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Takehiko Nohmi
Genes and Environment, Volume 29, pp 75-88; https://doi.org/10.3123/jemsge.29.75

Abstract:
Human genome is continuously exposed to exogenous and endogenous genotoxic agents. The most hazardous and ubiquitous exogenous mutagen may be cigarette smoke, which contains more than 4,000 chemicals including about 60 known carcinogens. About 1% of oxygen metabolism leads to production of reactive oxygen species, a major source of endogenous mutagens. These genotoxic agents induce a variety of lesions in DNA, which results in mutations and chromosome aberrations upon replication. If such genetic alterations occurred in the genes involved in cell proliferations and/or maintenance of genome stability, the cells would proceed in multi-steps of carcinogenesis. The goal of environmental mutagenesis and genetic toxicology is to elucidate the mechanistic links between exposure to genotoxic agents and the health consequences, and to prevent the health hazard associated with DNA damage. To this end, we have investigated the mechanisms of mutagenesis induced by environmental chemicals and contributed to establish the paradigm that Y-family DNA polymerases play central roles in mutagenesis via translesion DNA synthesis across damaged bases in DNA. We also developed genotoxicity assays with bacteria and mice to evaluate the potential risk of environmental chemicals. Here, I review the roles of Y-family DNA polymerases in mutagenesis and introduce features of the novel bacterial and rodent genotoxicity assays. Future directions of environmental mutagenesis and carcinogenesis are also discussed.
Satoko Ishikawa, , Satomi Kawaguchi, Masataka Mochizuki, Minako Nagao
Genes and Environment, Volume 28, pp 31-37; https://doi.org/10.3123/jemsge.28.31

Abstract:
Three lots of kojic acid (KA) which were produced for use as a reagent, food additive and in cosmetics were shown to be mutagenic in S. typhimurium TA100 with or without S9 mix, with a specific activity of around 100 revertants per mg of KA. Since there are contradictory reports on genotoxicity of KA, we examined, using HPLC, whether the mutagenicity to S. typhimurium is due to KA itself, or due to contaminants present in the KA samples. Although two UV absorbing fractions were separated by HPLC, mutagenicity was detected only in the major fraction and the specific mutagenic activity of KA did not change before and after HPLC separation. The material in the major peak fractions on HPLC was confirmed to be KA by NMR. Thus it was demonstrated that KA itself is mutagenic and no mutagenic contaminants were detected in the three lots of samples. Since KA is known to produce liver tumors in mice, we further examined the genotoxicity of KA in the liver of rodents. KA induced micronuclei (MN) in the regenerating liver of adult mice by its gastric intubation at 1 g per kg body weight. However, no MN were induced in young mice (3 weeks old) without partial hepatectomy. Since it was recently found that KA had no tumor-initiating activity in the liver of mice in a two-step carcinogenicity study, there is no evidence that the genotoxicity detected in the mouse liver is involved in liver carcinogenesis.
Hermann M. Bolt
Genes and Environment, Volume 30, pp 114-119; https://doi.org/10.3123/jemsge.30.114

Abstract:
In Europe, there has been a scientific discussion on possible thresholds in chemical carcinogens since the late 1990s. Based on this discussion, the Scientific Committee on Occupational Exposure Limits (SCOEL) of the European Union has discussed a number of chemical carcinogens and has issued recommendations. For some carcinogens, health-based Occupational Exposure Limits (OELs) were recommended, while quantitative assessments of carcinogenic risks were performed for others. For purposes of setting OELs the following groups of carcinogens were adopted: (A) Non-threshold genotoxic carcinogens; for low-dose assessment of risk, the linear non-threshold (LNT) model appears appropriate. For these chemicals, the risk management may be based on the ALARA principle (”as low as reasonably achievable”), technical feasibility, and other socio-political considerations. (B) Genotoxic carcinogens, for which the existence of a threshold cannot be sufficiently supported at present. In these cases, the LNT model may be used as a default assumption, based on the scientific uncertainty, and the ALARA principle may be applied as well. (C) Genotoxic carcinogens with a practical threshold is supported by studies on mechanisms and/or toxicokinetics; health-based exposure limits may be based on an established no-observed adverse effect level (NOAEL). (D) Non-genotoxic carcinogens and non DNA-reactive carcinogens; for these compounds a true (”perfect”) threshold is associated with a clearly founded NOAEL. The mechanisms shown by tumor promoters, spindle poisons, topoisomerase II poisons and hormones are typical examples of this category. Health-based OELs are derived for carcinogens of Groups C and D, while a risk assessment is carried out for carcinogens of Groups A and B. In order to highlight the most important differentiation between Groups B and C, the basic reasoning is given for the six compounds formaldehyde, vinyl acetate, acrylonitrile, acrylamide, trichloroethylene and methylene chloride.
Hiroshi Tanooka, Kouichi Tatsumi, Hideo Tsuji, , Hideo Hirokawa, Tomotari Mitsuoka
Genes and Environment, Volume 31, pp 119-122; https://doi.org/10.3123/jemsge.31.119

