著者

及川 伸二 大西 志保 村田 真理子 平工 雄介 川西 正祐

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.26, no.2, pp.125-133, 2004 (Released:2005-12-21)

参考文献数

24

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Reactive oxygen species generated by environmental factors, such as radiation, UV and chemicals can cause sequence-specific DNA damage and play important roles in mutagenesis and carcinogenesis. We have investigated sequence specificity of oxidative stress-mediated DNA damage by using 32P-labeled DNA fragments obtained from the human c-Ha-ras-1, p53 and p16 genes. Free hydroxyl radicals cause DNA damage with no marked site specificity. Copper-hydroperoxo complex caused DNA damage at thymine, cytosine and guanine residues. 1O2 preferentially induces lesions at guanine residues. Benzoyloxyl radical specifically causes damage to the 5’-G in GG sequence; this sequence is easily oxidized because a large part of the highest occupied molecular orbital of this radical is distributed on this site.Recently, we demonstrated that BP-7,8-dione, a metabolite of carcinogenic benzo [a] pyrene (BP) , strongly damaged the G and C of the 5’-ACG-3’ sequence complementary to codon 273 of the p53 gene in the presence of NADH and Cu (II) . BP-7,8-dione also caused preferential double base lesion at 5’-TG-3’ sequences. Since clustered DNA damage is poorly repaired, it is speculated that induction of the double base lesions in DNA might lead to activation of proto-oncogene or inactivation of the tumor suppressor gene. Therefore, oxidative DNA damage induced by BP-7,8-dione, especially double base lesions, may participate in the expression of carcinogenicity of BP in addition to DNA adduct formation. Here, we discuss the mechanisms of sequence-specific DNA damage including clustered DNA damage in relation to mutagenesis and carcinogenesis.

著者

本間 正充

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.26, no.3, pp.285-286, 2004 (Released:2005-12-24)

参考文献数

5

著者

Shizuyo Sutou

出版者

日本環境変異原学会

雑誌

Genes and Environment (ISSN:18807046)

巻号頁・発行日

pp.2014.019, (Released:2014-06-19)

参考文献数

81

被引用文献数

2

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Three characteristics, i.e., bipedalism, nakedness, and the family reproductive unit, distinguish humans from other primates. Once a hairless mutation was initially introduced, these three could be explained inseparately. All primates except humans can carry their babies without using their hands. A hairless mother would be forced to stand and walk upright to hold a baby. As her activities were markedly limited, the male partner had to collect food and carry it to her to keep their baby from starving. He must have been sexually accepted by her at any time as a reward for food. Sexual relations irrespective of estrus cycles might have strengthened the pair bond, leading to family formation. Savannahs appeared 2.5 million years ago (Ma), which forced hominins to terrestrial life, but the ground was full of danger and a larger brain became advantageous. Wildfires occurred frequently; naked hominins approached fire for warming, but soon must find burnt animals in the aftermath of wildfires. The taste of burnt meat must be a driving force for hominins to become meat-eaters. They must have learned how to control fire and how to repel hairy animals that hate fire. To compete with large carnivores with fangs and claws, they became not hunters but robbers. When robber hominins found that a carnivore had killed a prey animal, they approached the predator and repelled it away from the victim using fire, then claiming the prey intact. Major events such as the timing of global cooling, the appearance of savannahs, the appearance of early humans, decline of large predators, the manufacture of stone tools, and the start of cooking largely coincide at 2.5 Ma. Cooked meat must be tasty and easily digested, providing hominins with nutrients sufficient to enlarge the brain, while most large carnivores were forced to extinction. Thus, hairlessness created humans.

