bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutation spectrum of spontaneous frameshift revertants in yeast using double‐strand gap repair
Authors: Plewa Michael J. , Kalinowski Douglas P. , Larimer Frank W. 
Published: February 2007

AbstractA mutation spectrum was constructed from a series of randomly isolated spontaneous His+ revertants of the frameshift mutant his4–38 in Saccharomyces cerevisiae. For each true revertant, a 438 bp region encompassing his4–38 on chromosome III was recovered into a shuttle vector by double‐strand gap repair. Of the 45 independent His+ revertants sequenced, 44 were −1 base deletions and one revertant was a +2 base insertion. The −1 deletions exhibited a bimodal distribution. Of the bases encompassing the his4–38 region from +153–181, 45% were not involved in a reversion event, although a −1 frameshift within this region will result in a viable His+ revertant. Approximately 49% of −1 events occurred within runs of 3 repeated bases. At these sites the strand‐slippage model for frameshift mutation is supported. However, the −1 events occurring at sites of 2 repeated bases and the low frequency (2%) of +2 base insertions suggest that the transiently misaligned template model is a significant mechanism in reversion of his4–38. When the distribution of −1 events at repeated bases was discounted, a hotspot involving a ‐T at position +163 was resolved. © 1992 Wiley‐Liss, Inc.
DNA sequence analysis of spontaneous and n‐ethyl‐n‐nitrosourea‐lnduced hprt mutations arising in vivo in cynomolgus monkey t‐lymphocytes
Authors: Harbach P. R. , Filipunas A. L. , Wang Y. , Aaron C. S. 
Published: February 2007

AbstractThe study of hprt mutations in cynomolgus monkey T‐lymphocytes is part of our effort to understand the mechanisms of mutagenesis in vivo. This primate model allows us to study mutations and their kinetics at the molecular level under well‐controlled conditions using recently developed techniques for selection of mutant T‐cells and polymerase chain reaction (PCR) amplification of hprt cDNA, which is directly sequenced. This is the first report of the sequence of the coding region of the cynomolgus monkey hprt gene and PCR/DNA sequence analysis of seven spontaneous mutant T‐cell clones, as well as 23 mutant clones isolated 63 and 601 days after treatment with ethylnitrosourea (ENU, 77 mg/ kg, intraperitoneal). cDNA was reverse transcribed from hprt mRNA directly from a lysate of about 2–4 × 103 cells, and a 700 bp fragment including the coding region was amplified by PCR and sequenced. Of the seven spontaneous mutants, only one point mutation (GC↠ transition) was detected, and the other six failed to amplify by PCR, possibly due to functional deletions. Of the 14 mutant clones isolated 63 days after ENU treatment, nine base substitutions were detected in ten clones: four transitions (three AT↠GC and one GC↠AT) and five transversions (four AT↠TA and one AT↠CG). Of the nine mutants isolated 601 days after ENU treatment, six single base substitutions were detected in six clones (five AT↠TA and one AT↠CG transversions), and one mutant had a large deletion or insertion. No changes were detected in three clones (one Day 63 and two Day 601 clones). In summary, only one of 15 single base substitutions isolated after ENU treatment was a GC↠AT transition mutation and the rest were transitions and transversions at AT sites. © 1992 Wiley‐Liss, Inc.
structure‐activity relationship of genotoxic polycyclic aromatic nitro compounds: Further evidence for the importance of hydrophobicity and molecular orbital energies in genetic toxicity
Authors: Debnath Asim Kumar , Hansch Corwin 
Published: February 2007

AbstractA quantitative structure‐activity relationship (QSAR) has been formulated for 15 polycyclic aromatic nitro compounds acting on E. coli PQ37. Upon damage of DNA by these substances β‐galactosidase is induced and can be easily assayed colorimetrically, hence, this is a short‐term test for mutagenicity. The QSAR (log SOSIP = 1.07 log P ‐ 1.57 ± ‐ 6.41) is strikingly similar to that found earlier with nitroaromatics acting in the Ames test (TA100) and differs significantly for that found using TA98 organisms. The QSAR brings out in a unique manner the underlying similarity in the two test systems. © 1992 Wiley‐Liss, Inc.
Tissue‐specific genotoxic effects of acrylamide and acrylonitrile
Authors: Butterworth Byron E. , Eldridge Sandra R. , Sprankle Catherine S. , Working Peter K. , Bentley Karin S. , Hurtt Mark E. 
Published: February 2007

