bluuebunny/crossref_metadata_2025_split huggingface dataset:
Benzene‐induced micronuclei formation in mouse fetal liver blood, peripheral blood, and maternal bone marrow cells
Authors: Ning Hansun , Kado Norman Y. , Kuzmicky Paul A. , Hsieh Dennis P. H. , Littlefield L. G. 
Published: February 2007

AbstractThe transplacental cytogenetic effects of benzene were studied by using the micronucleus test of polychromatic erythrocytes (PCE) found in both fetal liver and fetal peripheral blood, and were compared with PCE from maternal bone marrow. Timed‐pregnant mice received single intraperitoneal doses of benzene (0, 109, 219, 437, or 874 mg/kg bw) on the 14th day of gestation and were sacrificed 21 hr after injection. Benzene elicited a significant increase (P < 0.01) in the frequency of micronucleated polychromatic erythrocytes (MNPCE) in fetal liver blood cells (0.55 to 1.36%, control 0.18%) at doses of 219 to 874 mg/kg, and in fetal peripheral blood cells (0.49 to 0.58%, control 0.25%) and maternal bone marrow cells (0.53 to 0.70%, control 0.10%) at doses of 437 and 874 mg/kg. The data demonstrate that benzene is a moderate transplacental clastogenic agent, and that the mouse transplacental micronucleus test using fetal liver blood cells is a potentially more sensitive indicator of the genotoxicity of benzene than either fetal peripheral blood or maternal bone marrow cells.
Chemical mutagenesis at the thymidine kinase locus in L5178Y mouse lymphoma cells: Results for 31 coded compounds in the national toxicology program
Authors: Myhr Brian C. , Caspary William J. , Holden H. E. 
Published: February 2007

AbstractExperimental data from the testing of 31 chemicals for mutagenicity at the TK locus in L5178Y mouse lymphoma cells are presented and evaluated. If mutagenic activity was not obtained for the chemical added to suspension cultures for 4 hr, then the testing was repeated in the presence of hepatic S9 mix prepared from Aroclor 1254‐induced male Fischer 344 rats. Multiple trials were performed for each chemical, and mutagenic treatments were analyzed for the induction of small and large mutant colony populations. Twelve chemicals were not detected as mutagenic, one (ascorbic acid) was questionable, and 18 were evaluated as mutagenic. These results were used in the evaluations presented by Tennant et al. [Science 236:933–941, 1987] in a critical comparison of four in vitro genotoxicity assays with rodent carcinogenicity results. The mouse lymphoma assay results were in general agreement with the carcinogenicity studies. Discordant evaluations with respect to carcinogenicity (four false negatives and six false positives) were discussed from the standpoint of how the predictive performance of the in vitro mutation assay might be improved.
Cytogenetic damage induced in vivo to mice by single exposure to cesium chloride
Authors: Ghosh Aditi , Sharma Archana , Talukder Geeta , Oleson F. B. 
Published: February 2007

AbstractFemale laboratory bred albino mice (2n = 40) were orally administered cesium chloride (CsCl) in aqueous solution as a single dose and the damage induced at the chromosomal level was observed in bone marrow cells after 6, 12, 18, and 24 hours of exposure. The concentrations of the chemical given were calculated as fractions of the LD50, namely 1/5, 1/10, and 1/20. The cytogenetic endpoints screened for were chromosomal aberrations (CA) and divisional frequency or mitotic index (MI). The frequency of chromosomal aberrations induced was directly proportional to the concentration of the chemical administered. The highest dose was the most toxic and was considered to be the maximum tolerance level. Effects on divisional frequency were variable, the highest concentration being significantly mitostatic, the middle one ineffective, and the lowest slightly mitogenic. In general, the observations indicate that CsCl is clastogenic when administered orally to mice in vivo and the effects are dose‐dependent.
Genotoxicity studies with the unstable Zeste‐White (UZ) system of Drosophila melanogaster: Results with ten carcinogenic compounds
Authors: Batiste‐Alentorn M. , Xamena N. , Creus A. , Marcos R. , Aaron C. S. 
Published: February 2007