著者

豊泉 友康 太田 亮 松本 浩孝 田面 喜之 中川 ゆづき 山影 康次

出版者

日本環境変異原学会

雑誌

日本環境変異原学会大会プログラム・要旨集

巻号頁・発行日

no.38, 2009-11-06

著者

野村 大成

出版者

日本環境変異原学会

雑誌

日本環境変異原学会大会プログラム・要旨集

巻号頁・発行日

no.27, 1998

著者

古川 絢子 及川 伸二 原田 夏菜子 杉山 浩一 平工 雄介 村田 真理子 島田 厚良 川西 正祐

出版者

日本環境変異原学会

雑誌

日本環境変異原学会大会プログラム・要旨集

巻号頁・発行日

no.39, 2010-10-29

著者

西田 裕 川西 優喜 高村 岳樹 若林 敬二 八木 孝司

出版者

日本環境変異原学会

雑誌

日本環境変異原学会大会プログラム・要旨集

巻号頁・発行日

no.33, 2004

著者

鈴木 啓司 児玉 靖司 渡邉 正己

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.27, no.2, pp.111-115, 2005-07-31

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Ionizing radiation induces genomic instability, which is transmitted through many generations after irradiation in the progeny of surviving cells. We have hypothesized that radiation-induced large deletion causes potentially unstable chromosome regions, which are involved in delayed induction of radiation-induced genomic instability. Using phosphorylation-specific antibodies against ATM and histone H2AX, whose phosphorylation is induced by DNA double strand breaks, we detected delayed induction of phosphorylated ATM and H2AX foci in the progeny of X-ray-surviving cells, which indicated delayed induction of DNA double strand breaks. Furthermore, we found delayed chromosomal instability in X chromosomes in clones which contain large deletion involving the HPRT loci. It is suggested that large deletion involving ~Mb region causes unstable chromatin structure, and it results in delayed rearrangement of chromosomes involved. These findings provide the possibility that manifestation of radiation-induced genomic instability results from delayed DNA breaks, i.e., the breaks lead to delayed chromosome rearrangements, delayed cell death etc., many generations after irradiation.

著者

中川 誠人

出版者

日本環境変異原学会

雑誌

日本環境変異原学会大会プログラム・要旨集

巻号頁・発行日

no.39, 2010-10-29

著者

能美 健彦 清水 雅富 グルーズ ピーター

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.26, no.2, pp.159-165, 2004 (Released:2005-12-21)

参考文献数

47

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Altered oxidative metabolism is a property of many tumor cells. Oxidation of dNTP pool as well as DNA is a source of genome instability. We report here that two Y-family DNA polymerases of the archaeon Sulfolobus solfataricus strains P1 and P2 incorporate oxidized dNTPs into nascent DNA in an erroneous manner: the polymerases exclusively incorporate 8-hydroxy-dGTP opposite template A, and incorporate 2-hydroxy-dATP opposite G and T. Extension onto the incorporated analogs is only slightly reduced. Human DNA polymerase η, a member of human Y-family DNA polymerases, incorporates the oxidized dNTPs in a similar erroneous manner. These DNA polymerases are shown to bypass a variety of DNA lesions. Thus, our results suggest the Y-family DNA polymerases promote mutagenesis through the erroneous incorporation of the oxidized dNTPs during DNA synthesis in addition to facilitating translesion DNA synthesis.

著者

豊國 伸哉

出版者

日本環境変異原学会

雑誌

日本環境変異原学会大会プログラム・要旨集

巻号頁・発行日

no.38, 2009-11-06

著者

小野 宏

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.27, no.2, pp.133-137, 2005-07-31

