Kazutaka Doi

Effects of acute γ-irradiation on community structure of the aquatic microbial microcosm

To characterise indirect effects of ionising radiation on aquatic microbial communities, effects of acute gamma-irradiation were investigated in a microcosm consisting of populations of green algae (Chlorella sp. and Scenedesmus sp.) and a blue-green alga (Tolypothrix sp.) as producer; a ciliate protozoan (Cyclidium glaucoma), rotifers (Lecane sp. and Philodina sp.) and an oligochaete (Aeolosoma hemprichi) as consumer; and more than four species of bacteria as decomposers. Population changes in the constituent organisms were observed over 160 days after irradiation. Prokaryotic community structure was also examined by denaturing gradient gel electrophoresis (DGGE) of 16S rDNA. Principle response curve analysis revealed that the populations of the microcosm as a whole were not significantly affected at 100Gy while they were adversely affected at 500-5000Gy in a dose-dependent manner. However, some effects on each population, including each bacterial population detected by DGGE, did not depend on radiation doses, and some populations in the irradiated microcosm were larger than those of the control. These unexpected results are regarded as indirect effects through interspecies interactions, and possible mechanisms are proposed originating from population changes in other organisms co-existing in the microcosm. For example, some indirect effects on consumers and decomposers likely arose from interspecies competition within each trophic level. It is also likely that prey-predator relationships between producers and consumers caused some indirect effects on producers.

Meta-analysis of second cancer risk after radiotherapy among childhood cancer survivors.

Cancer risks among childhood cancer survivors following radiotherapy have not yet been well characterised in terms of radiation dose. A meta-analysis of studies on the excess relative risk per gray (ERR) of second cancer was conducted previously; unfortunately, the small number of eligible studies restricted quantitative evaluations. To solve this problem, a statistical method to calculate ERR estimates from other estimates was developed, and a meta-analysis was conducted again. The PubMed database was searched and 26 relevant studies were identified. ERR estimates were available in 15 studies, and for the other 11 studies, the regression-based model was used to calculate ERR estimates from other estimates. The overall ERR estimate was 0.40, which was much lower than that of atomic bomb survivors exposed as young children. Heterogeneity of the risk among studies was suggested, and a further study is needed to explore the heterogeneity among studies.

Effects of acute γ-irradiation on the aquatic microbial microcosm in comparison with chemicals

Effects of acute gamma-irradiation were investigated in the aquatic microcosm consisting of green algae (Chlorella sp. and Scenedesmus sp.) and a blue-green alga (Tolypothrix sp.) as producers; an oligochaete (Aeolosoma hemprichi), rotifers (Lecane sp. and Philodina sp.) and a ciliate protozoan (Cyclidium glaucoma) as consumers; and more than four species of bacteria as decomposers. At 100 Gy, populations were not affected in any taxa. At 500-5000 Gy, one or three taxa died out and populations of two or three taxa decreased over time, while that of Tolypothrix sp. increased. This Tolypothrix sp. increase was likely an indirect effect due to interspecies interactions. The principal response curve analysis revealed that the main trend of the effects was a dose-dependent population decrease. For a better understanding of radiation risks in aquatic microbial communities, effect doses of gamma-rays compared with copper, herbicides and detergents were evaluated using the radiochemoecological conceptual model and the effect index for microcosm.

Chromosomal Aberrations in Wild Mice Captured in Areas Differentially Contaminated by the Fukushima Dai-Ichi Nuclear Power Plant Accident

Following the Fukushima Dai-ichi Nuclear Power Plant accident, radiation effects on nonhuman biota in the contaminated areas have been a great concern. The induction of chromosomal aberrations in splenic lymphocytes of small Japanese field mice (Apodemus argenteus) and house mice (Mus musculus) inhabiting Fukushima Prefecture was investigated. In mice inhabiting the slightly contaminated area, the average frequency of dicentric chromosomes was similar to that seen in mice inhabiting a noncontaminated control area. In contrast, mice inhabiting the moderately and heavily contaminated areas showed a significant increase in the average frequencies of dicentric chromosomes. Total absorbed dose rate was estimated to be approximately 1 mGy d(-1) and 3 mGy d(-1) in the moderately and heavily contaminated areas, respectively. Chromosomal aberrations tended to roughly increase with dose rate. Although theoretically, the frequency of chromosomal aberrations was considered proportional to the absorbed dose, chromosomal aberrations in old mice (estimated median age 300 days) did not increase with radiation dose at the same rate as that observed in young mice (estimated median age 105 days).

