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Yu F. Sasaki

Bio: Yu F. Sasaki is an academic researcher from Kwansei Gakuin University. The author has contributed to research in topics: DNA repair & DNA damage. The author has an hindex of 4, co-authored 4 publications receiving 289 citations.

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Journal ArticleDOI
TL;DR: In the 6th MMS/CSGMT collaborative study as mentioned in this paper, IARC groups 1 (human carcinogen), 2A (probable human carcinogen) and 2B (possible human carcinogens) were selected from 100 commercially available chemicals and chemical groups on which there was little or no micronucleus assay data.
Abstract: To assess the correlation between micronucleus induction and human carcinogenicity, the rodent micronucleus assay was performed on known and potential human carcinogens in the 6th MMS/CSGMT collaborative study Approximately 100 commercially available chemicals and chemical groups on which there was little or no micronucleus assay data were selected from IARC (International Agency for Research on Cancer) Groups 1 (human carcinogen), 2A (probable human carcinogen) and 2B (possible human carcinogen) As minimum requirements for the collaborative study, 5 male mice were treated by intraperitoneal injection or oral gavage once or twice with each chemical at three dose levels, and bone marrow and/or peripheral blood was analyzed Five positives and 2 inconclusives out of 13 Group 1 chemicals, 7 positives and 5 inconclusives of 23 Group 2A chemicals, and 26 positives and 6 inconclusives of 67 Group 2B chemicals were found Such low positive rates were not surprising because of a test chemical selection bias, and we excluded well-known micronucleus inducers The overall evaluation of the rodent micronucleus assay was based on the present data combined with published data on the IARC carcinogens After merging, the positive rates for Groups 1, 2A and 2B were 686, 545 and 456%, respectively Structure-activity relationship analysis suggested that the micronucleus assay is more sensitive to the genetic toxicity of some classes of chemicals Those to which it is sensitive consist of (1) aziridines and bis(2-chloroethyl) compounds; (2) alkyl sulfonate and sulfates; (3) acyl-type N-nitroso compounds; (4) hydrazines; (5) aminobiphenyl and benzidine derivatives; and (6) azo compounds Those to which it is less sensitive consist of (1) dialkyl type N-nitroso compounds; (2) silica and metals and their compounds; (3) aromatic amines without other functional groups; (4) halogenated compounds; and (5) steroids and other hormones After incorporation of structure-activity relationship information, the positive rates of the rodent micronucleus assay became 905, 652 and 600% for IARC Groups 1, 2A and 2B, respectively Noteworthy was the tendency of the test to be more sensitive to those carcinogens with stronger evidence human carcinogenicity

251 citations

Journal ArticleDOI
TL;DR: The spontaneous frequencies of micronucleated reticulocytes (MNRETs) were examined monthly over the life spans of animals belonging to nine mouse strains for the 7th collaborative study organized by the CSGMT/JEMS as discussed by the authors.
Abstract: The spontaneous frequencies of micronucleated reticulocytes (MNRETs) were examined monthly over the life spans of animals belonging to nine mouse strains for the 7th collaborative study organized by the CSGMT/JEMS.MMS. Both sexes of the BDF1 strain and females of the A/J strain showed a statistically significant increase in mean spontaneous MNRET frequency in their last month of life, suggesting the possibility of strain-specific, age-dependent chromosomal instability. SAMP6/Tan, an accelerated senescence-prone strain, showed the same tendency, although it was not statistically significant. The other strains studied, ddY, CD-1, B6C3F1, SAMR1, and MS/Ae, did not show significant age-related differences in mean of MNRET frequencies. More extensive statistical analyses are underway, and the outcomes will be reported separately.