Abstract:
Variants of the error-prone gene, mucAB, were found in Escherichia coli plasmids from 3 out of 63 healthy Japanese donors. As compared with mucAB of pKM101, one contained unaltered mucA only, while two others contained full-sized, mutated mucAB with mutation-enhancing activity in E. coli. Possible interaction between bacterial plasmid genes and host humans was discussed.
Genes and Environment, Volume 31, pp 105-118; https://doi.org/10.3123/jemsge.31.105

Abstract:
Transgenic rodent mutation assays are useful models for investigating the genotoxicity of chemicals in vivo. Transgenic gpt delta mice contain multiple copies of chromosomally integrated lambda EG10 phage shuttle vector, which contains reporter genes that allow detection of mutations. This system can identify both point mutations by the gpt assay (6-thioguanine selection) and certain types of deletions using the Spi assay. Transgenic gpt delta rats, which have the same lambda EG10 DNA copies as gpt delta mice, have also been developed. The average spontaneous gpt mutant frequency (MF) in both gpt delta mice and rats is approximately 4.5×10-6. In the Spi assay, the average spontaneous Spi MF is approximately 2.7×10-6 in gpt delta mice, similar to that of gpt delta rats. More than 20 chemicals and irradiations have been analyzed with these systems, and this review summarizes the MFs and treatment conditions. The data demonstrate that these transgenic rodent models are useful for detection and analysis of point mutations and deletions in vivo.
, Tomohiro Hasei, Osamu Kokunai, Souleymane Coulibaly, Sachi Nishimura, Moe Fukasawa, Ryohei Takahashi, Yasuko Mori, Kosuke Fujita, Yuri Yoshihara, et al.
Genes and Environment, Volume 36, pp 120-136; https://doi.org/10.3123/jemsge.2014.013

Abstract:
To reveal the contamination levels of ambient air with particulate matter and mutagens in Japan and the influence of their long-range transport from the Asian continent, we collected airborne particles at 10 sites, from rural sites to metropolitan areas, in central and western areas of Japan for a year, from July 2008 to June 2009. The fluctuation patterns and levels of airborne particle concentration were similar among the 10 sites, and remarkable increases of the concentrations were seen on a few sampling dates, including March 16 and 17, 2009. Most airborne particles collected at the 10 sites showed mutagenicity toward Salmonella typhimurium YG1024 without a mammalian metabolic system (S9 mix) in the Ames test. The mutagenicity levels were quite different among the sampling sites, and the levels seemed to be dependent on the extent of urbanization and industrialization of the subject areas. At Yurihama, a rural site on the west coast of Japan, the mutagenicity level of airborne particles was low, but the particles collected on March 16 and 17, 2009, showed relatively high mutagenicity, >40 revertants/m3, in YG1024 without S9 mix. Airborne particles collected on March 16 and 17, 2009, at most sites showed relatively high or high mutagenicity, >80 revertants/m3, in YG1024 without S9 mix. High coefficients of correlation were found between the concentration and mutagenicity of airborne particles collected in spring, from March to May, for many sites. The results of back trajectory analysis indicated that air masses for March 16 and 17, 2009, had moved from the Asian continent to Japan. The arrival of Asian dust in central and western areas of Japan on those days was reported by the Japan Meteorological Agency. These results suggest that the arrival of mutagens accompanied by Asian dust could be evidently found at Yurihama on March 2009.
Takehiko Nohmi
Genes and Environment, Volume 36, pp 29-32; https://doi.org/10.3123/jemsge.2014.009

Abstract:
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.
Sakae Arimoto-Kobayashi, Gwyn A. Lord, Hikoya Hayatsu
Genes and Environment, Volume 29, pp 67-73; https://doi.org/10.3123/jemsge.29.67