Risk of second malignant neoplasms among childhood cancer survivors treated with radiotherapy: meta-analysis of nine epidemiological studies.

In the light of notable advances made in childhood cancer therapies, an understanding of the late effects of treatment is important for continued medical care. We conducted a meta-analysis of studies on the excess relative risk (ERR) of second malignant neoplasm (SMN) among childhood cancer survivors treated with radiotherapy. Relevant studies were retrieved by searching the PubMed database, supplemented by hand-searching of reference lists of already retrieved papers. Nine studies were identified and overall ERR estimates were calculated using a fixed effects model and a random effects model. The overall ERR per Gy (absorbed dose of ionising radiation) estimates of radiotherapy by a fixed effect model and a random effects model were 0.50 [95% CI 0.20, 1.21] and 0.53 [95% CI 0.22, 1.31] respectively. Heterogeneity among studies was suggested by Cochrans Q statistic (Q = 40.4, d.f. = 8, P < 0.001). The estimate obtained using a random effects model was far smaller than the corresponding estimate of 1.7 [95% CI 1.1, 2.5] from the study on atomic bomb survivors exposed as young children, suggesting underestimation of ERR estimates among the nine studies compared with the estimates from the study of atomic bomb survivors. In view of the heterogeneity and underestimation in ERR estimates, more studies concerning the risk of SMN among childhood cancer survivors are still needed for further understanding of the carcinogenic effects of radiotherapy on children.

Influence of Age on the Relative Biological Effectiveness of Carbon Ion Radiation for Induction of Rat Mammary Carcinoma

PURPOSE The risk of developing secondary cancer after radiotherapy, especially after treatment of childhood cancers, remains a matter of concern. The high biological effects of carbon-ion radiation have enabled powerful radiotherapy, yet the approach is commonly restricted to the treatment of adults. Susceptibility of the fetus to particle radiation-induced cancer is also unclear. The present study is aimed to investigate the effect of carbon-ion irradiation in childhood on breast carcinogenesis. METHODS AND MATERIALS We irradiated female Sprague-Dawley rats of various ages (embryonic days 3, 13, and 17 and 1, 3, 7, and 15 weeks after birth) with (137)Cs γ rays or a 290-MeV/u monoenergetic carbonion beam (linear energy transfer, 13 keV/μm). All animals were screened weekly for mammary carcinoma by palpation until they were 90 weeks old. RESULTS Irradiation of fetal and mature (15-week-old) rats with either radiation source at a dose of 0.2 or 1 Gy did not substantially increase the hazard ratio compared with the nonirradiated group. Dose responses (0.2-2.0 Gy) to γ rays were similar among the groups of rats irradiated 1, 3, and 7 weeks after birth. The effect of carbon ions increased along with the age at the time of irradiation, indicating relative biological effectiveness values of 0.2 (-0.3, 0.7), 1.3 (1.0, 1.6), and 2.8 (1.8, 3.9) (mean and 95% confidence interval) for animals that were 1, 3, and 7 weeks of age, respectively. CONCLUSIONS Our findings imply that carbonion therapy may be associated with a risk of secondary breast cancer in humans, the extent of which may depend on the age of the patient at the time of irradiation.

Genomic and gene expression signatures of radiation in medulloblastomas after low-dose irradiation in Ptch1 heterozygous mice

Accurate cancer risk assessment of low-dose radiation poses many challenges that are partly due to the inability to distinguish radiation-induced tumors from spontaneous ones. To elucidate characteristic features of radiation-induced tumors, we analyzed 163 medulloblastomas that developed either spontaneously or after X-ray irradiation at doses of 0.05-3 Gy in Ptch1 heterozygous mice. All spontaneous tumors showed loss of heterozygosity in broad regions on chromosome 13, with losses at all consecutive markers distal to Ptch1 locus (S-type). In contrast, all tumors that developed after 3 Gy irradiation exhibited interstitial losses around Ptch1 with distal markers retained (R-type). There was a clear dose-dependent increase in the proportion of R-type tumors within the intermediate dose range, indicating that the R-type change is a reliable radiation signature. Importantly, the incidence of R-type tumors increased significantly (P = 0.007) at a dose as low as 50 mGy. Integrated array-comparative genomic hybridization and expression microarray analyses demonstrated that expression levels of many genes around the Ptch1 locus faithfully reflected the signature-associated reduction in genomic copy number. Furthermore, 573 genes on other chromosomes were also expressed differently between S-type and R-type tumors. They include genes whose expression changes during early cerebellar development such as Plagl1 and Tgfb2, suggesting a recapitulation of gene subsets functioning at distinct developmental stages. These findings provide, for the first time, solid experimental evidence for a significant increase in cancer risk by low-dose radiation at diagnostic levels and imply that radiation-induced carcinogenesis accompanies both genomic and gene expression signatures.

