Mutation Research/Genetic Toxicology最新文献

{"title":"QSARS of mutagens and carcinogens: Two case studies illustrating problems in the construction of models for noncongeneric chemicals","authors":"Romualdo Benigni ,&nbsp;Ann M. Richard","doi":"10.1016/S0165-1218(96)90092-0","DOIUrl":"10.1016/S0165-1218(96)90092-0","url":null,"abstract":"<div><p>There is a strong motivation to develop QSAR models for toxicity prediction for use in screening, for setting testing priorities, and for reducing reliance on animal testing. Decisions must be made daily by toxicologists in governments and industry to direct limited testing resources to the most urgent public health problems, and to direct the types of chemical synthesis and product development efforts undertaken. This need has motivated attempts to construct general QSAR models (e.g., for rodent carcinogenicity), not tailored to congeneric series of chemicals. These various attempts have provided interesting and important scientific evidence; however, they have also shared a limited overall performance. The goal of this paper is to illustrate, by two unrelated actual examples of QSARs for mutagens and carcinogens, some fundamental problems relative to the application of general QSAR approaches to noncongeneric chemicals. Both examples consider data sets that are noncongeneric in a chemical structure and mechanism of action sense: in the first case, a mean mutagenic potency defined as an average over multiple genetic toxicity endpoints, and, in the second case, the NTP two-sexes, two species rodent carcinogenicity bioassay results for 280 carcinogens and noncarcinogens. The problems encountered with the QSAR analyses of these two cases indicate that a successful approach to the problem of QSAR modeling of noncongeneric data will need to consider the multidimensional nature of the problem in both a chemical and a biological sense. Since different chemical classes represent largely independent action mechanisms, some means for extracting local QSARs for constituent classes will be necessary. Alternatively, a general QSAR derived for a noncongeneric data set will need to be scrutinized and decomposed along chemical class lines in order establish boundaries for application and confidence levels for prediction.</p></div>","PeriodicalId":100938,"journal":{"name":"Mutation Research/Genetic Toxicology","volume":"371 1","pages":"Pages 29-46"},"PeriodicalIF":0.0,"publicationDate":"1996-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0165-1218(96)90092-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19913686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutagenicity of 24-hour duplicate of Japanese diet","authors":"Hiroshi Mano ,&nbsp;Norio Shibuya ,&nbsp;Hiroto Nakadaira Tatsuo Ohta ,&nbsp;Teiji Ishizu ,&nbsp;Osamu Yamazaki ,&nbsp;Shuko Takagi ,&nbsp;Kazuo Endoh ,&nbsp;Masaharu Yamamoto ,&nbsp;Tomio Hirohata","doi":"10.1016/S0165-1218(96)00077-8","DOIUrl":"10.1016/S0165-1218(96)00077-8","url":null,"abstract":"<div><p>In order to elucidate the genotoxicological characteristics of the Japanese diet, the mutagenicity of 24-h duplicate of the diet samples were investigated. The mutagenicity of blue rayon extract was examined in the Ames Salmoneila/microsome assay. Thirty-two (91.4%) of 35 samples revealed mutagenicity toward <em>Salmonella typhimurium</em> TA98 in the presence of S9 mix. The mutagenic activities showed significant correlations with the consumption rates of broiled fish (<em>r</em> = 0.517, <em>p</em> = 0.0021) and broiled meat (<em>r</em> = 0.494, <em>p</em> = 0.0036). In other test conditions, 6 (17.1%), 5 (14.3%) and 8 (22.9%) samples were mutagenic to <em>Salmonella typhimurium</em> TA98 without S9 mix, TA100 with S9 mix and TA100 without S9 mix, respectively. Findings in the present study suggest that high consumption of broiled fish and broiled meat are important as the source of mutagens/carcinogens in the Japanese diet. In the present study, however, biological inference of these findings could not be made in relation to the occurrence of cancers, especially of the gastric cancer, which is the most prevalent form of cancer in Japan.</p></div>","PeriodicalId":100938,"journal":{"name":"Mutation Research/Genetic Toxicology","volume":"370 3","pages":"Pages 203-208"},"PeriodicalIF":0.0,"publicationDate":"1996-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0165-1218(96)00077-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19882134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutagenicity to the mouse bone marrow by the mouse germ cell mutagen N-propyl-N-nitrosourea","authors":"H. Tinwell,&nbsp;J. Yendle,&nbsp;J. Ashby","doi":"10.1016/S0165-1218(96)00047-X","DOIUrl":"10.1016/S0165-1218(96)00047-X","url":null,"abstract":"<div><p><em>N</em>-Propyl-<em>N</em>-nitrosourea (PNU) is shown to be active in male mouse bone marrow micronucleus assays when dosed at either 100 or 200 mg/kg in saline. Activity was observed following either intraperitoneal (i.p.) injection or oral gavage. This observation is consistent with the demonstration by Murota and Shibuya of the specific-locus mutagenicity caused by <strong>PNU</strong> in male mouse spermatogonia when dosed at 200 mg/kg by i.p. injection. These data strengthen further the observation that rodent germ cell mutagens are also mutagenic to rodent somatic cells.