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The OECD established the Guidelines for Testing of Chemicals in 1981, which is the basis of the mutual acceptance of data (MAD) system among the member countries to prevent unnecessary repetition of toxicity tests, and consequently to reduce the number of animals used. The Guidelines was soon subjected to revision from the viewpoint of animal welfare besides its periodical updating with the state-of-art in the toxicological sciences. Revision of the Test Guidelines is in progress according to the 3Rs principle, reduction, refinement and replacement. The acute toxicity test and the skin and eye irritation/corrosion tests were assumed to be the most problematic ones among the animal tests in animal welfare aspect. Three different test methods have been adopted for the alternative to acute oral toxicity test (Test Guideline (TG) 401), namely, the fixed dose procedure (TG420), acute toxic class method (TG423) and up-and-down procedure (TG425), and the reduction of animals was accomplished. Then the traditional acute oral toxicity test (TG401) has been deleted from the Guidelines. Procedures for irritation/corrosion tests for skin (TG404) and eye (TG405) were reorganized into tier-test system in order to prevent any corrosion or strong irritation to take place. The tier system consists of survey of toxicities of the test chemical, structure-activity relationship, pH, and testing with in vitro methods. Moreover, at the final tier animal testing should proceed by one animal. Three kinds of in vitro corrosivity tests have been adopted in the Guidelines.

著者

Tetsuji Nagao Naomi Takada Noriko Onoda

出版者

日本環境変異原学会

雑誌

Genes and Environment (ISSN:18807046)

巻号頁・発行日

vol.33, no.2, pp.50-60, 2011 (Released:2011-05-25)

参考文献数

82

被引用文献数

1 2

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Congenital malformations can be induced in the offspring of laboratory animals treated with the mutagens, ethylnitrosourea, methylnitrosourea, mitomycin C, triethylenemelamine or procarbazine before copulation. The spectra of malformations in the offspring classified as male-mediated malformations after exposure of paternal mice to mutagens showed no evidence of mutagen-specificity or germ-cell stage-dependent variations. Recently, we demonstrated the increased incidence of congenital malformations in the offspring of male mice exposed in utero to synthetic estrogens such as diethylstilbestrol (DES), 17β-estradiol (E2) or ethynyl estradiol (EE), and that the induction of male-mediated malformations by DES, E2 or EE showed a clear threshold effect. Developmental exposure to DES, E2 or EE caused partial atrophy and feminization in the genital tract. They also showed transgenerational effects when applied prenatally at a dose which caused histopathological changes in the testes. Germ-cell series in normal testis have mechanisms to select against spontaneously arising mutation; but these selection mechanisms may not function efficiently in chemically-damaged testes. Based on these results and considerations, we propose as a hypothesis that transgenerational teratogenesis by prenatal exposure to synthetic estrogens may occur as a consequence of testicular toxicity. Moreover, since DES has been reported to be non-genotoxic, epigenetic mechanisms such as DNA methylation may be involved in the transgenerational teratogenesis induced by estrogenic drugs. The expression patterns of DNA methyltransferases (Dnmts) mRNA, global DNA methylation levels in testicular cells of embryos exposed to estrogenic drugs or in epididymal sperm of mature male mice exposed prenatally to estrogenic drugs were different from those in the controls. Results shown in this review support the proposal that, when evaluating the toxicities of environmental chemicals including endocrine disruptors, epigenetic effects such as DNA methylation should be taken into account.

著者

林 裕造

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.27, no.2, pp.81-89, 2005 (Released:2005-12-26)

参考文献数

9

被引用文献数

2 2

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A threshold represents the theoretically defined dose, below which no abnormal increase in response is observed. Genotoxic carcinogens are known to have an irreversible effect on the genetic cellular structure. Even in small amounts, genotoxic carcinogens are assumed to have additive effects and therefore to subject individuals exposed to them to an incremental risk of developing cancer.Based on this assumption, the no-threshold concept was introduced exclusively for genotoxic carcinogens and has been adopted in Japan as a basis for the regulatory risk assessment in case of such chemicals. The current regulatory policy adheres to the fundamental principle of food safety i.e. to the precedence of protecting people's health.Dose-response studies recently conducted on various genotoxic agents suggest the existence of a threshold. If confirmed, such findings may provide sufficient scientific evidence to substantiate the adoption of a threshold concept as the principle of the regulatory assessment of the risks of genotoxic carcinogens and their impact on health.It should however be emphasized that the limitations of a threshold approach must be clearly understood and presented to lend credence to the proposition of a paradigm shift from the current regulatory policy: A threshold is not a value that can be determined directly and precisely from dose-response data, but one that can be estimated from analytical data by means of a logically-elaborated mathematical model calculation.Scientific efforts in support of the adoption of a threshold in this context should therefore be focused on the development of appropriate mathematical models, and on the establishment of toxicological concepts that substantiate their application.A realistic first step towards a paradigm shift from the no-threshold concept is to seek general consensus on the introduction of an appropriately estimated“virtually safe dose”, instead of a threshold.

