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Jack Favor - One of the best experts on this subject based on the ideXlab platform.
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the mutagenic activity of ethylnitrosourea at low doses in spermatogonia of the mouse as assessed by the specific locus test
Mutation Research, 1998Co-Authors: Jack FavorAbstract:Abstract Ethylnitrosourea is the most efficient chemical mutagen in spermatogonial stem cells of the mouse and its mutagenic activity has been intensively studied. The pertinent specific-locus mutation test results for a discussion of low dose–effect studies have been summarized and indicate: (1) A threshold dose response best characterizes the relationship between dose and mutation rate. (2) The reduced effectiveness of ethylnitrosourea in the low dose range is likely due to a saturable repair process. (3) The recovery of the saturable repair process as assessed in fractionated dose experiments is long (ca. 168 h). The dynamics of stem cell spermatogonia suggests a long time interval before the cell population passes through at least one cell division and this may be relevant to an interpretation of the fractionation effects. (4) There is a slight but important discrepancy between the predicted and observed mutagenic activity of ethylnitrosourea in the low dose range. This is interpreted to be due to the differences between a mathematical abstraction and the biological realities of the system being studied.
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the effect of the interval between dose applications on the observed specific locus mutation rate in the mouse following fractionated treatments of spermatogonia with ethylnitrosourea
Mutation Research, 1997Co-Authors: Jack Favor, Andrea Wulff, U.h. Ehling, Angelika Neuhauserklaus, Albert A Van ZeelandAbstract:Abstract Our earlier analyses have suggested an apparent threshold dose-response for ethylnitrosourea-induced specific-locus mutations in treated spermatogonia of the mouse to be due to a saturable repair process. In the current study a series of fractionated-treatment experiments was carried out in which male (102×C3H)F 1 mice were exposed to 4×10, 2×40, 4×20 or 4×40 mg ethylnitrosourea per kg body weight with 24 h between applications; 4×40 mg ethylnitrosourea per kg body weight with 72 h between dose applications; and 2×40, 4×20 and 4×40 mg ethylnitrosourea per kg body weight with 168 h between dose applications. For all experiments with 24-h intervals between dose applications, there was no effect due to dose fractionation on the observed mutation rates, indicating the time interval between dose applications to be shorter than the recovery time of the repair processes acting on ethylnitrosourea-induced DNA adducts. In contrast, a fractionation interval of 168 h was associated with a significant reduction in the observed mutation rate due to recovery of the repair process. However, although reduced, the observed mutation rates for fractionation intervals of 168 h were higher than the spontaneous specific-locus mutation rate. These observations contradict the expectation for a true threshold dose response. We interpret this discrepancy to be due to the differences in the predictions of a mathematical abstraction of experimental data and the complexities of the biological system being studied. Biologically plausible explanations of the discrepancy are presented.
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somatic and germ cell mutagenesis in lambda lacz transgenic mice treated with acrylamide or ethylnitrosourea
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 1997Co-Authors: O Krebs, Jack FavorAbstract:Abstract The transgenic Muta™Mouse in vivo mutagenesis assay was employed to determine the activity of acrylamide and ethylnitrosourea in liver and germ cells after 3, 10 and 100 days following treatment. Each cell of the Muta™Mouse carries 80 copies of the lambda gt10 phage including the bacterial lacZ gene, which act as the target gene for the mutagenesis assay. Groups of Muta™Mice were given a single intraperitoneal injection of 80 or 160 mg/kg ethylnitrosourea or 50 or 100 mg/kg acrylamide. The tissues were prepared 3, 10 or 100 days post treatment. The liver genomic DNA was extracted with the manufacturer's standard protocoll, while the genomic germ cell DNA was extracted with 4 different methods due to problems encountered in DNA yields and packaging efficiency. The mutation analysis of the lacZ gene was carried out by the positive selective assay method [ Gossen et al. (1989) Proc. Natl. Acad. Sci. USA, 86, 7971–7975; Dean and Myhr (1994) Mutagenesis, 9, 183–185]. There was a slight increase due to treatment of the observed mutation frequencies in the acrylamide liver group for all three assay times. From the day 3 group to the day 100 group a time dependent decrease in all the absolute mutant frequencies was detectable. The ethylnitrosourea liver group showed a time – and dose-dependent increase in the mutant frequencies from day 3 to day 100. No meaningfull results were obtained for the germ cell tissue assays due to the low amount of genomic DNA extracted which was not packageable in the lambda lacZ assay. At present for the mutagenesis assay of isolated spermatozoa in our laboratory we would be forced to pool tissues from animals to obtain enough DNA for an assay. Since `jackpot'-animals may exist [ Heddle et al. (1992) Mutation Res., 272, 195–203] the individual animals of such a pooled analysis group must be tested before pooling.