AbstractAcrylamide (AA) has been reported to induce dominant lethal mutations in male rat germ cells and tumors in a variety of organs, including the scrotum, thyroid and mammary glands, but not the liver of rats. The structurally similar vinyl monomer acrylonitrile (ACN) does not induce dominant lethal mutations but does induce tumors of the brain, Zymbal gland, forestomach and mammary gland, but not the liver of rats. Several in vitro and/or in vivo unscheduled DNA synthesis (UDS) assays were employed to examine the potential tissue‐specific genotoxic activity of these compounds. Neither AA nor ACN induced DNA repair in either the in vitro or in vivo hepatocyte DNA repair assays. Glycidamide (GA), a mutagenic metabolite of AA, induced DNA repair in the in vitro hepatocyte DNA repair assay. Cyanoethylene oxide (CEO), a mutagenic metabolite of ACN, did not yield a DNA repair response in the in vitro hepatocyte DNA repair assay, but was highly toxic and could not be tested at doses equivalent to GA. AA, but not ACN, produced a DNA repair response in the in vivo spermatocyte DNA repair assay. AA produced a slight response in the in vitro human mammary epithelial cell (HMEC) DNA repair assay in normal cells derived from discarded surgical samples from five different women. GA produced a strong UDS response in all cases in the same assay. CEO, but not its parent compound ACN, produced a response in the HMEC DNA repair assay. These results show a highly tissue‐specific pattern of genotoxic activity for AA and ACN that correlates, to the extent that it has been examined, with the tissue‐specific pattern of carcinogenic and dominant lethal activity. The induction of DNA repair by GA and CEO confirms the genotoxic potential of these metabolites. While the observation of genotoxic activity of AA in the HMEC DNA repair assay suggests that mammary cells might be a target for carcinogenic activity of this compound in humans, other factors such as pharmacokinetics and epidemiology must be evaluated to establish that effect. © 1992 Wiley‐Liss, inc.
Chromosomal breakage following treatment of CHO‐K1 Cells in Vitro With U‐68,553B is due to Induction of Undercondensation of Heterochromatin
Authors: Yu R. L. , Aaron C. S. , Ulrich R. G. , Thilagar A. , Kumaroo P. V. , Wang Y. 
Published: February 2007

AbstractPreferential breakage of chromosomes af specific sites (so‐called “fragile sites”) has been observed to occur spontaneously, and has been induced by some metal salts and chemicals. Furthermore, a heterochromatic region of the long arm of the Chinese hamster ovary (CHO) M‐chromosome is known to be suceptible to a disproportionately high frequency of spontaneous breakage; unless there is physical displacement of chromatin the resulting achromatic lesions are not scored as structural aberrations. We have encountered such anomalous breakage associated with C‐band positive regions of the chromosomes of a CHO‐K1 cell line following exposure of the cells to toxic doses of U‐68,553B and in this report present evidence that the apparent breaks are due to undercondensed heterochromatin (UH) and evidence that the phenomenon appears to occur at higher frequency in a particular cell line of Chinese hamster. This finding has important implications on the assessment of potential risk due to exposure to the drug. Such apparent breaks at sites of UH in chromosome 1 was not observed in an alternate CHO cell line (CHO‐WBL) which supports the notion that the UH associated achromatic lesions in the CHO‐K1 line may be a cell line specific phenomenon. Furthermaore, careful electron microscopy of the chromosomes revaled chromatin fibers connecting the apparently broken chromosomes. The UH was not observed in the presence of the phenomenon in risk assessment is further reduced. The kata presented here provide evidence that sites of UH accur preferentially at locations of C‐band positive constitutive heterochromatin in CHO cells; we believe that this is the first report of induced fragile sites in rodent cells in vitro documented in this way. In addition, evidence is presented that U‐68,553B lacks the ability to induce breakage in vivo in rodents and locks the ability to induce chromosome breakage in human peripheral lympocytes in vitro. Therefore, it is concluded that the positive results with CHO‐k1 cells treated with U‐68,553B are unlikely to be predictive of a genotoxic hazard. This is a specific example of the importance of careful followup to an in vitro result in risk assessment. © 1992 Wiley‐Liss, Inc.
Development of a specific‐locus assay in the ad‐3 region of two‐component heterokaryons of neurospora: A review
Authors: De Serres Frederick J. 
Published: February 2007