30 citations

Journal ArticleDOI
TL;DR: Both sexes of the BDF1 strain and females of the A/J strain showed a statistically significant increase ni mean spontaneous MNRET frequency in their last month of life, suggesting the possibility of strain-specific, age-dependent chromosomal instability.
Abstract: The spontaneous frequencies of micronucleated reticulocytes (MNRETs) were examined monthly over the life spans of animals beloning to nine mouse strains for the 7th collaborative study organized by the CSGMT/JEMS · MMS. Both sexes of the BDF1 strain and females of the A/J strain showed a statistically significant increase ni mean spontaneous MNRET frequency in their last month of life, suggesting the possibility of strain-specific, age-dependent chromosomal instability. SAMP6/Tan, an accelerated senescence-prone strain, showed the same tendency, although it was not statistically significant. The other strains studied, ddY, CD-1, B6C3F1, SAMR1, and MS/Ae, did not show significant age-related differences in mean of MNRET frequencies. More extensive statistical analyses are underway, and the outcomes will be reported separately.

11 citations

Journal ArticleDOI
TL;DR: The results suggested that the enhancing effect of Trp-P-1 on UV-induced mutagenesis in E.coli stemmed from the inhibition of the removal of photolesions from the DNA.
Abstract: Heterocyclic amines have been isolated from cooked foods and found to be mutagens and carcinogens. Among them, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) were also found to enhance UV-induced mutation frequencies in Escherichia coli at the concentrations where they were neither toxic nor mutagenic by themselves. Using an immunological method recently developed to detect UV-induced DNA damage, we investigated the inhibitory effect of Trp-P-1 on the removal of both cyclobutane dimers and (6-4)photoproducts from the DNA of UV-irradiated E.coli. Cells repaired 60% of the initial cyclobutane dimers within 30 min and 75% at 120 min after UV-irradiation. Furthermore, the same cells repaired 90% of the initial (6-4)photoproducts within 30 min. On the other hand, Trp-P-1 clearly showed inhibition of repair of both photolesions in a concentration-dependent manner. The levels of repair inhibition by Trp-P-1 were almost the same between cyclobutane dimers and (6-4)photoproducts. These results suggested that the enhancing effect of Trp-P-1 on UV-induced mutagenesis in E.coli stemmed from the inhibition of the removal of photolesions from the DNA.

7 citations


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TL;DR: Of all the additives, dyes were the most genotoxic and induced DNA damage in the colon at close to the acceptable daily intakes (ADIs), and more extensive assessment of food additives in current use is warranted.
Abstract: We determined the genotoxicity of 39 chemicals currently in use as food additives. They fell into six categories—dyes, color fixatives and preservatives, preservatives, antioxidants, fungicides, and sweeteners. We tested groups of four male ddY mice once orally with each additive at up to 0.5×LD50 or the limit dose (2000 mg/kg) and performed the comet assay on the glandular stomach, colon, liver, kidney, urinary bladder, lung, brain, and bone marrow 3 and 24 h after treatment. Of all the additives, dyes were the most genotoxic. Amaranth, Allura Red, New Coccine, Tartrazine, Erythrosine, Phloxine, and Rose Bengal induced dose-related DNA damage in the glandular stomach, colon, and/or urinary bladder. All seven dyes induced DNA damage in the gastrointestinal organs at a low dose (10 or 100 mg/kg). Among them, Amaranth, Allura Red, New Coccine, and Tartrazine induced DNA damage in the colon at close to the acceptable daily intakes (ADIs). Two antioxidants (butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT)), three fungicides (biphenyl, sodium o-phenylphenol, and thiabendazole), and four sweeteners (sodium cyclamate, saccharin, sodium saccharin, and sucralose) also induced DNA damage in gastrointestinal organs. Based on these results, we believe that more extensive assessment of food additives in current use is warranted.