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a dose response analysis of ethylnitrosourea induced recessive specific locus mutations in treated spermatogonia of the mouse
Mutation Research, 1990Co-Authors: Jack Favor, Angelika Neuhauserklaus, Malin Sund, U.h. EhlingAbstract:Abstract A dose-response analysis was carried out with 2 independent data sets available for ethylnitrosourea-induced specific-locus mutations in spermatogonia of the mouse. It was assumed that the occurence of mutation is binomially distributed and maximum-likelihood procedures were employed to determine the appropriateness of 4 alternative models, Linear, Linear-Quadratic, Power, and Threshold, in describing the dependence of the binomial parameter on dose. For both data sets, the Threshold model yielded a far superior fit and the threshold dose was estimated to be between 34 and 39 mg/kg. These results are supported by the relatively inefficient response of ethylnitrosourea at lower doses in inducing DNA adducts. Relevant specific-locus mutation results in the mouse for low-dose fractionated treatment as well as the recovery of mutation mosaics indicate the threshold model to be an oversimplification. Rather than a threshold dose below which 100% of the induced DNA adducts are repaired, we propose that some DNA adducts which may eventually be fixed as a mutation persist through a number of repair-competent cell divisions and do not interfere with normal cell function nor do they induce a repair response before being eventually fixed as a mutation. We interpret the threshold response for ethylnitrosourea-induced specific-locus mutations to be due to a saturable repair process which at lower doses results in ethylnitrosourea being less efficient in inducing mutation. Once this repair process is saturated, a clear dose-related increase in the mutation rate is observed.
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the frequency of dominant cataract and recessive specific locus mutations and mutation mosaics in f1 mice derived from post spermatogonial treatment with ethylnitrosourea
Mutation Research, 1990Co-Authors: Jack Favor, Angelika Neuhauserklaus, U.h. EhlingAbstract:Abstract The frequency of dominant cataract and recessive specific-locus mutations and mutation mosaics was determined in F 1 mice derived from post-spermatogonial germ-cell stage treatment with 2 × 80, 160 or 250 mg/kg ethylnitrosourea. A total of 5 dominant cataract mutations, 3 dominant cataract mutation mosaics, 1 specific-locus mutation and 9 specific-locus mutation mosaics were recovered in 15,542 screened F 1 offspring. Results indicate that ethylnitrosourea treatment increases the mutation rate of dominant cataract and recessive specific-locus alleles in post-spermatogonial germ-cell stages of the mouse and that the mutations occur mainly as mosaics. Genetic confirmation of newly induced mutations occurring as mosaics is more problemtical for induced recessive alleles than for induced dominant alleles and should be considered when evaluating such mutagenicity results.
U.h. Ehling - One of the best experts on this subject based on the ideXlab platform.
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the effect of the interval between dose applications on the observed specific locus mutation rate in the mouse following fractionated treatments of spermatogonia with ethylnitrosourea
Mutation Research, 1997Co-Authors: Jack Favor, Andrea Wulff, U.h. Ehling, Angelika Neuhauserklaus, Albert A Van ZeelandAbstract:Abstract Our earlier analyses have suggested an apparent threshold dose-response for ethylnitrosourea-induced specific-locus mutations in treated spermatogonia of the mouse to be due to a saturable repair process. In the current study a series of fractionated-treatment experiments was carried out in which male (102×C3H)F 1 mice were exposed to 4×10, 2×40, 4×20 or 4×40 mg ethylnitrosourea per kg body weight with 24 h between applications; 4×40 mg ethylnitrosourea per kg body weight with 72 h between dose applications; and 2×40, 4×20 and 4×40 mg ethylnitrosourea per kg body weight with 168 h between dose applications. For all experiments with 24-h intervals between dose applications, there was no effect due to dose fractionation on the observed mutation rates, indicating the time interval between dose applications to be shorter than the recovery time of the repair processes acting on ethylnitrosourea-induced DNA adducts. In contrast, a fractionation interval of 168 h was associated with a significant reduction in the observed mutation rate due to recovery of the repair process. However, although reduced, the observed mutation rates for fractionation intervals of 168 h were higher than the spontaneous specific-locus mutation rate. These observations contradict the expectation for a true threshold dose response. We interpret this discrepancy to be due to the differences in the predictions of a mathematical abstraction of experimental data and the complexities of the biological system being studied. Biologically plausible explanations of the discrepancy are presented.