AbstractIn recognition of the need for a more comprehensive data base for genetic risk assessment of human exposure to mutagenic agents in the environment, a model system was developed for specific‐locus studies in Neurospora crassa. This lower eukaryotic organism permits the utilization of microbial techniques for recovery of large numbers of specific‐locus mutations at two closely linked loci as well as their subsequent genetic analysis. In particular, this assay makes possible exploratory experiments with different environmental mutagens to obtain data on a wide variety of experimental conditions. Such data make it possible to study induction kinetics and mutational spectra in a manner that is not as yet feasible in higher eukaryotic organisms. The adenine‐3 (ad‐3) specific‐locus assay was modeled after the 2–gene, morphological specific‐locus assay in the dilute‐short‐ear region of the mouse, and it also detects forward‐mutations at two closely linked loci, namely, ad‐3A and ad‐3B. Because ad‐3 mutations are recovered by a direct method, based on the accumulation of a reddish‐purple pigment in the vacuoles of the mycelium rather than their requirement for adenine, this system is both a morphological and biochemical specific‐locus assay. The use of the ad‐3 assay system in experiments with different environmental mutagens has provided precise dose‐response curves not only for inactivation, but also the overall induction of ad‐3 mutations. Genetic characterization of these ad‐3 mutations by a series of 3 rapid and simple genetic tests permits the identification of 18 subclasses of gene/point mutations, and 12 subclasses of multilocus deletion mutations. These subclasses also include 3 different classes of multiple‐locus mutations with separate sites of recessive lethal damage either in the immediately adjacent regions or elsewhere in the genome. In summary, this specific‐locus assay provides a capability that is unique among eukaryotic organisms for the recovery and analysis of genetic damage at 2 closely linked loci. © 1992 Wiley‐Liss, Inc.
Certain tryptophan photoproducts are inhibitors of cytochrome p450‐dependent mtuagenicity
Authors: Rannug U. , Agurell E. , Rannug A. , Cederberg H. 
Published: February 2007

AbstractTwo photoproducts, derived from UV‐irradiation of the amino acid L‐tryptophan and with high Ah (TCDD) receptor binding affinity, were tested for genotoxic and antimutagenic effects. The two indolo[3,2‐b]carbazole derivatives, with the molecular weights of 284 and 312, respectively, were tested in Saccharomyces cerevisiae strain D7 for mitotic gene conversion and reverse mutation and in strain RS112 for sister chromatid conversion and gene conversion. No significant (P > 0.05) genotoxic effects were found in strain D7, while strain RS112 showed a small but significant increase in the frequency of sister chromatid conversions. In Chinese hamster ovary (CHO) cells the two compounds induced a statistically significant but less than twofold increase in the frequency of sister chromatid exchanges (SCE). No mutations were detected when the compounds were tested in Salmonella typhimurium strains TA98 and TA100. However, both 284 and 312 acted as antimutagens on strain TA100+S9 in the presence of benzo(a)pyrene. The decrease in mutagenicity by the most potent compound 284 was 20 revertants/nmol. This effect could be explained by an inhibitory effect on the cytochrome P450‐dependent ethoxyresorufin O‐deethylase (EROD) activity as seen in rat hepatocytes. The two compounds were also tested with hamster cells expressing rat cytochrome [P‐450IA]. The results support the conclusion that this cytochrome P‐450 isozyme is inhibited by the tryptophan photoproducts. Similar results were also seen with two other high affinity Ah receptor ligands the quinazolinocarboline alkaloids rutaecarpine and dehydrorutaecarpine. © 1992 Wiley‐Liss, Inc.
Assessment of oxidative DNA damage in the oxyR‐deficient sos chromotest strain escherichia coli PQ300
Authors: Müller Jürgen , Janz Siegfried 
Published: February 2007

AbstractThe SOS chromotest is a simple short‐term genotoxicity assay measuring the induction of gene sfiA in Escherichia coli K‐12. The recent availability of SOS tester strains with additional mutations in DNA repair or protection systems allows testing of DNA damaging compounds for genotoxic specificity. E. coli PQ300 differs from the standard SOS tester strain PQ37 in that it contains an additional mutation in gene oxyR that renders it more sensitive to oxidative genotoxins. The generation of reactive oxygen intermediates (ROI) by hydroperoxides (H2O2, t‐butyl hydroperoxide, cumene hydroperoxide), γ‐radiation, glucose oxidase, and xanthine oxidase resulted in a more vigorous SOS response in strain PQ300 compared to strain PQ37. PQ300 was also more sensitive than PQ37 for the detection of reducing agents such as ascorbic acid, cysteine, and glutathione, which also alter the redox status of the bacterial cells. However, intercalating agents (adriamycin, bleomycin, and mitomycin C) and the UV‐and radiomimetic compound 4‐nitroquinoline‐1‐oxide whose DNA damaging potential are known also to involve ROI did not show significant differences between strains PQ37 and PQ300. It is concluded that the oxyR‐deficient strain PQ300 is useful for detecting certain classes of genotoxins that change the oxidative/antioxidative balance of tester bacteria in the SOS chromotest. © 1992 Wiley‐Liss, Inc.
Mutagenicity test schemes and guidelines: U.S. EPA office of pollution prevention and toxics and office of pesticide programs
Authors: Auletta Angela E. , Dearfield Kerry L. , Cimino Michael C. 
Published: February 2007