AbstractTo increase the number of chemicals tested using the zeste‐white (UZ) somatic mutation assay, ten selected carcinogens (acetamide, acrylamide, benzo(α)pyrene, cyclophospha‐mide, diethylstilbestrol, 4‐nitroquinoline N‐oxide, propyleneimine, safrole, thiourea, and o‐toluidine) have been evaluated in this assay. Our results show that all the compounds tested produce significant increases in the eye spot frequency at, at least, one of the concentrations assayed, indicating that the zeste‐white assay appears to be highly sensitive to these carcinogenic compounds. That is in agreement with data previously reported by other authors.
Induction of micronuclei in mouse bone marrow cells: An evaluation of nucleoside analogues used in the treatment of AIDS
Authors: Phillips Marcia D. , Nascimbeni Bruce , Tice Raymond R. , Shelby Michael D. , Van Zeeland A. A. 
Published: February 2007

AbstractVarious nucleoside analogues are being used or are being considered for use as therapeutic drugs to inhibit replication of the HTLV‐III/LAV virus in infected human cells. Here, the ability of seven nucleoside analogues, a combination of two analogues, and two other therapeutic compounds to induce genotoxic and cytotoxic damage in vivo was evaluated in the mouse bone marrow micronucleus test. Using a 3‐consecutive‐day oral treatment protocol, almost all of the test chemicals induced a significant increase in the frequency of micronucleated polychromatic erythrocytes (MN‐PCE) in male B6C3F1 mice, ranked in decreasing potency as 6‐thioguanine > Cytarabine HCl > 3′‐azido‐3′‐deoxythymidine (AZT)/2′,3′‐dideoxycytidine combination = AZT > Ribavirin = 2′,3′‐didehydro‐3′‐deoxythymidine > 2′,3′‐dideoxyadenosine = 2′,3′‐dideoxycytidine. The frequency of MN‐PCE was not increased significantly by treatment with 2′,3‐dideoxyinosine (DDI) or pentamidine isethionate (PI). The differential ability of AZT and DDI to induce MN in mouse bone marrow was verified from peripheral blood smears prepared from subchronic (90 day) oral studies. The lack of genotoxic activity by DDI was route‐specific since, when tested by intraperitoneal injection, a small but significant increase in MN‐PCE was observed. A number of these chemicals induced a significant depression in erythropoiesis. However, there was not a significant correlation between the increase in MN‐PCE and the depression in the percentage of PCE. This lack of a correlation suggests that factors other than DNA damage may contribute to the inhibition in the rate of erythropoiesis. The presence of increased levels of micronuclei in bone marrow PCE following treatment with various nucleoside analogues suggests that intrinsic genotoxic activity in mammalian cells should be one factor considered during drug selection for AIDS therapy.
Lack of genotoxicity of cross‐linked acrylate polymers in four short‐term genotoxicity assays
Authors: Thompson E. D. , Seymour J. L. , Aardema M. J. , Leboeuf R. A. , Evans B. L. B. , Cody D. B. , Littlefield L. G. 
Published: February 2007

AbstractThree cross‐linked polyacrylate polymers containing either methylenebis‐acrylamide (MBA), trimethylolpropane triacrylate (TMPTA), or triallylamine (TAA) cross‐linkers were tested for genotoxicity with the Salmonella mammalian microsome assay, the L5178Y mouse lymphoma TK ± assay, the unscheduled DNA synthesis assay in primary cultures of rat hepatocytes, and the in vivo bone marrow cytogenetic assay. The results indicate that none of the three polymers was genotoxic in these assays.
Analysis of Salmonella typhimurium hisD3052 revertants: The use of oligodeoxyribonucleotide colony hybridization, PCR, and direct sequencing in mutational analysis
Authors: Kupchella Eugene , Cebula Thomas A. 
Published: February 2007

AbstractA rapid method for determining the DNA sequences of Salmonella typhimurium hisD3052 revertants is presented. DNA colony hybridization was used to analyze revertants previously studied by Isono and Yourno [Proc Natl Acad Sci USA 71:1612–1617, 1974]. Synthetic oligodeoxy‐ribonucleotide probes (18‐mers) were able to distinguish sequences that differed by a single base pair. Mutant his sequences not identified by probing analysis were amplified using polymerase chain reaction (PCR) and directly sequenced. The combined use of DNA‐colony hybridization and direct sequencing offers a precise and rapid means for the molecular characterization of hisD3052 revertants.
Use of PCR amplification of cDNA to study mechanisms of human cell mutagenesis and malignant transformation
Authors: Maher Veronica M. , Yang Jia‐Ling , Chen Ruey‐Hwa , McGregor W. Glenn , Lukash Lubov , Scheid Jeanette M. , Reinhold David S. , McCormick J. Justin 
Published: February 2007