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a dose response analysis of ethylnitrosourea induced recessive specific locus mutations in treated spermatogonia of the mouse
Mutation Research, 1990Co-Authors: Jack Favor, Angelika Neuhauserklaus, Malin Sund, U.h. EhlingAbstract:Abstract A dose-response analysis was carried out with 2 independent data sets available for ethylnitrosourea-induced specific-locus mutations in spermatogonia of the mouse. It was assumed that the occurence of mutation is binomially distributed and maximum-likelihood procedures were employed to determine the appropriateness of 4 alternative models, Linear, Linear-Quadratic, Power, and Threshold, in describing the dependence of the binomial parameter on dose. For both data sets, the Threshold model yielded a far superior fit and the threshold dose was estimated to be between 34 and 39 mg/kg. These results are supported by the relatively inefficient response of ethylnitrosourea at lower doses in inducing DNA adducts. Relevant specific-locus mutation results in the mouse for low-dose fractionated treatment as well as the recovery of mutation mosaics indicate the threshold model to be an oversimplification. Rather than a threshold dose below which 100% of the induced DNA adducts are repaired, we propose that some DNA adducts which may eventually be fixed as a mutation persist through a number of repair-competent cell divisions and do not interfere with normal cell function nor do they induce a repair response before being eventually fixed as a mutation. We interpret the threshold response for ethylnitrosourea-induced specific-locus mutations to be due to a saturable repair process which at lower doses results in ethylnitrosourea being less efficient in inducing mutation. Once this repair process is saturated, a clear dose-related increase in the mutation rate is observed.
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the frequency of dominant cataract and recessive specific locus mutations and mutation mosaics in f1 mice derived from post spermatogonial treatment with ethylnitrosourea
Mutation Research, 1990Co-Authors: Jack Favor, Angelika Neuhauserklaus, U.h. EhlingAbstract:Abstract The frequency of dominant cataract and recessive specific-locus mutations and mutation mosaics was determined in F 1 mice derived from post-spermatogonial germ-cell stage treatment with 2 × 80, 160 or 250 mg/kg ethylnitrosourea. A total of 5 dominant cataract mutations, 3 dominant cataract mutation mosaics, 1 specific-locus mutation and 9 specific-locus mutation mosaics were recovered in 15,542 screened F 1 offspring. Results indicate that ethylnitrosourea treatment increases the mutation rate of dominant cataract and recessive specific-locus alleles in post-spermatogonial germ-cell stages of the mouse and that the mutations occur mainly as mosaics. Genetic confirmation of newly induced mutations occurring as mosaics is more problemtical for induced recessive alleles than for induced dominant alleles and should be considered when evaluating such mutagenicity results.
Angelika Neuhauserklaus - One of the best experts on this subject based on the ideXlab platform.
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the effect of the interval between dose applications on the observed specific locus mutation rate in the mouse following fractionated treatments of spermatogonia with ethylnitrosourea
Mutation Research, 1997Co-Authors: Jack Favor, Andrea Wulff, U.h. Ehling, Angelika Neuhauserklaus, Albert A Van ZeelandAbstract:Abstract Our earlier analyses have suggested an apparent threshold dose-response for ethylnitrosourea-induced specific-locus mutations in treated spermatogonia of the mouse to be due to a saturable repair process. In the current study a series of fractionated-treatment experiments was carried out in which male (102×C3H)F 1 mice were exposed to 4×10, 2×40, 4×20 or 4×40 mg ethylnitrosourea per kg body weight with 24 h between applications; 4×40 mg ethylnitrosourea per kg body weight with 72 h between dose applications; and 2×40, 4×20 and 4×40 mg ethylnitrosourea per kg body weight with 168 h between dose applications. For all experiments with 24-h intervals between dose applications, there was no effect due to dose fractionation on the observed mutation rates, indicating the time interval between dose applications to be shorter than the recovery time of the repair processes acting on ethylnitrosourea-induced DNA adducts. In contrast, a fractionation interval of 168 h was associated with a significant reduction in the observed mutation rate due to recovery of the repair process. However, although reduced, the observed mutation rates for fractionation intervals of 168 h were higher than the spontaneous specific-locus mutation rate. These observations contradict the expectation for a true threshold dose response. We interpret this discrepancy to be due to the differences in the predictions of a mathematical abstraction of experimental data and the complexities of the biological system being studied. Biologically plausible explanations of the discrepancy are presented.