AbstractNew requirement for chemicals subject to mutagenicity testing from the U.S. Environmental Protection Agency (USEPA) are discussed. Also detailed are two categories in the 1986 Mutagenicity Risk Assessment Guidelines. © 1993 Wiley‐Liss, Inc.
Mutagenicity of peroxyacetyl nitrate (PAN) in vivo: Tests for somatic mutations and chromosomal aberrations
Authors: Heddle J. A. , Shepson P. B. , Gingerich J. D. , So K. W. 
Published: February 2007

AbstractA series of experiments was conducted in which Chinese hamsters inhaled PAN, an ubiquitous pollutant that is present in the atmosphere at concentrations that are as high as, or higher than, other known genotoxic agents. The animals were exposed to PAN in air at concentrations of = 3 ppm for up to 1 month and then examined for somatic mutations and chromosomal aberrations. Mutations were assayed by measuring the frequency of thioguanine‐resistant lung fibroblasts (isolated de novo and cultured). Chromosomal aberrations were assayed by measuring the frequency of micronuclei in either the bone marrow (polychromatic erythrocytes) or the lungs (binucleate lung fibroblasts cultured in the presence of cytochalasin B). The results for the test animals were compared to those from animals exposed similarly, but without PAN. Although in each experiment the mutation frequencies for the test animals were higher than the corresponding controls, the mutation frequencies were not significantly different from the concurrent negative controls (P > .05) or the historical controls, except for experiment C. In experiment C, there was a significant regression of mutation frequency versus dose (P < 0.001) if all of the historical controls for pooled animals are included at zero dose. No reproducible evidence of chromosomal breakage was found in either lung or bone marrow. Thus, although PAN has been found to be a bacterial mutagen, we did not find statistically significant evidence of mutagenicity in vivo. The toxicity of PAN limited the exposure concentration that could be used. When all of the PAN data were used, the best estimate of the mutagenic potency proved to be comparable to that of ethylene dibromide, a carcinogenic atmospheric pollutant. © 1993 Wiley‐Liss, Inc.
Incorporation of a micronucleus study into a developmental toxicology and pharmacokinetic study of L‐selenomethionine in nonhuman primates
Authors: Choy Wai Nang , Henika Philip R. , Willhite Calvin C. , Tarantal Alice F. 
Published: February 2007

AbstractConcomitant to a developmental toxicology study of selenium in long‐tailed macaques (Macaca fascicularis), a transplacental bone marrow micronucleus assay was conducted in the fetuses of treated animals. Selenium was administered as L‐selenomethionine by nasogastric intubation at 0, 150 or 300 μg/kg‐day to pregnant macaques daily throughout organogenesis (gestation days 20–50). Pregnancy was terminated on gestation day 100 ± 2 and fetuses were obtained by hysterotomy. Selenium concentrations in maternal blood were monitored throughout pregnancy and selenium concentrations in fetal blood were measured at hysterotomy. Maternal circulating selenium did not exceed 4 ppm in plasma or 3.7 ppm in erythrocytes. Selenium in cord blood was ≤ 0.1 ppm in plasma and ≤ 1.1 ppm in erythrocytes at 300 μg/kg‐day. Fetal bone marrow smears were prepared from the humerus and micronucleated polychromatic erythrocytes were scored. No increase of micronucleus frequency was detected in any dose group, although signs of maternal selenosis were obvious. This finding is compared to the previous observation that micronuclei were induced in the bone marrow of adult nonpregnant macaques treated at 600 μg/kg‐day, a lethal dose yielding blood selenium levels to 7.3 ppm in plasma and 5.7 ppm in erythrocytes after 15 days of daily treatment, when death occurred. These data demonstrate that measurement of circulating xenobiotics can be useful for the interpretation of genetic toxicology results. © 1993 Wiley‐Liss, Inc.
Mutagenicity of the human carcinogen treosulphan, and its hydrolysis product, dl‐1,2:3,4‐diepoxybutane in mammalian cells
Authors: Zhu Songyun , Zeiger Errol 
Published: February 2007