AbstractPCR is widely employed to amplify short segments of genomic DNA to determine if a specific change has occurred. But some investigators need to sequence the entire coding region of mammalian genes to determine what specific changes have occurred. In 1989, we [Yang et al: Gene 83:347–354] described a method to copy mRNA of the hypoxanthine (guanine) phosphoribosyl transferase (HPRT) gene directly from the lysate of a clone of 6‐thioguonine‐resistant mutant diploid human fibroblasts without the need for RNA extraction or DNA template purification. To avoid detecting random changes introduced by polymerases, 100 to 500 cells from an individual clone, each containing the identical mutation, are lysed and the cDNA is amplified 1010‐ to 1011‐fold to obtain 5 to 10 μg of DNA. The consensus sequence of the cDNA is determined by direct nucleotide sequencing. Using this method, we have investigated the kinds of mutations induced by carcinogens in the coding region of the HPRT gene and their location in the gene and examined the role of DNA repair in this process. Normal repair‐proficient human cells and cells deficient in DNA repair were exposed to mutagens in exponential growth or synchronized and exposed at the beginning of S phase or in G1 phase several hr prior to DNA replication. The kinds and location of mutations in the HPRT gene were determined and knowledge of the nature of the DNA lesions formed by the various mutagens allowed assignment of the DNA strand in which the premutagenic lesion that gave rise to the mutation had been located. Related assays involving PCR have been used to determine the nature of mutations in the coding region of the H‐, N‐, or K‐ras genes of tumor‐derived malignant human cells and to determine whether or not such cells express specific growth factor genes.
Analysis of human HPRT deletion mutations with X‐linked probes and pulsed field gel electrophoresis
Authors: Nicklas J. A. , Lippert M. J. , Hunter T. C. , O'Neill J. P. , Albertini R. J. 
Published: February 2007

AbstractBecause the human hprt gene is used in numerous mutation studies, it is important to fully characterize this gene. Therefore, our laboratory has undertaken to map the region around the hprt gene at band q26 of the human X chromosome. Utilizing hprt mutant T‐cell clones isolated using the hprt clonal assay, which have deletions of all or part of the hprt gene, we have ordered 5 anonymous probes previously known to map in Xq26. Results suggest that this region includes between 460 kb and 18 Mb of DNA, which is at least 10 times the size of the hprt gene itself (43 kb). Pulsed field gel analysis of the region is underway to determine the exact distances between each of the anonymous probes and hprt and to determine deletion sizes in the mutant T‐cell clones.
EPA use of in vivo germ cell mutagenicity data
Authors: Cimino Michael C. 
Published: February 2007

AbstractThe Toxic Substances Control Act (TSCA) provides the U.S. Environmental Protection Agency, Office of Toxic Substances (EPA, OTS) with the authority to regulate chemical use by requiring testing and use restrictions as appropriate to protect human health. Regulation on the basis of heritable mutation induction is specifically mentioned in the Test Rule section of the law and has also been pursued for new chemical substances. A tiered scheme of mutagenicity testing has been employed and recently revised to assess mutagenicity hazard. In vivo assay systems play key roles at all three levels in the scheme, beginning with the first level of determining intrinsic mutagenicity hazard. Once intrinsic mutagenicity has been identified, the revised scheme requires an assay or assays to assess chemical interaction with gonadal DNA. Finally, the scheme contains tests that permit risk assessment for a chemical. The recently‐revised Office of Pesticide Programs (OPP) mutagenicity lest‐ing requirements closely parallel those of OTS.
Validation studies with Muta™ mouse: A transgenic mouse model for detecting mutations in vivo
Authors: Myhr Brian C. 
Published: February 2007