A report from the 2013 international symposium: the evaluation of the effects of low-dose radiation exposure in the life span study of atomic bomb survivors and other similar studies.

AbstractThe RERF International Low-Dose Symposium was held on 5–6 December 2013 at the RERF campus in Hiroshima, Japan, to discuss the issues facing the Life Span Study (LSS) and other low-dose studies. Topics included the current status of low-dose risk detection, strategies for low-dose epidemiological and statistical research, methods to improve communication between epidemiologists and biologists, and the current status of radiological studies and tools. Key points made by the participants included the necessity of pooling materials over multiple studies to gain greater insight where data from single studies are insufficient; generating models that reflect epidemiological, statistical, and biological principles simultaneously; understanding confounders and effect modifiers in the current data; and taking into consideration less studied factors such as the impact of dose rate. It is the hope of all participants that this symposium be used as a trigger for further studies, especially those using pooled data, in order to reach a greater understanding of the health effects of low-dose radiation.

Combined exposure to X-irradiation followed by N-ethyl-N-nitrosourea treatment alters the frequency and spectrum of Ikaros point mutations in murine T-cell lymphoma.

Ionizing radiation is a well-known carcinogen, but its potency may be influenced by other environmental carcinogens, which is of practical importance in the assessment of risk. Data are scarce, however, on the combined effect of radiation with other environmental carcinogens and the underlying mechanisms involved. We studied the mode and mechanism of the carcinogenic effect of radiation in combination with N-ethyl-N-nitrosourea (ENU) using doses approximately equal to the corresponding thresholds. B6C3F1 mice exposed to fractionated X-irradiation (Kaplans method) followed by ENU developed T-cell lymphomas in a dose-dependent manner. Radiation doses above an apparent threshold acted synergistically with ENU to promote lymphoma development, whereas radiation doses below that threshold antagonized lymphoma development. Ikaros, which regulates the commitment and differentiation of lymphoid lineage cells, is a critical tumor suppressor gene frequently altered in both human and mouse lymphomas and shows distinct mutation spectra between X-ray- and ENU-induced lymphomas. In the synergistically induced lymphomas, we observed a low frequency of LOH and an inordinate increase of Ikaros base substitutions characteristic of ENU-induced point mutations, G:C to A:T at non-CpG, A:T to G:C, G:C to T:A and A:T to T:A. This suggests that radiation doses above an apparent threshold activate the ENU mutagenic pathway. This is the first report on the carcinogenic mechanism elicited by combined exposure to carcinogens below and above threshold doses based on the mutation spectrum of the causative gene. These findings constitute a basis for assessing human cancer risk following exposure to multiple carcinogens.

Biological measures to minimize the risk of radiotherapy-associated second cancer: a research perspective

Abstract Purpose Second cancers are among the most serious sequelae for cancer survivors who receive radiotherapy. This article aims to review current knowledge regarding how the risk of radiotherapy-associated second cancer can be minimized by biological measures and to discuss relevant research needs. Results The risk of second cancer can be reduced not only by physical measures to decrease the radiation dose to normal tissues but also by biological means that interfere with the critical determinants of radiation-induced carcinogenesis. Requirements for such biological means include the targeting of tumor types relevant to radiotherapy-associated risk, concrete safety and efficacy evidence and feasibility and minimal invasiveness. Mechanistic insights into the process of radiation carcinogenesis provide rational approaches to minimize the risk. Five mechanism-based strategies are proposed herein based on the current state of knowledge. Epidemiological studies on the joint effects of radiation and lifestyle or other factors can provide evidence for factors that modify radiation-associated risks if deliberately controlled. Conclusions Mechanistic and epidemiological evidence indicates that it is possible to develop interventional measures to minimize the second cancer risk associated with radiotherapy. Research is needed regarding the critical determinants of radiation-induced carcinogenesis available for intervention and joint effects of radiation and controllable factors.