Ionizing radiation is one of a few well-characterized etiologic factors of human breast cancer. Laboratory rodents serve as useful experimental models for investigating dose responses and mechanisms of cancer development. Using these models, a lot of information has been accumulated about mammary gland cancer, which can be induced by both chemical carcinogens and radiation. In this review, we first list some experimental rodent models of breast cancer induction. We then focus on several topics that are important in understanding the mechanisms and risk modification of breast cancer development, and compare radiation and chemical carcinogenesis models. We will focus on the pathology and natural history of cancer development in these models, genetic changes observed in induced cancers, indirect effects of carcinogens, and finally risk modification by reproductive factors and age at exposure to the carcinogens. In addition, we summarize the knowledge available on mammary stem/progenitor cells as a potential target of carcinogens. Comparison of chemical and radiation carcinogenesis models on these topics indicates certain similarities, but it also indicates clear differences in several important aspects, such as genetic alterations of induced cancers and modification of susceptibility by age and reproductive factors. Identification of the target cell type and relevant translational research for human risk management may be among the important issues that are addressed by radiation carcinogenesis models.

JRRS Incentive Award in 2009

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Centrosomes function in proper cell division in animal cells. The centrosome consists of a pair of centrioles and the surrounding pericentriolar matrix (PCM). After cytokinesis, daughter cells each acquire one centrosome, which subsequently duplicates at the G1/S phase in a manner that is dependent upon CDK2/cyclin-E activity. Defects in the regulation of centrosome duplication lead to tumorigenesis through abnormal cell division and resulting inappropriate chromosome segregation. Therefore, maintenance of accurate centrosome number is important for cell fate. Excess number of centrosomes can be induced by several factors including ionizing radiation (IR). Recent studies have shown that several DNA repair proteins localize to the centrosome and are involved in the regulation of centrosome number possibly through cell cycle checkpoints or direct modification of centrosome proteins. Furthermore, it has been reported that the development of microcephaly is likely caused by defective expression of centrosome proteins, such as ASPM, which are also involved in the response to IR. The present review highlights centrosome duplication in association with genotoxic stresses and the regulatory mechanism mediated by DNA repair proteins.

Translated and modified from Radiat. Biol. Res. Comm. Vol.43; 343-356 (2008.12, in Japanese)

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Radioprotective activity of pure compounds isolated from the plant Phyllanthus amarus was studied using rat liver mitochondria and pBR322 plasmid DNA as an in vitro model system. These compounds were ellagitannins namely amariin, 1-galloyl-2,3-dehydrohexahydroxydiphenyl (DHHDP)-glucose, repandusinic acid, geraniin, corilagin, phyllanthusiin D, and flavonoids namely rutin, and quercetin 3-O-glucoside. The activity was then correlated with their hydroxyl and superoxide radical scavenging activity. Both ellagitannins and flavonoids effectively prevented lipid peroxidation and protein oxidation in mitochondria. The compounds also prevented radiation induced single strand breaks in pBR322 plasmid DNA. The radioprotective activity of ellagitannins and flavonoids could be due to their ability to scavenge different radicals more or less efficiently, relieving the oxidative stress. Protection conferred by flavonoids, rutin and quercetin 3-O-glucoside to rat liver mitochondria and plasmid pBR322 DNA from radiation induced damage was due to their strong hydroxyl radical scavenging activity. The inhibitory effect of ellagitannins on lipid peroxidation in liver mitochondria was due to their efficient superoxide radical scavenging ability. This is the first report about the radioprotective activity of pure ellagitannins from Phyllanthus amarus.