619 citations

Journal ArticleDOI
TL;DR: Doses that do not cause sustained cytotoxicity and regenerative cell proliferation would subsequently be protective of liver tumors if this is the primary mode of action, according to a body of scientific evidence.
Abstract: Under the 2005 U.S. EPA Guidelines for Carcinogen Risk Assessment (1), evaluations of carcinogens rely on mode of action data to better inform dose response assessments. A reassessment of carbon tetrachloride, a model hepatotoxicant and carcinogen, provides an opportunity to incorporate into the assessment biologically relevant mode of action data on its carcinogenesis. Mechanistic studies provide evidence that metabolism of carbon tetrachloride via CYP2E1 to highly reactive free radical metabolites plays a critical role in the postulated mode of action. The primary metabolites, trichloromethyl and trichloromethyl peroxy free radicals, are highly reactive and are capable of covalently binding locally to cellular macromolecules, with preference for fatty acids from membrane phospholipids. The free radicals initiate lipid peroxidation by attacking polyunsaturated fatty acids in membranes, setting off a free radical chain reaction sequence. Lipid peroxidation is known to cause membrane disruption, resulting in the loss of membrane integrity and leakage of microsomal enzymes. By-products of lipid peroxidation include reactive aldehydes that can form protein and DNA adducts and may contribute to hepatotoxicity and carcinogenicity, respectively. Natural antioxidants, including glutathione, are capable of quenching the lipid peroxidation reaction. When glutathione and other antioxidants are depleted, however, opportunities for lipid peroxidation are enhanced. Weakened cellular membranes allow sufficient leakage of calcium into the cytosol to disrupt intracellular calcium homeostasis. High calcium levels in the cytosol activate calcium-dependent proteases and phospholipases that further increase the breakdown of the membranes. Similarly, the increase in intracellular calcium can activate endonucleases that can cause chromosomal damage and also contribute to cell death. Sustained cell regeneration and proliferation following cell death may increase the likelihood of unrepaired spontaneous, lipid peroxidation- or endonuclease-derived mutations that can lead to cancer. Based on this body of scientific evidence, doses that do not cause sustained cytotoxicity and regenerative cell proliferation would subsequently be protective of liver tumors if this is the primary mode of action. To fulfill the mode of action framework, additional research may be necessary to determine alternative mode(s) of action for liver tumors formed via carbon tetrachloride exposure.

394 citations

Journal ArticleDOI
TL;DR: The published in vivo UDS, TG and Comet-assay results for 67 carcinogens that were negative or equivocal in the micronucleus test suggest that they both should play a more prominent role in regulatory testing strategies than the UDS test.
Abstract: There has been much discussion in recent years regarding the most appropriate follow-up testing in vivo when positive results are obtained in vitro but the in vivo micronucleus (MN) test (traditionally the most widely-used test) is negative. Not all rodent carcinogens give positive results in the micronucleus test, and so it has been common practice to include a second in vivo assay such as the unscheduled DNA synthesis (UDS) test. This has proved useful but is usually limited to analysis of rodent (usually rat) liver. With the increased evaluation and use of other in vivo assays, e.g. for transgenic mutations (TG) and DNA damage (Comet assay) it was important to investigate their usefulness. We therefore examined the published in vivo UDS, TG and Comet-assay results for 67 carcinogens that were negative or equivocal in the micronucleus test. Between 30 and 41 chemicals were evaluated in each of the three in vivo tests, with some overlap. In general, the UDS test was disappointing and gave positive results with 50% of the carcinogens, but the Comet assay detected almost 90% of the micronucleus-negative or equivocal carcinogens. This pattern of results was virtually unchanged when the in vitro profile (gene mutagen or clastogen) was taken into account. High sensitivity (ability to detect carcinogens as positive) is only really useful when the specificity (ability to give negative results with non-carcinogens) is also high. Based on small numbers of publications with non-carcinogens, the TG and Comet assays gave negative results with non-carcinogens on 69 and 78% of occasions, respectively. Although further evaluation of the Comet and TG assays, particularly with non-carcinogens, is needed, these data suggest that they both should play a more prominent role in regulatory testing strategies than the UDS test.

320 citations

01 Jan 2008

312 citations