We have previously shown that chronic exposure of plateau-phase C3H 10 T1/2 cells to (60)Co gamma radiation at doses as low as 10 cGy protected the cells against neoplastic transformation by a subsequent large acute radiation exposure. We have also shown that this induced resistance to neoplastic transformation correlated with an increased ability to repair radiation-induced chromosome breaks. We now show that a single exposure of quiescent cells to doses as low as 0.1 cGy also reduces the risk of neoplastic transformation, from the spontaneous level to a rate three- to fourfold below that level. Higher doses, up to 10 cGy at the same dose rate (0.24 cGy/min), did not reduce the neoplastic transformation frequency further. This protective effect was seen only in irradiated cells that were allowed to incubate at 37 degrees C before release from contact inhibition. Cells released into low-density subcultures immediately after irradiation had unchanged neoplastic transformation frequencies. These results demonstrate that low or chronic exposure to radiation can induce processes which protect the cell against naturally occurring as well as radiation-induced alterations that lead to cell transformation. If similar processes are induced in human cells, the results also suggest that a single low dose, at background or occupational exposure levels, may in some circumstances reduce rather than increase cancer risk, a conclusion inconsistent with the linear no-threshold model of cancer risk from radiation.

Mice heterozygous for Trp53 are radiation-sensitive and cancer-prone, spontaneously developing a variety of cancer types. Osteosarcomas in the spine lead to paralysis, while lymphomas lead rapidly to death, distinct events that provide objective measures of latency. The effects of a single low-dose (10 or 100 mGy), low-dose-rate (0.5 mGy/min) (60)Co gamma irradiation on lymphoma or spinal osteosarcoma frequency and latency, defined as time of death or of onset of paralysis, respectively, were examined. Compared to spontaneous lymphomas or to spinal osteosarcomas leading to paralysis in unexposed mice, an exposure of 7-8-week-old Trp53(+/-) mice to 10 or 100 mGy had no significant effect on tumor frequency, indicating no effect on tumor initiation. All tumors are therefore assumed to be of spontaneous origin. However, a 10-mGy exposure reduced the risk of both lymphomas and spinal osteosarcomas by significantly increasing tumor latency, indicating that the main in vivo effect of a low-dose exposure is a reduction in the rate at which spontaneously initiated cells progress to malignancy. The effect of this adaptive response persisted for the entire life span of all the animals that developed these tumors. Exposure to 100 mGy delayed lymphoma latency longer than the 10-mGy exposure. However, the 100-mGy dose increased spinal osteosarcoma risk by decreasing overall latency compared to unexposed control mice. That result suggested that this higher dose was in a transition zone between reduced and increased risk, but that the dose at which the transition occurs varies with the tumor type.

The hypothesis that single low dose exposures (0.025–0.5 Gy) to low LET radiation, given at either high (about 150 mGy/min) or low (1 mGy/min) dose rate, would promote aortic atherosclerosis was tested in female C57BL/6J mice genetically predisposed to this disease (ApoE−/− ). Mice were exposed either at early stage disease (2 months of age) and examined 3 or 6 months later, or at late stage disease (8 months of age) and examined 2 or 4 months later. Changes in aortic lesion frequency, size and severity, as well as total serum cholesterol levels and the uptake of lesion lipids by lesion associated macrophages were assessed. Statistically significant changes in each of these measures were observed, depending on dose, dose rate and disease stage. In all cases, the results were distinctly non-linear with dose, with maximum effects tending to occur at 25 or 50 mGy. In general, low doses given at low dose rate at either early or late stage disease were protective, slowing the progression of the disease by one or more of these measures. Most effects appeared and persisted for months after the single exposures, but some were ultimately transitory. In contrast to exposure at low dose rate, high dose rate exposure at early stage disease produced both protective and detrimental effects, suggesting that low doses may influence this disease by more than one mechanism, and dose rate is an important parameter. These results contrast with the known, generally detrimental effects of high doses on the progression of this disease in the same mice, and in humans, suggesting that a linear extrapolation of the known increased risk from high doses to low doses is not appropriate.

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Dysregulation of certain microRNAs (miRNAs) in cancer can promote tumorigenesis, metastasis and invasion. However, the functions and targets of only a few mammalian miRNAs are known. In particular, the miRNAs that participates in radiation induced carcinogenesis and the miRNAs that target the tumor suppressor gene Big-h3 remain undefined. Here in this study, using a radiation induced thymic lymphoma model in BALB/c mice, we found that the tumor suppressor gene Big-h3 is down-regulated and miR-21 is up-regulated in radiation induced thymic lymphoma tissue samples. We also found inverse correlations between Big-h3 protein and miR-21 expression level among different tissue samples. Furthermore, our data indicated that miR-21 could directly target Big-h3 in a 3′UTR dependent manner. Finally, we found that miR-21 could be induced by TGFβ, and miR-21 has both positive and negative effects in regulating TGFβ signaling. We conclude that miR-21 participates in radiation induced carcinogenesis and it regulates TGFβ signaling.