After the outstanding and successful 11th International Conference on Environmental Mutagens (11th ICEM) in Brazil and its associated satellite meetings, I would like to take this time to write about the International Association of Environmental Mutagenesis and Genomics Societies (IAEMGS) as we begin the next four years before the 12th ICEM in Korea. In this report, I will provide a short history of the IAEMS/IAEMGS and then describe three challenges that I see as the most critical for the Society during the next four years. These are: (i) enhance interdisciplinary research on environmental genomics and genotoxicology, (ii) establish opportunities for young scientists in developing countries to meet and collaborate with experienced scientists in industrialized countries, and (iii) improve the financial status of the IAEMGS.
Carcinogenic N-methyl-N-nitrosourea (MNU) has been reported to be formed in vivo and suspected to be a causative agent for human cancer. Therefore, for cancer chemoprevention it is important to find compounds which inhibit N-alkyl-N-nitrosoureas-induced mutagenicity. The inhibitory effect of plant extracts against MNU mutagenicity was evaluated using the umu test. Among thirty aqueous extracts, derived from medicinal plants, seventeen extracts inhibited N-alkyl-N-nitrosoureas-induced mutagenicity using Salmonella typhimurium TA1535/pSK1002. Nine aqueous extracts; Astragalus Root, Bupleurum Root, Cimicifuga Rhizome, Cnidium Rhizome, Glycyrrhiza, Paony Root, Polygonatum Rhizome, Poria Sclerotium, and Processed Ginger, moderately inhibited N-alkyl-N-nitrosoureas-induced mutagenicity (IC50>7.0 mg/mL), and eight aqueous extracts; Cinnamon Bark, Cinnamon Twig, Dodder Seed, Malaytea Scurfpea Fruit, Phellodendron Bark, Prunella Spike, Scisandra Fruit, and Suberect spatholobus Stem strongly inhibited N-alkyl-N-nitrosoureas-induced mutagenicity (IC50<7.0 mg/mL) in Salmonella typhimurium TA1535/pSK1002. An aqueous extract from Suberect spatholobus Stem showed the most potent antimutagenic effects against N-alkyl-N-nitrosoureas.
N-Nitroso compounds are suspected to be causative agents for human cancer. N-Methyl-N-nitrosourea (MNU) is a typical direct acting mutagen with alkylation activity of DNA, and has been reported to be formed in vivo. Therefore, it is important for cancer chemoprevention to find some compounds to inhibit mutagenicity induced by MNU. The inhibitory effect of plant extracts against the mutagenicity of MNU was evaluated using the Ames assay with Salmonella typhimurium TA1535. Among 43 extracts derived from medicinal and edible plant assayed, Glycyrrhiza aspera ethanolic extract, Glycine max extract with 40% isoflavone aglycone (ISOMAX AG40) and Zingiber officinale ethanolic extract at the range 0.01-1.0 mg/plate inhibited MNU-induced mutagenicity in S. typhimurium TA1535. No cytotoxicity of the three extracts were observed in Salmonella typhimuirum TA1535, indicating that inhibition of MNU-induced mutagenicity was apparently due to the antimutagenic potency of Glycyrrhiza aspera ethanolic extract, ISOMAX AG40 and Zingiber officinale ethanolic extract. Therefore, the results of relative mutagenicity showed that Glycyrrhiza aspera ethanolic extract and ISOMAX AG40 decreased the mutagenic effects to 5.4% and 2.6%, respectively, whereas Zingiber officinale ethanolic extract decreased it to 45%.
Earlier studies in our laboratory showed that UVA-irradiated N-nitrosoproline (NPRO) could produce mutagenic compounds and strand breaks in treated DNA with the release of nitric oxide and active oxygen species. In the present study, we investigated the phosphate-dependence of photomutagenicity and solvent effects on nitric oxide release from irradiated NPRO. We also investigated the UVA-driven reaction of NPRO with 2′-deoxyguanosine (dG) in neutral solution, and identified the chemical structure of the photoproduct. A mixture of NPRO and dG dissolved in neutral solution was irradiated with UVA at 320-400 nm for 6 h, and the solution was then subjected to HPLC analysis. The photoproduct isolated from the NPRO and dG mixture in neutral buffer was identified as 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG). We propose a photoreaction mechanism involving the absorption of UVA photons by NPRO followed by UVA-driven photolysis of NPRO, and subsequent production of active oxygen radicals that generate 8-oxodG.
Changes in gene expression profile in rodent liver at the acute stage within 48 h after administration of a hepatocarcinogen have not been extensively reported. In the present study we examined changes in gene expression in mouse liver within 48 h induced by chrysene, a polycyclic aromatic hydrocarbon and genotoxic hepatocarcinogen, by quantitative real-time PCR (qPCR). We quantified 50 candidate genes which discriminated genotoxic hepatocarcinogens from non-genotoxic hepatocarcinogens as determined from our previous DNA microarray studies. Chrysene (100 mg/kg bw) was injected intraperitoneally into male 9-week-old B6C3F1 mice, and at 4, 16, 20, 24 and 48 h after chrysene administration, livers were dissected and processed for gene expression. A total of 35 genes exhibited statistically significant increases at least once within 48 h after chrysene administration. Cyp1a1 and Cyp1a2 showed remarkably consistent increases in gene expression during 4 to 48 h. Fifteen genes (Bhlhe40, Btg2, Casp4, Ccng2, Cdkn1a, Crp, Cyp1a1, Cyp1a2, Fkbp5, Gadd45b, Gadd45g, Hmox1, Igfbp1, Lcn2 and Ly6a) at 4 h, 6 genes at 16 h, 7 genes at 20 h, 7 genes at 24 h, and 10 genes (Bhlhe40, Ccnf, Cyp1a1, Cyp1a2, Ephx1, Hhex, Hmox1, Rcan1, Tubb2a and Tubb4b) at 48 h exhibited statistically significant increases of more than two-fold. At 4 h, 10 of 15 expression-increased genes were associated with DNA damage, DNA repair, cell cycle, cell proliferation and apoptosis. The expression-increased genes at 16 to 48 h were associated with a variety of biological processes. In conclusion three time-dependent patterns in gene expression were observed within 48 h after chrysene administration in mouse liver: Cyp1a1 and Cyp1a2 exhibited consistent increases; the highest number of genes (15 genes) increased in expression at 4 h; and 6 different genes expressed at 4 h increased at 48 h.
The loss of the p53 tumor suppressor protein causes genomic instability. The double strand break is the most severe form of DNA damage, and homologous recombination (HR) acts as a defense against it. In this study, the effects of p53 reduction on HR were investigated, using plasmid DNA in human U2OS cells. The plasmid DNA was designed to contain two inactivated kanamycin resistance genes that reconstitute the functional gene after HR. The p53 protein was knocked-down by siRNA, and then linearized plasmid DNA was introduced into the knockdown cells. The knockdown of p53 reduced the frequency of short tract gene conversion in the plasmid. These results suggested that p53 may enhance the HR of episomal DNA in human cells.
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