</p></div>","PeriodicalId":100938,"journal":{"name":"Mutation Research/Genetic Toxicology","volume":"370 3","pages":"Pages 141-143"},"PeriodicalIF":0.0,"publicationDate":"1996-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0165-1218(96)00047-X","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19882219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Salmonella assay negative and positive carcinogens on intrachromosomal recombination in G1-arrested yeast cells","authors":"Alvaro Galli ,&nbsp;Robert H. Schiestl","doi":"10.1016/S0165-1218(96)00078-X","DOIUrl":"10.1016/S0165-1218(96)00078-X","url":null,"abstract":"<div><p>A wide variety of carcinogens including Ames assay (Salmonella) positive as well as Salmonella-negative carcinogens induce intrachromosomal recombination (DEL recombination) in strain RS112 of <em>Saccharomyces cerevisiae.</em> It has been previously shown that the Salmonella-positive carcinogens ethyl methanesulfonate (EMS), methyl methanesulfonate (MMS) and 4-nitroquinoline-<em>N</em>-oxide (4-NQO) and the Salmonella-negative carcinogens safrole, benzene, thiourea, carbon tetrachloride and urethane induce DEL recombination in G₂-arrested yeast cells. DEL recombination is preferentially induced by safrole, benzene and carbon tetrachloride in G₂-arrested cells which might be explained by preferential induction of unequal sister chromatid recombination leading to deletions. To test this, cells of strain RS112 were arrested in the G₁ phase of the cell cycle, exposed to these carcinogens and the frequencies of DEL and interchromosomal recombination (ICR) were determined. EMS, MMS and 4-NQO induced DEL recombination and ICR in G₁-arrested cells with a linear dose-response curve. In contrast, the Salmonella-negative carcinogens safrole, benzene, carbon tetrachloride, thiourea and urethane induced DEL recombination and ICR with a threshold below which no significant increase was seen and only at already cytotoxic doses. EMS, MMS and 4-NQO were more recombinagenic in previous experiments with growing cells than in G₁-arrested cells. On the other hand, safrole, benzene and carbon tetrachloride were more recombinagenic in G₁-arrested than in growing cells. Thus, inducibility of DEL recombination in G₁-arrested cells parallels inducibility in G₂-arrested cells making it less likely that sister chromatid recombination events might be involved. These data are discussed in terms of the mechanism of induced DEL recombination and the possible biological activities of these carcinogens.</p></div>","PeriodicalId":100938,"journal":{"name":"Mutation Research/Genetic Toxicology","volume":"370 3","pages":"Pages 209-221"},"PeriodicalIF":0.0,"publicationDate":"1996-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0165-1218(96)00078-X","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19882135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lack of induction of chromosome aberrations and micronuclei by N-(1,3-dimethylbutyl)-N-phenylparaphenylenediamine in mouse bone marrow cells","authors":"Josely George,&nbsp;Ramadasan Kuttan","doi":"10.1016/S0165-1218(96)00072-9","DOIUrl":"10.1016/S0165-1218(96)00072-9","url":null,"abstract":"<div><p><em>N</em>-(1,3-Dimethylbutyl)-<em>N</em>-phenylparaphenylenediumine (DMPPD) is a derivative of phenylenediamine (PPD) which is widely used in the rubber industry as an antioxidant. DMPPD which is a strong allergen, is least studied for its clastogenic potency. This study evaluated the genotoxic property of DMPPD in Swiss albino mice bone marrow cells by using chromosomal aberration and micronuclei assay. Three concentrations of DMPPD, i.e., 100, 150 and 200 mg/kg body wt. did not significantly increase the micronuclei in polychromatic erythrocytes or the ratio of poly to normochromatic erythrocytes. Chromosome aberration studies using 100 mg and 200 mg/kg body wt. showed that DMPPD is a non-inducer of chromosome aberrations. The results indicated non-clastogenicity of DMPPD in mice marrow cells up to a concentration of 200 mg/kg body wt. under our experimental conditions.