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Radiotherapy has been used as an adjunctive local-control modality for high-risk neuroblastoma. However, relapse due to radioresistance affects the success of radiotherapy. Ascertaining the fractionated radiation (FIR) modulated molecular targets is imperative in targeted molecular therapy. Accordingly, we investigated the (i) expression of genes representing six functional pathways; (ii) NFκB DNA-binding activity and (iii) expression of radioresponsive molecules after single dose (10 Gy) radiation (SDR) and FIR (2 Gy × 5) in human neuroblastoma cells. Alterations in gene expression were analyzed using QPCR-profiling, NFκB activity using electrophoretic mobility shift assay (EMSA) and pIκBα using immunoblotting. Modulations in TNFα, IL-1α, pAKT, IAP1, IAP2, XIAP, survivin, MnSOD, BID, Bak, MyD88 and Vegfc were determined using quantitative real-time PCR (Q-PCR) and immunoblotting. Compared to SDR, FIR significantly induced the expression of 25 genes and completely suppressed another 30 genes. Furthermore, FIR induced NFκB-DNA-binding activity and IκBα phosphorylation. Similarly, we observed an induced expression of IAP1, IAP2, XIAP, Survivin, IL-1α, MnSOD, Bid, Bak, MyD88, TNFα and pAKT in cells exposed to FIR. The results of the study clearly show distinct differences in the molecular response of cells between SDR and FIR. We identified several potential targets confining to NFκB signaling cascade that may affect radio-resistance after FIR.

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A large amount of radioiodine isotopes (mainly ¹³¹I, t_1/2 = 8 days) was released from the accident at Chernobyl Nuclear Power Plant (CNPP) in April-May 1986. An increase in childhood-thyroid cancer in the contaminated areas in Belarus, Russia and the Ukraine was demonstrated to be caused by radioiodine released at the time of the accident. However, there is a lack of quantitative data on the ¹³¹I levels in the local environment (e.g. air, plant, soil). At this point, a long-lived iodine isotope, ¹²⁹I (t_1/2 = 15.7 million years), also released with a certain ratio to ¹³¹I from CNPP, could be used for estimating the ¹³¹I levels in the environment. In this paper we present analytical results of the ¹²⁹I concentrations and ¹²⁹I/¹²⁷I atom ratios in soil samples collected from the CNPP exclusion zone (30-km zone), with the aim of assessing current contamination levels and distribution patterns. For the analysis of the iodine fraction in the investigated soil samples, the pyrohydrolysis method was utilized for separation of ¹²⁷I and ¹²⁹I nuclides, and subsequently their concentration was determined using inductively coupled plasma mass spectrometry (ICP-MS) and accelerator mass spectrometry (AMS), respectively. The concentration of ¹²⁹I and the ¹²⁹I/¹²⁷I atom ratio in the surface soil samples in the 30 km-zone of CNPP ranged from 4.6 to 170 mBq/kg, and from 1.4 × 10^-6 to 13 × 10^-6, respectively. These values are significantly higher than those from global ¹²⁹I fallout, indicating that most of the measured ¹²⁹I was due to the deposition of the accident. Stable iodine concentrations in this area were found to be very low (below 1 ppm) for most of the samples, suggesting the environmental iodine levels in this area to be potentially low. The ¹²⁹I/¹³⁷Cs activity ratio in surface and sub-surface soils was not so constant, i.e., in the range (7.3-20.2) × 10^-7. This might be due to the different behavior of deposition and/or migration of these nuclides in soil. These results suggest the obtained data of ¹²⁹I to be useful for the reconstruction of the ¹³¹I deposition in the contaminated areas.

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We simultaneously measured radon and thoron exhalation rates in areas of weathered acid rocks in Japan to investigate the relationship between them and between measured and calculated radon exhalation rates. To calculate the radon exhalation rate, we used an equation proposed by UNSCEAR. Our analysis showed that both the radon and thoron exhalation rates measured at one location in a natural environment fluctuated widely, even within one day. We found a strong correlation between the radon and thoron exhalation rates. The measured radon exhalation rates tended to be lower than the calculated values: the mean ratio of the measured exhalation rate to the calculated rate was 0.65. We concluded that the UNSCEAR equation is applicable under a controlled environment (temperature, humidity, etc.), but not where there are artificial underground structures that may influence the transportation of radon in soil.

