out a study in pKZ1 heterozygous ATM mice and found that the responses were the same as in normal ATM animals. We were the first to show that the low conditioning dose could be administered 3 hours after the high dose and still induce an adaptive response. In the previous grant we also commenced temporal studies to determine if the changes in the frequency of inversions after radiation exposure were permanent effects. We developed a lymphocyte adoptive transfer method with the aim of providing evidence for bystander effects in vivo and we started investigating intercellular induced apoptosis as a potential mechanism to explain adaptive responses for cancer end-points via radiation-induced removal of pre-tumour cells. We also studied the effect of the chemical radioprotector, amifostine, on pKZ1 chromosomal inversions where we found remarkable similarities to the pKZ1 chromosomal inversion dose-response patterns and adaptive response patterns that we had previously observed with low dose radiation. In this renewal grant we continued on with many of these experiments and concentrated on understanding the mechanism of adaptive responses in vivo. Studying mechanism in vivo is very difficult, time consuming and expensive. The pKZ1 assay, because of its extreme sensitivity to low doses of ionising radiation, potentially provides a system whereby we can gain some insight into low dose radiation adaptive response mechanisms in vivo. The overall goal of this project was to identify mechanisms responsible for low dose radioprotective responses in vivo.