AbstractMutaMouse is a transgenic mouse engineered to detect mutations in vivo in any tissue of choice by using simple laboratory methods. The target is a bacterial lacZ gene incorporated via lambda phage into the genome of each mouse cell such that a concatamer of approximately 40 copies exists at a single site on both chromosomes of a homologous pair. In order to assess the potential usefulness of MutaMouse in detecting in vivo mutagenesis, several known mutagens/carcinogens were applied to male animals of 8–10 weeks in age. Intraperitoneal injections (single or 5 daily doses) of N‐ethyl‐N‐nitrosourea (ENU), chlorambucil, procarbazine, cyclophosphamide, and acrylamide were investigated for mutagenic effects in bone marrow, liver, and testes. In addition, skin painting studies (single application) were performed with dimethylbenzanthracene (DMBA), N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG), and acetic acid. Increases in mutant frequency were clearly induced by all eight chemicals, the magnitudes of which were dependent on the chemical, dose, method of dosing, tissue analyzed, and the time lapse between treatment and isolation of DNA. Data on variability in mutant frequency was presented relative to the analyzed population of lacZ genes and number of animals per treatment group. Application of the MutaMouse model to the detection of heritable mutations was discussed.
Analysis of spontaneous and induced mutations in transgenic mice using a lambda ZAP/lacl shuttle vector
Authors: Kohler Steven W. , Provost G. Scott , Fieck Annabeth , Kretz Patricia L. , Bullock William O. , Putman Donald L. , Sorge Joseph A. , Short Jay M. 
Published: February 2007

AbstractA short term, in vivo mutagenesis assay has been developed utilizing a lacl target gene contained within a lambda ZAP shuttle vector which has been incorporated into transgenic mice. Following chemical exposure, the target gene was recovered from mouse genomic DNA by mixing the DNA with in vitro lambda phage packaging extract. Mutations within the lacl target were identified by infecting host E. coli with the packaged phage and plating on indicator plates containing Xgal. Phage plaques with mutations in the lacl appeared blue, while intact phage were colorless. The ratio of blue plaques to colorless plaques is a measure of the mutagenicity of the compound. This system was used to obtain significant induction (up to 74‐fold) over background levels for a variety of compounds, including N‐ethyl‐N‐nitrosourea, benzo(a)pyrene (BaP), cyclophosphamide, and methylnitrosourea. Sequence analysis of selected mutant clones derived from this system was accomplished through the use of partial filamentous phage origins which allow rapid transfer of the target gene from phage to plasmid. Sequence analysis of spontaneous mutants derived from the mice primarily found of base substitutions, differing markedly from the previous data for spontaneous mutations in lacl derived from E. coli, where the preponderance of mutations were found at a single site, a repeated tetramer sequence. Upon sequence analysis of BaP derived base substitutions, only transversions were obtained, consistent with the known mechanism of BaP mutagenesis. Use of the well‐characterized lacl gene in transgenic mice should allow for extrapolation of the extensive pool of in vitro data to whole animals, as well as provide insight into the tissue specific effects of mutagenic compounds.
Centromere detection in vinblastine‐ and radiation‐induced micronuclei of cytokinesis‐blocked mouse cells by using in situ hybridization with a mouse gamma (Major) satellite DNA probe
Authors: Salassidis K. , Huber R. , Zitzelsberger H. , Bauchinger M. 
Published: February 2007

AbstractNon‐isotopic in situ hybridization using a mouse gamma (major) satellite probe DNA was applied to detect centromeres in micronuclei, which were induced in vitro in mouse liver cells by ionizing radiation and by vinblastine sulfate. In a cytokinesis‐blocked micronucleus assay a dose‐dependent induction of micronuclei was found for both agents. After vinblastine exposure the observed micronuclei showed centromere‐positive hybridization signals in an order of magnitude of 70–90%, but after radiation exposure the magnitude was only 10–20%. Since the in situ hybridization technique detects centromeric DNA directly, it can be used in a cytokinesis‐blocked micronucleus assay for a rapid and reliable discrimination between aneuploidy‐inducing and clastogenic agents.
Antimutagenicity of a low molecular weight superoxide dismutase mimic against oxidative mutagens
Authors: Degraff William G. , Krishna Murali C. , Russo Angelo , Mitchell James B. 
Published: February 2007

AbstractA set of stable nitroxide free radicals that are used as spin labels have been shown to possess metal‐independent superoxide dismutase‐like activity. Unlike superoxide dismutase (SOD), these compounds are low molecular weight, and readily penetrate into the cell. A representative nitroxide, 4‐hydroxy‐2,2,6,6‐tetramethylpiperidinyloxy (Tempol), was investigated for antimutagenic activity in the XPRT forward mutation assay in CHO AS52 cells. AS52 cells were exposed to hydrogen peroxide, or the hypoxanthine/xanthine oxidase superoxide generating system, in the presence or absence of 10 mM Tempol. Tempol itself was not mutagenic or toxic to AS52 cells. Tempol protected cells nearly completely from the cytotoxic and mutagenic effects of hydrogen peroxide and hypoxanthine/xanthine oxidase. We have previously shown that nitroxides do not alter the extracellular concentration of hydrogen peroxide, and that they are taken up by mammalian cells, suggesting that the antimutagenic activity of Tempol is an intracellular phenomenon.
A QSAR investigation of the role of hydrophobicity in regulating mutagenicity in the ames test: 1. Mutagenicity of aromatic and heteroaromatic amines in Salmonella typhimurium TA98 and TA100
Authors: Debnath Asim Kumar , Debnath Gargi , Shusterman Alan J. , Hansch Corwin 
Published: February 2007

