389 research outputs found
Microarray-based global mapping of integration sites for the retrotransposon, intracisternal A-particle, in the mouse genome
Mammalian genomes contain numerous evolutionary harbored mobile elements, a part of which are still active and may cause genomic instability. Their movement and positional diversity occasionally result in phenotypic changes and variation by causing altered expression or disruption of neighboring host genes. Here, we describe a novel microarray-based method by which dispersed genomic locations of a type of retrotransposon in a mammalian genome can be identified. Using this method, we mapped the DNA elements for a mouse retrotransposon, intracisternal A-particle (IAP), within genomes of C3H/He and C57BL/6J inbred mouse strains; consequently we detected hundreds of probable IAP cDNA–integrated genomic regions, in which a considerable number of strain-specific putative insertions were included. In addition, by comparing genomic DNAs from radiation-induced myeloid leukemia cells and its reference normal tissue, we detected three genomic regions around which an IAP element was integrated. These results demonstrate the first successful genome-wide mapping of a retrotransposon type in a mammalian genome
Induction of Non-Targeted Stress Responses in Mammary Tissues by Heavy Ions
Purpose
Side effects related to radiation exposures are based primarily on the assumption that the detrimental effects of radiation occur in directly irradiated cells. However, several studies have reported over the years of radiation-induced non-targeted/ abscopal effects in vivo that challenge this paradigm. There is evidence that Cyclooxygenase-2 (COX2) plays an important role in modulating non-targeted effects, including DNA damages in vitro and mutagenesis in vivo. While most reports on radiation-induced non-targeted response utilize x-rays, there is little information available for heavy ions.
Methods and Materials
Adult female transgenic gpt delta mice were exposed to an equitoxic dose of either carbon or argon particles using the Heavy Ion Medical Accelerator in Chiba (HIMAC) at the National Institute of Radiological Sciences (NIRS) in Japan. The mice were stratified into 4 groups of 5 animals each: Control; animals irradiated under full shielding (Sham-irradiated); animals receiving whole body irradiation (WBIR); and animals receiving partial body irradiation (PBIR) to the lower abdomen with a 1 x 1 cm2 field. The doses used in the carbon ion group (4.5 Gy) and in argon particle group (1.5 Gy) have a relative biological effectiveness equivalent to a 5 Gy dose of x-rays. 24 hours after irradiation, breast tissues in and out of the irradiated field were harvested for analysis. Induction of COX2, 8-hydroxydeoxyguanosine (8-OHdG), phosphorylated histone H2AX (γ-H2AX), and apoptosis-related cysteine protease-3 (Caspase-3) antibodies were examined in the four categories of breast tissues using immunohistochemical techniques. Analysis was performed by measuring the intensity of more than 20 individual microscopic fields and comparing the relative fold difference.
Results
In the carbon ion group, the relative fold increase in COX2 expression was 1.01 in sham-irradiated group (p > 0.05), 3.07 in PBIR (p 0.05), 11.31 in PBIR (p 0.05), 8.41 in PBIR (p < 0.05) and 10.59 in WBIR (p < 0.05). Results for the argon particle therapy group showed a similar magnitude of changes in the various biological endpoints examined. There was no statistical significance observed in Caspase-3 expression among the 4 groups.
Conclusions
Our data show that both carbon and argon ions induced non-targeted, out of field induction of COX2 and DNA damages in breast tissues. These effects may pose new challenges to evaluate the risks associated with radiation exposure and understanding radiation-induced side effects
Recommended from our members
Establishing the Japan-Store House of Animal Radiobiology Experiments (J-SHARE), a large-scale necropsy and histopathology archive providing international access to important radiobiology data
Purpose: Projects evaluating the effects of radiation, within the National Institutes of Quantum and Radiological Science and Technology (QST), National Institute of Radiological Sciences (NIRS), have focused on risk analyses for life shortening and cancer prevalence using laboratory animals. Genetic and epigenetic alterations in radiation-induced tumors have been also analyzed, with the aim of better understanding mechanisms of radiation carcinogenesis. As well as the economic and practical limitations of repeating such large-scale experiments, ethical considerations make it vital that we store and share the pathological data and samples of the animal experiments for future use. We are now constructing such an archive called the Japan-Storehouse of Animal Radiobiology Experiments (J-SHARE).
Methods: J-SHARE records include information such as detailed experimental protocols, necropsy records and photographs of organs at necropsy. For each animal organs and tumor tissues are dissected, and parts are stored as frozen samples at -80 ˚C. Samples
fixed with formalin are also embedded in paraffin blocks for histopathological analyses. Digital copies of stained tissues are being systematically saved using a virtual slide system linked to original records by barcodes. Embedded and frozen tissues are available for molecular analysis.
