46. Sprit-dose Fractionation Dose Not Mitigate Radiation-induced Intestinal Death in Atm-disrupted Mice

Takeshi Furuse, Yuko Noda and Kouichi Tatsumi

Keywords: ataxia telangiectasia, LD50/8, intestinal death, crypt

Mice homozygous for the disrupted Atm allele was reported to exhibit an extreme hypersensitivity to ionizing radiation (IR), and rapid death in particular was caused by the severe selective toxicity of the gastrointestinal tracts rather than global radiation toxicity (Barlow et al., 1996). The wealth of information regarding the deficient recovery of IR-induced damages in cultured cells from ataxia telangiectasia (AT) patients has not been tested to see if it holds true for in vivo circumstances by utilizing these Atm-disrupted mice. We tred to determine if these mice were in fact defective in recovery from the sublethal effect of acute doses of IR to the whole body by looking at responses to split-dose fractionations.

Mice in 129/SvEv background were subjected to total body irradiation (TBI) with 200 kVp X-rays at 72 cGy/min and obserbed for 30 days thereafter to determine survival in the clean-conventional environment. No wild-type (Atm+/+) mice died after a single irradiation at 6 Gy. Early deaths were noted, however, between the 4th and 9th day post-irradiation among mice receiving a single 12 Gy dose, and also between the 10th to 14th day among mice given a single dose of 8, 9 or 10 Gy. Histopathological analyses on the mice that died within 8days post-irradiation revealed severe epithelial crypt destruction in the intestine together with congestion in tissures including lung, liver, heart and brain, indicating that death was due to the gastrointestinal syndrome. Mice that died between the 10th and 14th day post-irradiation showed histological features of death from bone marrow syndrome, i.e., degradation of bone marrow and extravasation in the brain, heart and lung. Dose-response curves for intestinal death by the 8th day after single TBI indicated that the median lethal dose, LD50/8, was approximately 4.5 Gy, 11 Gy and 11 Gy for Atm-disrupted mice (Atm-/-), heterozygous mice (Atm+/-) and wild type mice, respectively. When wild-type mice were irradiated with two equal doses of 6 Gy separated by an 8-hour interval, they died between the 6th and 13th day post-irradiation, surviving significantly longer than those irradiated one at 12 Gy. In contrast, there was no delay in early death of Atm-disrupted mice receiving two doses of 3 Gy with an 8-hour interval, as compared with those irradiated once at 6 Gy. These resutts suggest that the capacity to recover from sub-lethal damage is impaired in intestinal crypt cells of Atm-disrupted mice.