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a dose response analysis of ethylnitrosourea induced recessive specific locus mutations in treated spermatogonia of the mouse
Mutation Research, 1990Co-Authors: Jack Favor, Angelika Neuhauserklaus, Malin Sund, U.h. EhlingAbstract:Abstract A dose-response analysis was carried out with 2 independent data sets available for ethylnitrosourea-induced specific-locus mutations in spermatogonia of the mouse. It was assumed that the occurence of mutation is binomially distributed and maximum-likelihood procedures were employed to determine the appropriateness of 4 alternative models, Linear, Linear-Quadratic, Power, and Threshold, in describing the dependence of the binomial parameter on dose. For both data sets, the Threshold model yielded a far superior fit and the threshold dose was estimated to be between 34 and 39 mg/kg. These results are supported by the relatively inefficient response of ethylnitrosourea at lower doses in inducing DNA adducts. Relevant specific-locus mutation results in the mouse for low-dose fractionated treatment as well as the recovery of mutation mosaics indicate the threshold model to be an oversimplification. Rather than a threshold dose below which 100% of the induced DNA adducts are repaired, we propose that some DNA adducts which may eventually be fixed as a mutation persist through a number of repair-competent cell divisions and do not interfere with normal cell function nor do they induce a repair response before being eventually fixed as a mutation. We interpret the threshold response for ethylnitrosourea-induced specific-locus mutations to be due to a saturable repair process which at lower doses results in ethylnitrosourea being less efficient in inducing mutation. Once this repair process is saturated, a clear dose-related increase in the mutation rate is observed.
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the frequency of dominant cataract and recessive specific locus mutations and mutation mosaics in f1 mice derived from post spermatogonial treatment with ethylnitrosourea
Mutation Research, 1990Co-Authors: Jack Favor, Angelika Neuhauserklaus, U.h. EhlingAbstract:Abstract The frequency of dominant cataract and recessive specific-locus mutations and mutation mosaics was determined in F 1 mice derived from post-spermatogonial germ-cell stage treatment with 2 × 80, 160 or 250 mg/kg ethylnitrosourea. A total of 5 dominant cataract mutations, 3 dominant cataract mutation mosaics, 1 specific-locus mutation and 9 specific-locus mutation mosaics were recovered in 15,542 screened F 1 offspring. Results indicate that ethylnitrosourea treatment increases the mutation rate of dominant cataract and recessive specific-locus alleles in post-spermatogonial germ-cell stages of the mouse and that the mutations occur mainly as mosaics. Genetic confirmation of newly induced mutations occurring as mosaics is more problemtical for induced recessive alleles than for induced dominant alleles and should be considered when evaluating such mutagenicity results.
Kunihiko Sakumi - One of the best experts on this subject based on the ideXlab platform.
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Roles of DNA repair methyltransferase in mutagenesis and carcinogenesis
Japanese Journal of Human Genetics, 1997Co-Authors: Mutsuo Sekiguchi, Kunihiko SakumiAbstract:Alkylation of DNA at the O ^6-position of guanine is one of the most critical events leading to induction of mutation as well as cancer. An enzyme, O ^6-methylguanine-DNA methyltransferase, is present in various organisms, from bacteria to human cells, and appears to be responsible for preventing the occurrence of such mutations. The enzyme transfers methyl groups from O ^6-methylguanine and other methylated moieties of the DNA to its own molecule, thereby repairing DNA lesions in a single-step reaction. To elucidate the role of methyltransferase in preventing cancer, animal models with altered levels of enzyme activity were generated. Transgenic mice carrying extra copies of the foreign methyltransferase gene showed a decreased susceptibility to alkylating carcinogens, with regard to tumor formation. By means of gene targeting, mouse lines defective in both alleles of the methyltransferase gene were established. Administration of Methylnitrosourea to these gene-targeted mice led to early death while normal mice treated in the same manner showed no untoward effects. Numerous tumors were formed in the gene-defective mice exposed to a low dose of Methylnitrosourea, while none or only few tumors were induced in the methyltransferase-proficient mice. It seems apparent that the DNA repair methyltransferase plays an important role in lowering a risk of occurrence of cancer in organisms.