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Radiation-induced enteritis is a well-recognized sequel of therapeutic irradiation. Therefore we examined the radioprotective properties of Punica granatum peel extract (PPE) on the oxidative damage in the ileum. Rats were exposed to a single whole-body X-ray irradiation of 800 cGy. Irradiated rats were pretreated orally with saline or PPE (50 mg/kg/day) for 10 days before irradiation and the following 10 days, while control rats received saline or PPE but no irradiation. Then plasma and ileum samples were obtained. Irradiation caused a decrease in glutathione and total antioxidant capacity, which was accompanied by increases in malondialdehyde levels, myeloperoxidase activity, collagen content of the tissue with a concomitant increase 8-hydroxy-2'-deoxyguanosine (an index of oxidative DNA damage). Similarly, pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) and lactate dehydrogenase were elevated in irradiated groups as compared to control. PPE treatment reversed all these biochemical indices, as well as histopathological alterations induced by irradiation. Furthermore, flow cytometric measurements revealed that leukocyte apoptosis and cell death were increased in irradiated animals, while PPE reversed these effects. PPE supplementation reduced oxidative damage in the ileal tissues, probably by a mechanism that is associated with the decreased production of reactive oxygen metabolites and enhancement of antioxidant mechanisms. Adjuvant therapy of PPE may have a potential to support a successful radiotherapy by protecting against radiation-induced enteritis.

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Based on results of fieldwork in the Balkan Region of Serbia from 2005 to 2007, soil gas radon and thoron concentrations as well as gamma dose rates were measured. Campaigns were conducted in two different geological regions: Niška Banja, considered a high natural radiation area, and Obrenovac around the TentB Thermal Power Plant (TPP), a low natural radiation area. Radon and thoron gas measurements were made by using two types of Japanese passive radon/thoron detectors, which included GPS data and gamma dose rates. The concentrations of soil radon gas in Niška Banja ranged from 1.8 to 161.1 kBq m^-3, whereas the concentrations for soil thoron gas ranged from 0.9 to 23.5 kBq m^-3. The gamma dose rates varied from 70 to 320 nGy h^-1. In the TentB area, radon concentration was found to range from 0.8 to 24.9 kBq m^-3 and thoron from 0.6 to 1.9 kBq m^-3. The gamma dose rate ranged from 90 to 130 nGy h^-1. In addition, the natural radioactivity of the soil was investigated at the low background area. The radium and thorium contents in collected soil samples ranged from 23 to 58 and 33 to 67 Bq kg^-1, respectively. As a result of correlation analyses between the measured values, the highest correlation coefficient (R > 0.95) was found for thorium in the soil and the thoron gas concentration.

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Many medical linear accelerators generate not only high-energy photons, but also high-energy electrons, and they are no longer equipped with beam stoppers. Therefore, shields might be necessary against bremsstrahlung and photoneutron generated by high-energy electron beams. However, there are few physical studies, and no recommendations are made about shields nowadays. In this report, the leakage doses of bremsstrahlung and photoneutron were calculated by the use of Monte Carlo simulation. To verify the calculated results, the photoneutron leakage dose was measured with a rem counter. The results clearly show that the bremsstrahlung and photoneutron leakage dose generated by electron beams of 24 MeV or below is negligible.

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Using heavy-ion microbeam, we report target irradiation of selected compartments within the diapause-terminated egg and its mutational consequences in the silkworm, Bombyx mori. On one hand, carbon-ion exposure of embryo to 0.5-6 Gy increased the somatic mutation frequency, suggesting targeted radiation effects. On the other, such increases were not observed when yolk was targeted, suggesting a lack of nontargeted bystander effect.

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Background and Purpose; ¹⁰B deriving from ¹⁰B-para-boronophenylalanine (BPA) and ¹⁰B-borocaptate sodium (BSH) have been detected in blood samples of patients undergoing boron neutron capture therapy (BNCT) using prompt gamma ray spectrometer or Inductively Coupled Plasma (ICP) method, respectively. However, the concentration of each compound cannot be ascertained because boron atoms in both molecules are the target in these assays. Here, we propose a simple and rapid method to measure only BPA by detecting fluorescence based on the characteristics of phenylalanine. Material and Methods; ¹⁰B concentrations of blood samples from human or mice were estimated by the fluorescence intensities at 275 nm of a BPA excited by light of wavelength 257 nm using a fluorescence spectrophotometer. Results; The relationship between fluorescence to increased BPA concentration showed a positive linear correlation. Moreover, we established an adequate condition for BPA measurement in blood samples containing BPA, and the estimated ¹⁰B concentrations of blood samples derived from BPA treated mice were similar between the values obtained by our method and those by ICP method. Conclusion; This new assay will be useful to estimate BPA concentration in blood samples obtained from patients undergoing BNCT especially in a combination use of BSH and BPA.

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