Conclusion: Similar archive systems for radiation biology have been also under construction in the USA and Europe, the Northwestern University Radiation Archive (NURA), and STORE at the BfS, respectively. The J-SHARE will be linked with the sister-archives and made available for collaborative research to institutions and universities all over the world
Calorie restriction alters the mechanisms of radiation-induced mouse thymic lymphomagenesis
Calorie restriction (CR) suppresses not only spontaneous but also chemical- and radiation-induced carcinogenesis. Our previous study revealed that the cancer-preventive effect of CR is tissue dependent and that CR does not effectively prevent the development of thymic lymphoma (TL). We investigated the association between CR and the genomic alterations of resulting TLs to clarify the underlying resistance mechanism. TLs were obtained from previous and new experiments, in which B6C3F1 mice were exposed to radiation at 1 week of age and fed with a CR or standard (non-CR) diet from 7 weeks throughout their lifetimes. All available TLs were used for analysis of genomic DNA. In contrast to the TLs of the non-CR group, those of the CR group displayed suppression of copy-neutral loss of heterozygosity (LOH) involving relevant tumor suppressor genes (Cdkn2a, Ikzf1, Trp53, Pten), an event regarded as cell division–associated. However, CR did not affect interstitial deletions of those genes, which were observed in both groups. In addition, CR affected the mechanism of Ikzf1 inactivation in TLs: the non-CR group exhibited copy-neutral LOH with duplicated inactive alleles, whereas the CR group showed expression of dominant-negative isoforms accompanying a point mutation or an intragenic deletion. These results suggest that, even though CR reduces cell division–related genomic rearrangements by suppressing cell proliferation, tumors arise via diverse carcinogenic pathways including inactivation of tumor suppressors via interstitial deletions and other mutations. These findings provide a molecular basis for improved prevention strategies that overcome the CR resistance of lymphomagenesis
Evaluation of threshold and mechanisms of the combined effect of radiation and ethyl-nitrosourea
We are living in the environment with numerous natural and man-made radiation and chemicals. Cancer development in human, therefore, is considered as a result of interactions of these factors. It becomes clear that carcinogenic response of radiation could be influenced by these factors. The aim of this study is to elucidate the mode and mechanism of the combined effect of chemicals with radiation, especially at low or threshold dose range. The cancer models used in the current study are mouse T-cell lymphomas (TL), which develop after exposure to ionizing radiation and/or ethyl-nitrosourea (ENU). We demonstrated here that synergistic effect was obvious for pre-exposure to high dose radiation, while the effect was marginal or antagonistic for low or threshold dose radiation. When order of exposure was reversed, i.e., ENU followed by X-rays, the mode of combined exposure became additive, indicating the order of exposure plays a key role. The threshold for X-rays was not altered by subsequent-exposure to ENU, while threshold of ENU disappeared by X-ray-exposure. Molecular analysis showed that loss of heterozygosity (LOH) on chromosome 11 and Ikaros mutations were associated with X-ray-induced TL, but not ENU-induced TL. TL developed after combined treatment of X-rays followed by ENU showed molecular changes similar to ENU-induced TL, while TL after treatment of ENU followed by X-rays showed X-ray-type changes. The order is also important for determining molecular pathways of carcinogenesis. Taken together, it is concluded that the mode of combined effect is dependent upon the treatment order and dose of carcinogens
TCRbeta gene D to J rearrangement in thymic lymophomas induced by X-ray irradation is indistinguishable from that by ENU, but V to DJ rearrangement is not
2011日本免疫学会総
TRANSCRIPTIONAL REGULATION OF Il9r IN RADIATION-INDUCED MOUSE T-CELL LEYKEMIA CELL LINE
Interleukin-9 (IL-9) is a multifunctional cytokine secreted from Th2 cell. Besides its role in immune and inflammatory responses, its growth promoting and antiapoptotic activities on multiple transformed cells suggest a potential role in tumorigenesis. We previously reported over-expression and activation of the receptor of IL-9 (IL-9R) in radiation-induced mouse T-cell leukemia (TL), which is an animal model of human T-cell acute lymphoblastic leukemia. In this study we established an Il9r-highly-expressing TL cell line, and examined the promoter activity with luciferase reporter assay. We found that promoter regulatory region was located at a 5` AT-rich region from -410 bp to -487 bp upstream translation start codon. EMSA and ChIP assay were also carried out to investigate the associated transcription factor(s).68th Annual Meeting of the Japanese Cancer Associatio
Anti-cancer effect of calorie restriction on radiation-induced liver tumor of mice
The most significant risk of radiation is cancer development, resulting in the increase in age-specific mortality and the shortening of life expectancy. Since the largest increase in cancer risk in human with obesity was seen for liver cancer, calorie restriction (CR) has emerged as the most potent acting dietary intervention for suppressing hepatocarcinogenesis. In order to estimate anti-cancer effect of CR, B6C3F1 mice were irradiated at 1-week or 10-weeks-old. From 7-week-old, mice were divided into CR (65 kcal/week) and ad libitum (AL, 95 kcal/week) groups. All mice examined histologically for cancer incidence at death. We found that 1-week-old-irradiated mice with AL diet were most susceptible to radiation-induced liver tumor. As the effect of CR that started from 7-weeks-old, both tumor incidence reduction and life span extension were confirmed. Delayed cancer development was detected in sham-irradiated and 10-weeks-old-irradiated groups too. Our results suggest that CR from 7-weeks-old is effective against radiation-induced liver tumor especially after exposure at 1-week-old, indicate that CR is arguably the most useful remedy to prevent radiation-induced cancer.The 70th annual meeting of the Japanese Cancer Associatio
- …