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Methylnitrosourea-induced Tumorigenesis in MGMT Gene Knockout Mice
Cancer research, 1997Co-Authors: Kunihiko Sakumi, Akiko Shiraishi, Seiichiro Shimizu, Teruhisa Tsuzuki, Takatoshi Ishikawa, Mutsuo SekiguchiAbstract:Gene targeting was used to obtain mice defective in the MGMT gene, encoding O 6 -methylguanine-DNA methyltransferase [Tsuzuki et al., Carcinogenesis (Lond.), 17: 1215-1220, 1996]. These MGMT -/- mice were most sensitive to the alkylating carcinogen, Methylnitrosourea; when varied doses of Methylnitrosourea were administered to 6-week-old mice and survivals at the 30th day were determined, LD 50 s of MGMT -/- and MGMT +/+ mice were 20 and 240 mg/kg of body weight, respectively. MGMT +/- mice were as resistant as MGMT +/+ mice, but some difference in survival time was noted when the two genotypes of mice were exposed to a relatively high dose of Methylnitrosourea. A large number of thymic lymphomas, as well as lung adenomas, occurred in MGMT -/- mice exposed to Methylnitrosourea at a dose of 2.5 mg/kg of body weight. In case of exposure to the same dose of drug, no or few tumors occurred in the MGMT +/+ and MGMT +/- mice. It appears that the DNA repair methyltransferase protein protected these mice from Methylnitrosourea-induced tumorigenesis.
Mutsuo Sekiguchi - One of the best experts on this subject based on the ideXlab platform.
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Roles of DNA repair methyltransferase in mutagenesis and carcinogenesis
Japanese Journal of Human Genetics, 1997Co-Authors: Mutsuo Sekiguchi, Kunihiko SakumiAbstract:Alkylation of DNA at the O ^6-position of guanine is one of the most critical events leading to induction of mutation as well as cancer. An enzyme, O ^6-methylguanine-DNA methyltransferase, is present in various organisms, from bacteria to human cells, and appears to be responsible for preventing the occurrence of such mutations. The enzyme transfers methyl groups from O ^6-methylguanine and other methylated moieties of the DNA to its own molecule, thereby repairing DNA lesions in a single-step reaction. To elucidate the role of methyltransferase in preventing cancer, animal models with altered levels of enzyme activity were generated. Transgenic mice carrying extra copies of the foreign methyltransferase gene showed a decreased susceptibility to alkylating carcinogens, with regard to tumor formation. By means of gene targeting, mouse lines defective in both alleles of the methyltransferase gene were established. Administration of Methylnitrosourea to these gene-targeted mice led to early death while normal mice treated in the same manner showed no untoward effects. Numerous tumors were formed in the gene-defective mice exposed to a low dose of Methylnitrosourea, while none or only few tumors were induced in the methyltransferase-proficient mice. It seems apparent that the DNA repair methyltransferase plays an important role in lowering a risk of occurrence of cancer in organisms.
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Methylnitrosourea-induced Tumorigenesis in MGMT Gene Knockout Mice
Cancer research, 1997Co-Authors: Kunihiko Sakumi, Akiko Shiraishi, Seiichiro Shimizu, Teruhisa Tsuzuki, Takatoshi Ishikawa, Mutsuo SekiguchiAbstract:Gene targeting was used to obtain mice defective in the MGMT gene, encoding O 6 -methylguanine-DNA methyltransferase [Tsuzuki et al., Carcinogenesis (Lond.), 17: 1215-1220, 1996]. These MGMT -/- mice were most sensitive to the alkylating carcinogen, Methylnitrosourea; when varied doses of Methylnitrosourea were administered to 6-week-old mice and survivals at the 30th day were determined, LD 50 s of MGMT -/- and MGMT +/+ mice were 20 and 240 mg/kg of body weight, respectively. MGMT +/- mice were as resistant as MGMT +/+ mice, but some difference in survival time was noted when the two genotypes of mice were exposed to a relatively high dose of Methylnitrosourea. A large number of thymic lymphomas, as well as lung adenomas, occurred in MGMT -/- mice exposed to Methylnitrosourea at a dose of 2.5 mg/kg of body weight. In case of exposure to the same dose of drug, no or few tumors occurred in the MGMT +/+ and MGMT +/- mice. It appears that the DNA repair methyltransferase protein protected these mice from Methylnitrosourea-induced tumorigenesis.