Radiation-quality dependence of genomic instability in mutation induced by the pre-treatment with low-fluence heavy ions.

A central paradigm in radiation biology has been that only a cell hit by a track of radiation would be affected to induce radiobiological effects, and a cell not hit should not be. This paradigm is the basis for the current system for risk estimation from radiation. However, it recently has been challenged by so called non-targeted effects, including bystander effect and genomic instability, and such radiation-induced non-targeted effects may have important implications for risk evaluation of low dose / low dose rate radiations. In this study we have investigated cellular responses in normal human fibroblasts induced with low dose / low dose rate irradiations of qualitatively different radiation types, such as gamma rays, neutrons and high-LET heavy ions. Cells were pre-treated with low-fluence irradiation (~1mGy/7-8h) of 137Cs gamma rays, 241Am-Be neutrons, helium ions (LET=2.3keV/µm) and carbon ions (LET=13.3keV/µm) before following irradiation with a 200kV X-ray challenge dose. The helium- and carbon-ion beams were produced by the Heavy Ion Medical Accelerator in Chiba (HIMAC) at National Institute of Radiological Sciences in Japan. There was observed no difference in X-ray induced cell-killing effects, which was detected with the colony-forming assay, when using pre-treatment with low-dose irradiations of gamma rays, neutrons, helium ions and carbon ions. For mutation induction at hprt locus detected as 6-thioguanine resistant clones, there was no difference in X-ray-induced mutation frequency at 1.5Gy of X-ray challenge dose between un-pretreated and gamma-ray pre-treated cells. In the case of the pre-treatment with high-LET ions, mutation frequency was around 4.0 times higher in carbon-ion pre-treated cells and 1.9 times higher in helium-ion pre-treated cells than in un-pretreated cells. On the contrary, it was reduced in neutron pre-treated cells, when comparing to un-pretreated cells. Furthermore, the enhancement of X-ray-induced mutation frequency in cells pre-treated with helium and carbon ions was reduced at the control level, when using a specific inhibitor of gap-junction mediated cell-cell communication (40µM lindane). There is evidence that gap-junction mediated cell-cell communication play an important role of inducing genomic instability by pre-treatment with heavy ions.Heavy Ion Research Joint Meetin