著者

鈴木 孝昌

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.24, no.3, pp.179-184, 2002-11-13

参考文献数

10

被引用文献数

3

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この原稿は,今年の7月に淡路島で開かれたMMS研究会第31回定例会での特別講演をもとに作成したものです.これまで,10年以上にわたり国立医薬品食品衛生研究所変異遺伝部において,環境変異原研究に携わってきましたが,この4月に部を移動になり,環境変異原研究とは今後少し距離を置かざるを得なくなりました.この機会に自分としても一歩離れた立場からこれまで歩んできた道を振り返り,少し大胆に提言をさせていただきたいと考え,「環境変異原研究の光と陰」というタイトルで講演をさせていただきました.講演後の反響もあり,内容に関する問い合わせもいただいたことから,今回環境変異原研究の原稿として,まとめ直させていただきました.これがきっかけとなり,環境変異原研究の方向性に関する議論が盛り上がることを期待します.

著者

西尾 恵里子 森田 士郎 豊川 徹 富田 純史

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.26, no.2, pp.81-88, 2004 (Released:2005-12-21)

参考文献数

13

被引用文献数

5 5

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The Ames Salmonella/microsome assay (Ames test) is a convenient method for screening mutagens in our diet including those in drinking water. In this study, we assayed the mutagenicity levels of tap water in Kitakyushu-city and of humic acid solutions treated with chlorine. The amount of chlorine added was calculated to maintain the residual chlorine level constant at 20°C as in city office tap water. The samples were concentrated with adsorbent (CSP800) and the mutagenic activity was assayed with Salmonella typhimurium TA100 and TA98 strains with or without S9 mix. The tap water was analyzed for volatile organic compounds and some factors in conventional water quality monitoring every two months from March 1998 to January 2000. The tap water samples tested showed mutagenicity on strain TA100 without S9 mix. The mutagenicity of the samples tended to be higher from winter to spring than that from summer to fall.Chlorine-treated humic acid solutions were used as a model to examine the effect of the concentrations of humic acid and chlorine, and the temperature on the mutagenicity. The descending order of sensitivity to mutagenicity was TA100 without S9 mix, TA98 without S9 mix, and TA100 with S9 mix; no mutagenicity was observed for TA98 with S9 mix. Mutagenicity seemed to increase with increasing concentrations of humic acid and chlorine, and with lowering the water temperature. The observed seasonal variation of mutagenicity of the tap water may be partly explained by the rainfall and the water temperature during the rainy season, from summer to fall, because the organic substances of river water decreased and the water temperature increased over that season.

著者

小野 宏

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.27, no.2, pp.133-137, 2005 (Released:2005-12-26)

参考文献数

5

---

The OECD established the Guidelines for Testing of Chemicals in 1981, which is the basis of the mutual acceptance of data (MAD) system among the member countries to prevent unnecessary repetition of toxicity tests, and consequently to reduce the number of animals used. The Guidelines was soon subjected to revision from the viewpoint of animal welfare besides its periodical updating with the state-of-art in the toxicological sciences. Revision of the Test Guidelines is in progress according to the 3Rs principle, reduction, refinement and replacement. The acute toxicity test and the skin and eye irritation/corrosion tests were assumed to be the most problematic ones among the animal tests in animal welfare aspect. Three different test methods have been adopted for the alternative to acute oral toxicity test (Test Guideline (TG) 401), namely, the fixed dose procedure (TG420), acute toxic class method (TG423) and up-and-down procedure (TG425), and the reduction of animals was accomplished. Then the traditional acute oral toxicity test (TG401) has been deleted from the Guidelines. Procedures for irritation/corrosion tests for skin (TG404) and eye (TG405) were reorganized into tier-test system in order to prevent any corrosion or strong irritation to take place. The tier system consists of survey of toxicities of the test chemical, structure-activity relationship, pH, and testing with in vitro methods. Moreover, at the final tier animal testing should proceed by one animal. Three kinds of in vitro corrosivity tests have been adopted in the Guidelines.