AbstractThe cytotoxicity and mutagenicity of the human carcinogen, treosulphan, and its hydrolysis product, dl‐1,2:3,4‐diepoxybutane (DEB), were studied in Chinese hamster ovary, AS52, cells. Treosulphan (0.1–1.0 mM) is toxic and mutagenic at the gpt locus. A strong pH dependence was noted. DEB is cytotoxic and mutagenic at a much lower dose (0.025 mM), but these effects were not affected by pH. The results suggest that the toxic and mutagenic effects of treosulphan are mediated by its hydrolysis product DEB, and that the conversion of treosulphan to DEB is highly pH‐dependent. © 1993 Wiley‐Liss, Inc.
Analysis of the six additional chemicals for in vitro assays of the european economic communities' EEC aneuploidy programme using saccharomyces cerevisiae D61.M and the in vitro porcine brain tubulin assembly assay
Authors: Albertini Silvio , Brunner Martin , Würgler Friederich E. 
Published: February 2007

AbstractWe tested six additional chemicals (acetaldehyde, benomyl, diethylstilboestrol, diethylstilboestrol dipropionate, griseofulvin, and mercaptoethanol) for in vitro systems of the coordinated programme to study aneuploidy induction sponsored by the Commission of the European Communities in two in vitro test systems.Using Saccharomyces cerevisiae D61.M (mitotic chromosomal malsegregation assay), benomyl showed a dose‐dependent increase in the frequency of chromosomal malsegregation with a lowest effective dose tested (LEDT) of 30 μg/ml (0.1 mM). Diethylstilboestrol (DES) showed solvent‐dependent effects. DES dissolved in ethanol induced an increase in chromosomal malsegregation as well as in the frequency of total resistant colonies (mutations and recombinations) with a LEDT arround 13 μg/ml (0.048 mM). Using dimethylsulfoxide as the solvent, no increases were observed with DES up to 333 μg/ml (1.24 mM). Acetaldehyde induced an increase in chromosomal malsegregation with the cold treatment protocol (LEDT: 1.25 μl/ml (21 mM) and 0.75 μ/ml (13 mM), respectively) but no increase with the overnight protocol (highest dose tested (HDT): 1.75 μ/ml; 30 mM). Concerning the frequency of total cycloheximide‐resistant colonies (mutations and recombinations) increases were obtained with both protocols. The other three compounds were negative when tested up to toxic doses (survival below 10%), up to the maximum solubility in the solvent used or up to heavy precipitation in the incubation mix. The HDT were 333 μ/ml (0.88 mM) for diethylstilboestrol dipropionate, 1,600 μg/ml (4.5 mM) for griseofulvin and 0.5 μl/ml (7 mM) for mercaptoethanol.Concerning effects on porcine brain tubulin assembly in vitro, diethylstilboestrol and griseofulvin inhibited the assembly process. The IC30% (30% inhibition concentration) values were 12.5 μM and 100 μM for DES and griseofulvin, respectively. Mercaptoethanol showed no effects up to 50 mM. © 1993 Wiley‐Liss, Inc.
In vitro system for detecting nongenotoxic carcinogens
Authors: Dertinger Stephen D. , Torous Dorothea K. , Tometsko Andrew M. 
Published: February 2007

AbstractChemical risk assessment has been limited by the inability of in vitro short‐term assays to identify the true carcinogenic potential of many substances. Numerous methods exist for identifying mutagenic and clastogenic agents, but a practical means of identifying nongenotoxic carcinogens has remained elusive. Experiments described here suggest that some chemicals may participate in carcinogenesis by modulating the enzymatic processes of drug metabolism. The tumor promoters butylated hydroxyanisole, butylated hydroxytoluene, deoxycholic acid, reserpine, trypan blue, and 12,‐O‐tetradecanoyl phorbol‐13‐acetate were chosen as model non‐genotoxic carcinogens. The enzyme‐modulating action of these chemicals was measured using a modified Ames plate incorporation assay whereby the known tumor promoters were plated with a promutagen in the presence of a mammalian metabolic activation system (S9). Each of the nongenotoxic carcinogens significantly increased the mutagenic response of metabolically activated promutagen(s). These experiments suggest that the carcinogenic role of some chemicals may be attributed to their ability to modify the biochemical pathways of drug metabolism. By enhancing or inhibiting the activity of various enzymes, some tumor promoters may create an environment that increases a cell's mutational burden, thereby contributing to neoplastic transformation.