Gene expression profiles in mouse liver after long-term low-dose-rate irradiation with gamma rays.

Changes in gene expression profiles in mouse liver induced by long-term low-dose-rate γ irradiation were examined by microarray analysis. Three groups of male C57BL/6J mice were exposed to whole-body radiation at dose rates of 17-20 mGy/day, 0.86-1.0 mGy/day or 0.042-0.050 mGy/day for 401-485 days with cumulative doses of approximately 8 Gy, 0.4 Gy or 0.02 Gy, respectively. The gene expression levels in the livers of six animals from each exposure group were compared individually with that of pooled sham-irradiated animals. Some genes revealed a large variation in expression levels among individuals within each group, and the number of genes showing common changes in individuals from each group was limited: 20 and 11 genes showed more than 1.5-fold modulation with 17-20 mGy/day and 0.86-1.0 mGy/day, respectively. Three genes showed more than 1.5-fold modulation even at the lowest dose-rate of 0.04-0.05 mGy/day. Most of these genes were down-regulated. RT-PCR analysis confirmed the expression profiles of the majority of these genes. The results indicate that a few genes are modulated in response to very low-dose-rate irradiation. The functional analysis suggests that these genes may influence many processes, including obesity and tumorigenesis.

Radiation dose-rate effect on mutation induction in spleen and liver of gpt delta mice.

The effect of dose rate on radiation-induced mutations in two somatic tissues, the spleen and liver, was examined in transgenic gpt delta mice. These mice can be used for the detection of deletion-type mutations, and these are the major type of mutation induced by radiation. The dose rates examined were 920 mGy/min, 1 mGy/min and 12.5 microGy/min. In both tissues, the number of mutations increased with increasing dose at each of the three dose rates examined. The mutation induction rate was dependent on the dose rate. The mutation induction rate was higher in the spleen than in the liver at the medium dose rate but was similar in the two tissues at the high and low dose rates. The mutation induction rate in the liver did not show much change between the medium and low dose rates. Analysis of the molecular nature of the mutations indicated that 2- to 1,000-bp deletion mutations were specifically induced by radiation in both tissues after high- and low-dose-rate irradiation. The occurrence of deletion mutation without any sequence homology at the break point was elevated in spleen after high-dose-rate irradiation. The results indicate that the mutagenic effects of radiation in somatic tissues are dependent on dose rate and that there is some variability between tissues.

Dose and dose-rate effects of low-dose ionizing radiation on activation of Trp53 in immortalized murine cells.

A derivative of immortalized murine NIH/PG13Luc cells stably transfected with a Trp53-dependent luciferase reporter plasmid was used to study the transcriptional activity of Trp53 in response to radiation. The cell line was sensitive enough to detect the response of Trp53 to 0.2 cGy of (60)Co gamma radiation. To examine the biological effects of low-dose-rate (60)Co gamma radiation (from 0.1-10 cGy/h), we have analyzed the cell cycle, Trp53 transcriptional activity, and gene expression profiles of control and treated cells. Microarray analysis revealed up-regulation of six Trp53-mediated genes (Cdkn1a/ p21, Mdm2, Sip27, Ccng1/cyclin G1, Ei24/Pig8 and Dinb/ Polk) after exposure of cells to low-dose-rate radiation for 72 h. Using real-time PCR, a significant elevation in the expression of Ccng1/cyclin G1, Mdm2 and Cdkn1A/p21 was observed with low-dose-rate irradiation at dose rates over 5 cGy/ h. A dose-rate dependence was also observed for these three Trp53-mediated genes. The expression of Ccng1/cyclin G1 at high dose rates of gamma rays was higher than that for low dose rate. However, the expression of Mdm2 for low-dose-rate gamma rays was higher than for the high dose rate. Cells irradiated at low dose rates of 0.1 cGy/h and 1 cGy/h underwent G(1)-phase arrest. Furthermore, G(2)-phase growth arrest was observed in cells irradiated at the low dose rates of 5 cGy/h and 10 cGy/h, which correlated with Trp53-mediated Ccng1/cyclin G1 up-regulation. These results show that cellular response to radiation depended on the dose rate used; i.e., the responses seen at dose rates from 0.1-1 cGy/h were different from those observed at dose rates over 5 cGy/h.