</p></div>","PeriodicalId":100938,"journal":{"name":"Mutation Research/Genetic Toxicology","volume":"370 3","pages":"Pages 191-194"},"PeriodicalIF":0.0,"publicationDate":"1996-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0165-1218(96)00072-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19882132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chromosome painting analysis of spontaneous and methyl methanesulfonate-induced trifluorothymidine-resistant L5178Y cell colonies","authors":"Li-Shi Zhang ,&nbsp;Masamitsu Honma,&nbsp;Atsuko Matsuoka,&nbsp;Takayoshi Suzuki,&nbsp;Toshio Sofuni,&nbsp;Makoto Hayashi","doi":"10.1016/S0165-1218(96)00069-9","DOIUrl":"10.1016/S0165-1218(96)00069-9","url":null,"abstract":"<div><p>Spontaneous and methyl methanesulfonate-induced trifluorothymidine-resistant mutants in mouse lymphoma L5178Y cells were analyzed using fluorescence in situ hybridization with mouse probes specific for chromosome 11, on which the <em>tk</em> gene is located, and chromosome 3, as the control. 76.5% (13/17) of small-colony mutants (thought to be the result of chromosomal mutation) and 28.6% (4/14) of large-colony mutants (thought to be the result of gene mutation) showed rearranged chromosome 11. Of the mutants with abnormal chromosome 11 painting pattern, 5 small- and 2 large-colony mutants carried clonal aberrations, while the remaining 8 small- and 2 large-colony mutants showed mosaic aberrations. Most abnormalities in the small-colony mutants involved the distal region of one painted chromosome 11, where the <em>tk</em>⁺ gene maps. An increase, rather than a decrease, in chromosome 11 material was found in a majority of abnormally painted mutants. On the contrary, no rearrangements involving chromosome 3 were found in any small- and large-colony mutants analyzed except one large-colony mutant, which showed chromosome rearrangements involving both chromosome 11 and 3. The present study confirms that the majority of small-colony mutants in L5178Y cells have chromosome 11 rearrangements that can be detected by chromosome painting and that the majority of the chromosomal abnormalities in TFT-resistant mutants involved complex rearrangements.</p></div>","PeriodicalId":100938,"journal":{"name":"Mutation Research/Genetic Toxicology","volume":"370 3","pages":"Pages 181-190"},"PeriodicalIF":0.0,"publicationDate":"1996-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0165-1218(96)00069-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19882131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutagenicity of cobalt and reactive oxygen producers","authors":"Jun Kitahara ,&nbsp;Kenzo Yamanaka ,&nbsp;Koichi Kato ,&nbsp;Yong-Woo Lee ,&nbsp;Catherine B. Klein ,&nbsp;Max Costa","doi":"10.1016/S0165-1218(96)00042-0","DOIUrl":"10.1016/S0165-1218(96)00042-0","url":null,"abstract":"<div><p>Oxidative stress has been implicated in carcinogenesis yet there are chemicals that produce oxidative stress that are not carcinogenic. Mutations are the inherited results of DNA damage and are critical events in carcinogenesis. The mutagenicity of oxidative stress induced by peroxide, paraquat and cobalt compounds was examined in transgenic <em>gpt</em>⁺ Chinese hamster cell lines (G12 and G10). These two cell lines are known to be more sensitive to mutagens such as X-rays and UV than their parental V-79 cells. In these studies, the mutagenic activity of cobalt chloride, a metal that induces oxidative stress but is not carcinogenic, was measured to be 7.7 times higher than the spontaneous mutant frequency in G12, but was only 1.5 to 2.5 times higher than spontaneous mutant frequency in G10 cells. The mutant frequency of cobalt sulfide was somewhat lower. Hydrogen peroxide was found to be only weakly mutagenic in G12 cells, and treatment of cells with a combination of hydrogen peroxide and cobalt did not alter the mutation frequency induced by cobalt sulfide alone. Paraquat did not elicit mutagenesis in either cell line. These results indicate that agents producing oxidative stress are not necessarily mutagenic and these results are discussed in the context of the oxidative stress produced by other carcinogens such as nickel compounds.</p></div>","PeriodicalId":100938,"journal":{"name":"Mutation Research/Genetic Toxicology","volume":"370 3","pages":"Pages 133-140"},"PeriodicalIF":0.0,"publicationDate":"1996-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0165-1218(96)00042-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19882218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotoxicity of lynoral (ethinyloestradiol, an oestrogen) in mouse bone marrow cells, in vivo","authors":"S.K. Shyama,&nbsp;M. Abdul Rahiman","doi":"10.1016/S0165-1218(96)00065-1","DOIUrl":"10.1016/S0165-1218(96)00065-1","url":null,"abstract":"<div><p>The genotoxic effect of Lynoral (ethinyloestradiol, an oestrogen) was studied using mouse bone marrow cells treated in vivo, employing a chromosomal aberration assay and micronucleus test. The dose and time-yield effects of the sex hormonal drug were investigated. Lynoral failed to induce significant genetic damage in the bone marrow erythrocytes of mice, regarding chromosomal aberrations and micronuclei.