Abstract:
Mutagenicity was monitored in the surface water from the river Thames in 1997, 2002, 2003 and 2005. All samples from the Thames taken at sites in London (a place close to Tower bridge and a site near Teddington lock) and in Windsor show significant mutagenicity in the Ames test. This suggests mutagenic pollution in the Thames was not improved from 1997 to 2005. Water samples from the Serpentine in Hyde Park, London and a sample from the river Dee in Chester also show mutagenic activities toward S. typhimurium YG1024. The mutagenicity (500-2500 revertants per liter) toward S. typhimurium YG1024 in the presence of metabolic activation found in the water from the Thames in London was comparable with that found in the water from the river Asahi in Okayama and the river Katsura in Kyoto, Japan in 2003 and 2005. A comparison of the degree of mutagenicity was made between water samples from the Thames, Asahi and the Katsura rivers. Higher mutagenicity was observed with the O-acetyltransferase-overproducing strains, S. typhimurium YG1024 and YG1029, than with the parental strains S. typhimurium TA98 and TA100. This suggests the presence of amino- or nitro-groups in the structure of molecules polluting the water from all three rivers. Water samples taken from the Thames in 2002 and 2005 exerted mutagenicity in S. typhimurium YG1029, YG1024 and TA98 in the presence of metabolic activation but not in the absence of S9 mix, whereas samples from the Asahi and the Katsura showed mutagenicity in S. typhimurium YG1029, YG1024 and TA98 both in the presence and in the absence of S9 mix. This suggests that mutagenic pollution in the Thames and the Japanese rivers took place with different mutagenic contaminants.
Hiroyuki Kamiya, Emiko Iida, Hideyoshi Harashima
Genes and Environment, Volume 29, pp 63-66; https://doi.org/10.3123/jemsge.29.63

Abstract:
The Escherichia coli Orf135 (NudG) protein, a MutT-type enzyme, catalyzes the hydrolysis of 2-hydroxy-dATP and 8-hydroxy-dGTP, and its deficiency causes an increase in the mutation frequency. In this study, Orf135 proteins with substitutions at the Gly-36, Gly-37, Lys-38, Glu-43, Arg-51, Glu-52, Leu-53, Glu-55, and Glu-56 residues, which are conserved in three MutT-type proteins (Orf135, MutT, and MTH1), were each expressed in the orf135- strain, and the rpoB mutant frequency upon H2O2 treatment was examined. The in vivo mutation suppression abilities and the in vitro enzymatic activities obtained in a previous study were compared. The expression of the enzymatically active Orf135 mutants in the orf135- strain tended to reduce the rpoB mutant frequency induced by H2O2. This result suggests the importance of the phosphohydrolase activity in the suppression of mutations by the Orf135 protein
Yukari Totsuka, Rena Nishigaki, Takeji Takamura-Enya, Nobuo Kawahara, Takashi Sugimura, Keiji Wakabayashi
Genes and Environment, Volume 29, pp 54-62; https://doi.org/10.3123/jemsge.29.54

Abstract:
9-(4′-Aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman, APNH), a novel endogenous mutagenic/ carcinogenic heterocyclic amine, is known to be a reaction product of 9H-pyrido[3,4-b]indole (norharman) and aniline. The major APNH-DNA adduct has been reported to be 2′-deoxyguanosin-8-yl-aminophenylnorharman (dGuo-C8-APNH). However, RNA adducts may also be important. We here demonstrated formation of APNH-RNA adducts and conducted a structural analysis using various spectrometric approaches. When a reaction mixture of an ultimate mutagenic form of APNH, N-acetoxy-APNH, and guanosine (Guo) was subjected to LC-ESI/MS analysis, one peak, with a similar UV spectrum to dGuo-C8-APNH, exhibited a molecular ion peak at m/z 541 along with a fragment peak at m/z 409, consistent with loss of a ribose moiety. From 1H-NMR analysis, its chemical structure was concluded to be N4-(guanosin-8-yl)-9-(4′-aminophenyl)-9H-pyrido[3,4-b]indole (Guo-C8-APNH). The same adduct was yielded in yeast tRNA incubated with N-acetoxy-APNH. Digestion of tRNA treated with N-acetoxy-APNH resulted in the appearance of one adduct spot visualized by the 32P-postlabeling method, corresponding to Guo-C8-APNH. No spot was seen with tRNA alone. Additional analysis of in vivo adduct formation in the livers of rats administered APNH at a concentration of 100 mg/kg revealed that several adduct spots, including one corresponded to Guo-C8-APNH, were observed. The total adduct levels of APNH-RNA were 28±13.3 (mean±SD) adducts per 106 nucleotides. Comparisons demonstrated six times higher levels of total APNH-RNA than total APNH-DNA adducts in the same rat liver samples. These results indicate that APNH-RNA might be a useful biomarker for exposure to APNH.
Yoshiya Shimada, Mayumi Nishimura, Shizuko Kakinuma, Kazumi Yamauchi, Tatsuhiko Imaoka, Yoshiko Amasaki, Yi Shang, Isao Kawaguchi, Masahiro Doi
Genes and Environment, Volume 29, pp 29-37; https://doi.org/10.3123/jemsge.29.29

, Ryo Matsuda, Yoko Matsuda, Shin-Ya Yanagisawa, Masae Ikura, Tsuyoshi Ikura, Tomonari Matsuda
Genes and Environment, Volume 36, pp 17-28; https://doi.org/10.3123/jemsge.2014.001

