Volume 107 · Issue 06 · 1994

The present paradigm of radiation-induced carcinogenesis has been based on somatic mutation theory initiating a mutation in somatic cells derived from DNA damage by ionizing radiation. A non-threshold linear model has been assumed from high doses to low doses. As an alternative to this, we are proposing a new model that epigenetic changes induced by low dose irradiation may be a first step of carcinogenesis. Our preliminary data suggesting the epigenetic nature and reports on various stress response to ionizing radiation are presented.

A new approach used to measure pre-cancer-induced genetic damage in a patient diagnosed as early B-precursor acute lymphoblastic leukemia, by totally separating the malignant B-lymphocytes and the normal T-lymphocytes is described. The lymphocytes separation by a rosetting method and chromosome translocation analysis using chromosome painting were employed. In the case presented here, the utility of this approach is illustrated using blood lymphocytes from a nuclear dockyard worker who claims that his leukemia was induced by work-related radiation exposures. Blood lymphocytes were obtained after diagnosis of the disease, but prior to therapy, and measurements made of (1) the translocation frequency in separated normal T-lymphocytes and (2) the translocation frequency in phytohemagglutinin (PHA) stimulated lymphocytes, which include a fraction of the malignant B cells. The approach described here makes possible biodosimetry of pre-cancer exposures in these patients and may provide the dosimetric information required to establish the "probability of causation" for the observed cancer.

Starting with observations that were first published in 1982, a series of additional findings led to the discovery of an important property of cells in late G2/mitosis. In addition to being the most sensitive to killing, cells in this age-interval were also shown to be the most sensitive to radiation-induced neoplastic transformation. In this work, C3H mouse cells, designated 10T1/2, were irradiated with fission-spectrum neutrons and assayed in vitro via the endpoint focus formation on a monolayer of normal cells. From these observations, a biophysical model was developed to explain the anomalous finding that the frequency of transformation by low doses was enhanced when the exposure was protracted. In contrast to transformation by X- and γ-rays where repair and kinetics during exposure play dominant roles, with radiations like reactor neutrons and α-particles repair has a minimal effect; only cell kinetics acts significantly to modify transformation due to protracted doses. In this report, the lack of responsiveness of mitotic cells to promotion by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate is shown further to agree with the findings with fission-neutrons and the model that, at low dose rate, enhanced transformation is due principally to the progression of cells into the window of sensitivity. Implications of this model for lung cancer due to environmental radon are also discussed.

The CRIEPI initiated the Radiation Hormesis Research based on the following rationale. If the Luckey's claim was true, our daily activities in the radiation management would be extremely erroneous. If the Luckey's claim was false, the concept publicated would bring us serious disturbance on the radiation management in Japan. We organized a hormesis research steering committee by the specialists in the concerned field, and started researches under cooperation with many universities, National Cancer Center Research Institute, and National Institute of Radiological Sciences. After interesting results obtained by various experiments on the health effects by low dose, we are now proceeding on the Round Robin tests program including fifteen research plans with universities all over Japan. These activities are categorized as: A. Effects of free radicals produced by the low dose radiation; B. Molecular biological responses to the low dose radiation; C. Radiation effects on the neurotransmission system; D. Stimulative effects of low dose radiation on the immune systems; and E. Epidemiological studies.

In human and animal cells, an adaptive response has been found to make cells somewhat refractory to the induction of chromosomal damage by high doses applied subsequently. These responses can also be induced in vivo by irradiating animals with low, or chronic doses. In regard to cytogenetic damage, and presumably those mutations that are cytogenetic in origin, the induced response leads to the repair, or rejoining, of broken chromosome ends, which means that chromosome aberrations, deletional (or null) mutations, DNA double-strand breaks, and even cellular survival that is dependent upon the genetic (cytogenetic) integrity of the cell can be endpoints that will show an adaptive response to ionizing radiations.

Mice were given whole-body irradiation (WBI) with 75 mGy X-rays which had previously been found to stimulate immunologic functions. This low dose radiation (LDR) potentiated [Ca2+]i mobilization in thymic and splenic lymphocytes in response to Con A and anti-CD3 McAb and activated protein kinase C in T and B lymphocytes of the spleen. The expression of TCR/CD3 molecules on the thymocytes was enhanced after LDR indicating an expedited maturation and differentiation process in the thymus. The changes in TCR/CD3 expression and [Ca2+]i mobilization in response to McAb-CD3 after LDR was found to be highly correlated. Meanwhile the transcription of c-fos and c-jun genes was up-regulated beginning 3 hours after LDR. The expression of IL2R in active thymocytes was potentiated 24 hours after LDR which coincided with the previous finding of increased secretion of IL2 by splenocytes after WBI with 75 mGy X-rays. It is first reported in the present paper that LDR could stimulate immunologic functions through facilitation of the signal transduction process in the lymphocytes.

To identify the role of circulating immune factor(s) in the development of proteinuria, the supernatant of peripheral blood mononuclear cells (PBMC) were obtained from 15 patients with steroid-responsive nephrotic syndrome, and its effect on the synthesis of sulfated compound by cultured rat glomerular epithelial cell (GEC) were studied by 35S, 3H-leucine dual-isotope labelling technique. The result showed that the supernatant of PBMC from 9 patients without steroid treatment increased 35S uptake in GEC (P<0.01), while there was no significant difference in 35S uptake between the 6 patients treated with prednisone (1.5-2.0 mg/kg.d-1) and 6 normal controls.

In the present study, the radioreceptor binding method was used to determine the changes of IP3 content in rat brain and dorsal spinal cord of high frequency (100 Hz) electroacupuncture (EA) analgesia and EA tolerance rat. The control levels of IP3 in rat brain (less cerebellum and cortex) and dorsal spinal cord were 6.3±0.78 pmol/mg protein and 3.4±0.60 pmol/mg protein, respectively. The results showed that IP3 in brain increased gradually within 45 min after stimulation in EA analgesia rat. Meanwhile, the dorsal spinal cord IP3 content decreased significantly 15 min, 30 min after EA stimulation and recovered to control level 45 min after EA stimulation. In EA tolerance rat, IP3 contents markedly increased in brain. And IP3 content in the spinal cord also increased dramatically within 30 min, but decreased rapidly to control level 45 min after EA stimulation. The IP3 level in EA tolerance rat brain and spinal cord was much higher than that in EA analgesia rat (P<0.01). The studies first reported that high frequency (100 Hz) EA may be linked to PI system in its signal transduction pathways.

Using repeated PAP or repeated PAP and ABC immunocytochemical methods, we were able to demonstrate viral antigens, Ig and Clq in the tissues of 20 autopsy materials that had been preserved for 3-30 years. Serial paraffin sections were stained with the first antibodies against both viral antigens (G2 and Np) and human IgG, IgM, C3 and Clq. Immunocomplex, composed of viral antigen, IgG and Clq were found diffusely in the cells of each organ and extracellularly in the sera, various secretions and exudates. When stained by A25 etc, coarse granular antigen or inclusion bodies were found without demonstrable Ig and Clq. It was concluded that the immunocomplex in tissues of epidemic hemorrhagic fever in Shaanxi Province, China was both intracellular and extracellular and was perhaps soluble due to antigens in excess, with characteristics quite different from that of other immune diseases.

A 53-year-old man with a restenotic large right coronary vein graft was successfully treated by double balloon angioplasty. The technique and clinical application of double balloon angioplasty were discussed.