AbstractQuantitative structure‐activity relationships (QSAR) have been derived for the mutagenic activity of 88 aromatic and heteroaromatic amines acting on Salmonella typhimurium TA98 + S9 and 67 amines acting on TA100 + S9. Mutagenic activity is linearly dependent on hydrophobicity, the energy of the highest occupied molecular orbital, and the energy of the lowest unoccupied molecular orbital of the amine. The dependence of mutagenic activity on hydrophobicity and electronic effects is nearly identical for TA98 and TA100. Mutagenic activity in TA98 is also found to depend on the size of the aromatic ring system. Different QSARs are derived for the mutagenic activity of hydrophilic amines (log P < 1) acting on either TA98 or TA100. The mechanism of amine activation and reaction with DNA is considered in light of these findings.
Coumarin inhibits micronuclei formation induced by benzo(a)pyrene in male but not female ICR mice
Authors: Morris Debra L. , Ward Jonathan B. 
Published: February 2007

AbstractCoumarin has been shown to be an effective inhibitor of carcinogenesis in rodents if given before and during the carcinogen treatment. We investigated the possibility that pretreatment with coumarin would inhibit the genotoxicity of benzo(a)pyrene (BP) in ICR mice as indicated by the bone marrow micronucleus test, a widely used in vivo test for genotoxicity. Our studies showed that pretreatment of male mice with doses of coumarin at 65 or 130 mg/kg/day for 1 week (with 1 day of no treatment at midweek) partially inhibited the genotoxicity of BP at a single intraperitoneal dose of 150 mg/kg. Time course experiments showed a decrease in induced micronuclei in the bone marrow at several time points after the BP treatment, thus indicating a true inhibition and not a lag in the induction of micronuclei. However, no inhibition in micronuclei formation was seen in female mice pretreated with the same doses of coumarin. Coumarin treatment alone did not induce micronuclei in either sex. Future studies are needed to analyze the mechanisms responsible for the difference noted between the sexes.
Specificity of arsenite in potentiating cytogenetic damage induced by the DNA crosslinking agent diepoxybutane
Authors: Wiencke John K. , Yager Janice W. 
Published: February 2007

AbstractIn the present study, the induction of sister chromatid exchanges (SCEs) and chromosomal aberrations were measured in normal human lymphocytes treated with low concentrations of arsenite alone (0.5–2.0 μM) and arsenite in combination with the potent DNA crosslinking agent diepoxybutane (DEB). Experiments were carried out with lymphocytes from blood donors with different sensitivities to SCE induction by DEB. Arsenite, beginning at concentrations as low as 1 μM, increased SCE frequencies; chromosomal aberration frequencies were increased at 2 μM of arsenite. DEB treatments alone increased SCE frequencies and chromosomal aberrations. The yields of chromatid deletions and exchanges in lymphocytes exposed to both arsenite and DEB were markedly increased above the levels expected if the effects of the two agents had been simply additive. The frequencies of chromatid deletions were 4‐ to 8‐fold greater than expected and chromatid exchanges were increased 7‐ to 40‐fold. Chromatid exchanges detected in cells treated with arsenite and DEB were predominately incomplete exchanges. The most dramatic increases in chromatid aberrations were observed in lymphocytes from an individual sensitive to SCE induction by DEB, indicating that individuals may vary in their sensitivity to the co‐clastogenic effects of arsenite. At concentrations that dramatically affect aberrations, arsenite had no effect on the induction of SCEs by DEB. These studies suggest a specific interaction of arsenite with the induction or repair of DNA damage produced by DEB that leads to chromosomal aberrations but not to SCEs. Based on the selective chemical reactivity of low concentrations of arsenite with proteins containing vicinal dithiols and the occurrence of these groups within DNA repair proteins, it is proposed that the specific co‐clastogenic effects of arsenite may be mediated by its interference with DNA repair activities.