Chihiro Odajima, Takanori Nakamura, Maki Nakamura, Masanori Miura, Kayoko Yamasaki, Gisho Honda, Yasuaki Kikuchi, Ayumi Yamamoto,
Genes and Environment, Volume 36, pp 10-16; https://doi.org/10.3123/jemsge.2013.012

Xing Fang, Tatsuo Nunoshiba, , Akiyoshi Nishikawa, , , Sakae Arimoto, , , Tomoe Negishi
Genes and Environment, Volume 36, pp 1-9; https://doi.org/10.3123/jemsge.2013.011

Abstract:
It remains uncertain why non-genotoxic compounds that result in liver hypertrophy cause liver tumors. In an effort to resolve this issue, we examined whether liver post-mitochondrial fraction (S9) prepared from rats treated with non-genotoxic compounds affected the genotoxicity of pro-mutagens. Known hepatotoxic compounds, such as piperonyl butoxide (PBO), decabromodiphenyl ether (DBDE), beta-naphthoflavone (BNF), indole-3-carbinol (I3C) and acetaminophen (AA), were orally administered to male and female F344 rats at doses sufficient to cause liver hypertrophy. Rats received diets containing each test compound for 3 days, 4 weeks or 13 weeks, and were then kept for 4 weeks without the test chemical. S9 prepared from the livers of each group was used for the Ames test with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), benzo[a]pyrene (BaP) and N-nitrosodimethylamine (NDMA). In both sexes, liver hypertrophy was observed following administration of all test compounds, and was then reversed to the control state when administration ceased. The mutagenicity of MeIQx, BaP and NDMA increased with the use of S9 derived from rats treated with non-genotoxic compounds other than AA. DBDE administration had a marked effect on the mutagenicity of BaP (over a 30-fold increase in females) and NDMA (about a 20-fold increase in males). To estimate the involvement of metabolic enzymes in the alteration of mutagenicity, we measured the activity of ethoxyresorufin-O-deethylase (EROD) and methoxyresorufin-O-demethylase (MROD) (phase I enzymes), and UDP-glucuronosyltransferase (UGT) and glutathione S-transferase (GST) (phase II enzymes) in each S9 sample. The activity of phase I enzymes increased, even at the 3rd day following administration, and then decreased gradually, except in the case of AA, while the activity of phase II enzymes increased slightly. These results suggest that non-genotoxic hepato-hypertrophic compounds may be partly involved in carcinogenesis by modulating the metabolism of pre-carcinogens incorporated from the environment, in a manner that is dependent on sex and pre-incorporated chemicals.
Dai Nakae, Hideki Wanibuchi, Yoichi Konishi, Shoji Fukushima
Genes and Environment, Volume 30, pp 125-131; https://doi.org/10.3123/jemsge.30.125

Abstract:
Recent findings have indicated that there may be a practical threshold or an ineffective dose range for the carcinogenicity of genotoxic carcinogens. In male Fischer 344 rats given a 16-week chronic feeding administration of 0.0001-1 ppm of N-nitrosodiethylamine (DEN), glutathione S-transferase placental form (GST-P)-positive liver preneoplasias developed at 0.1 ppm or higher, but hepatic level of 8-oxoguanine (8-oxoG), an oxidative DNA damage, was not elevated even at 1 ppm. In contrast, hepatic 8-oxoG level was elevated by a single intraperitoneal administration of 0.001-100 mg/kg body weight of DEN within 6 h and remained high within 72 h, in a clear dose-dependent manner without any ineffective doses, and GST-P-positive preneoplasias correspondingly developed through the selection procedure. The 8-oxoG level was elevated also in extrahepatic organs within 6 h but returned to the normal level within 72 h. In a separate experiment, hepatic 8-oxoG level remained high even 18 weeks after 2 weekly intraperitoneal administrations of 100 mg/kg body weight of DEN. The early prolonged elevation of 8-oxoG level in target organ DNA was similarly induced by heterocyclic amines and dimethylarsinic acid in association with the down-regulation of the Ogg1 gene encoding an 8-oxoG-specific repair enzyme. Taken together, it is suggested that adaptation mechanisms may be involved in the achievement of an ineffective dose range for the carcinogenicity of genotoxic carcinogens during their continuing exposure at sufficiently low level doses.
, Naomi Toyoda-Hokaiwado, , , Masamitsu Honma, Shoji Fukushima
Genes and Environment, Volume 30, pp 101-107; https://doi.org/10.3123/jemsge.30.101

Abstract:
Japan's largest platform for academic e-journals: J-STAGE is a full text database for reviewed academic papers published by Japanese societies
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