</p></div>","PeriodicalId":100938,"journal":{"name":"Mutation Research/Genetic Toxicology","volume":"370 3","pages":"Pages 175-180"},"PeriodicalIF":0.0,"publicationDate":"1996-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0165-1218(96)00065-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19882130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An investigation of bone marrow and testicular cells in vivo using the comet assay","authors":"Diana Anderson ,&nbsp;Alok Dhawan ,&nbsp;Tian-Wei Yu ,&nbsp;Michael J. Plewa","doi":"10.1016/S0165-1218(96)00061-4","DOIUrl":"10.1016/S0165-1218(96)00061-4","url":null,"abstract":"<div><p>The effects of the mutagens, cyclophosphamide (CP), ethyl methanesulphonate (EMS), bleomycin (BLM) and the testicular toxin ethylene glycol monomethyl ether (EGME) in bone marrow and testicular cells have been compared in the alkaline COMET assay. Sprague-Dawley rats were administered by gavage with 50, 100 and 150 mg/kg body weight (bw) of CP; 100, 200 and 300 mg/kg bw EMS; 50, 100 and 150 mg/kg bw BLM and 500, 1000 and 1500 mg/kg bw EGME. Effects were examined at week 2 after treatment for CP, EMS BLM and EGME and at weeks 5 and 6 for EGME. Bone marrow cells were removed and separated by aspiration of the femur and testicular cells by decapsulation of the testis, treating with collagenase followed by trypsin. Various statistical methods were used to analyse the data. For CP there was an increase in damage above control values for bone marrow at 50 mg/kg bw which decreased at 100 mg/kg bw, and there was mortality of the animals at 150 mg/kg bw. A similar response was found in the testicular cells. For EMS and BLM, there were only occasional slight increases in damage in bone marrow and testicular cells. Two studies were conducted with EGME. In the first, where effects were examined at week 2 after treatment, there was an increase in damage in bone marrow cells, but a larger response was observed in testicular cells. In the second study where effects were examined at weeks 5 and 6 after treatment, bone marrow and testicular cells were not affected. The overall results showed that damage persisted for 2 weeks after treatment with CP and EGME but not in weeks 5 and 6 for EGME. Various statistical methods were used to analyse the data. Statistically significant responses were produced after treatment with CP and EGME and were dose-related for EGME, but after treatment with EMS and BLM statistical increases were sporadic. These results suggest that the assay is useful for measuring DNA damage and its persistence, and for comparing the sensitivity of different target organs in vivo.</p></div>","PeriodicalId":100938,"journal":{"name":"Mutation Research/Genetic Toxicology","volume":"370 3","pages":"Pages 159-174"},"PeriodicalIF":0.0,"publicationDate":"1996-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0165-1218(96)00061-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19882129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of tinidazole, an antiprotozoal drug to a mutagen by mammalian liver S9","authors":"R.L. Gupta,&nbsp;V. Vats,&nbsp;T.R. Juneja","doi":"10.1016/S0165-1218(96)00076-6","DOIUrl":"10.1016/S0165-1218(96)00076-6","url":null,"abstract":"<div><p>Tinidazole was found to display much higher mutagenic activity compared to metronidazole in Salmonella strain TA100 and YG1029. Under anaerobiosis, the specific activity of this nitroimidazole was enhanced, at least, by about 1.75-fold in TA100 and several fold in TA100NR relative to aerobic conditions. The mutagenicity in the latter strain with S9 mix became further increased by 2.5-fold under anaerobiosis, indicating the role of oxygen sensitive bacterial and mammalian S9 nitroreductases in the activation of the drug. The mutagenicity of the drug was slightly lowered in TA100/1,8-DNP₆ (<em>O</em>-acetyltransferase deficient), YG1029 (<em>O</em>-acetyltransferase overexpressing) and TA100 in the presence of pentachlorophenol (PCP), an O-acetyltransferase inhibitor. These results rule out the possible involvement of <em>N</em>-acetoxyarylamine pathway in the metabolic activation of these nitroimidazoles.</p></div>","PeriodicalId":100938,"journal":{"name":"Mutation Research/Genetic Toxicology","volume":"370 3","pages":"Pages 195-201"},"PeriodicalIF":0.0,"publicationDate":"1996-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0165-1218(96)00076-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19882133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}