著者

林 真 長尾 美奈子 祖父尼 俊雄 森田 健 能美 健彦 本間 正充 宇野 芳文 葛西 宏 佐々木 有 太田 敏博 田中 憲穂 中嶋 圓 布柴 達夫

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.26, no.3, pp.275-283, 2004-12-20

被引用文献数

1

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食品関連物質の遺伝毒性の評価,解釈をするための戦略を構築するため,日本環境変異原学会に臨時委員会を設立し,厚生労働科学研究費補助金食品安全性確保研究事業「既存添加物等における遺伝毒性評価のための戦略構築に関する研究」の研究班と共同し,定例の検討会議を毎月開催し,統一的な考えについて検討を続けている.本戦略を構築するためのモデルとして,コウジ酸を選択し,評価に必要と考えられる試験を実施し,その結果の評価,解釈を国際的議論のもとに標準化可能なものとするため,海外から指導的立場にある研究者をコンサルタントとして招聘し,議論,提言を受けた.本臨時委員会の活動は3年計画で進められており,現在は約1年半が経過したところである.ここでは,本委員会の設置意図を中心に活動の中間報告を行う.

著者

浅野間 光治 荒木 春美 大澤 浩一 中井 康晴 林 宏行 若田 明裕 森田 健

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.25, no.1, pp.45-59, 2003 (Released:2005-08-19)

被引用文献数

2

著者

鈴木 孝昌

出版者

日本環境変異原学会

雑誌

環境変異原研究 (ISSN:09100865)

巻号頁・発行日

vol.25, no.2, pp.119-125, 2003 (Released:2005-08-19)

参考文献数

15

被引用文献数

1 1

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The transgenic mouse mutation assay was developed as a striking new tool for mutation research in 1990. This assay enables the detection of mutations in a transgene in multiple organs including germinal tissues and thus reveals organ-specific genotoxicity of the mutagen. Following its introduction in MutaMouse and Big Blue mouse systems, modification of the methodology, mainly the introduction of the positive selection system and development of other transgenic animal models including rat, improved and assured the relevance of the assay. Accumulation of experimental data suggests the transgenic mouse mutation assay can be used as a standard in vivo test for mutagenesis.We have developed a multi-endpoint test, by combining the peripheral blood micronucleus assay with the transgenic mouse mutation assay. This test allows simultaneous detection of clastogenecity and mutagenecity in vivo. Since these two endpoints indicate different characteristics of the mutagen, data from many chemicals suggest the importance of detecting both endpoints. With this approach, the transgenic assay could detect the mutagenecity of diethylnitrosamine, which failed to be detected in micronucleus assay.Another important advantage of this assay is its suitability for sequence analysis. Sequencing of the transgene enables to draw mutagen-specific mutation spectrum, a molecular signature of the mutagen, and is very useful to deduce the mechanism of mutagenesis. In this regard, we have intensively used a positively selectable target gene ‘cII’. This gene is relatively short (300 bp) which made the sequencing process easier and less time consuming and enables us to generate data on mutagenesis of several mutagens. We hope the database will be useful for molecular epidemiology in future.A quantitative comparison of carcinogenic and mutagenic potency of chemicals revealed a good correlation with transgenic mutation assay and therefore suggesting a usefulness of this assay for the quantitative risk assessment.