bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of polyploidy in human lymphocytes in vitro by excess adenine, but not by adenosine
Authors: Edwards Anne J. , Anderson Diana , Phillips B. J. 
Published: February 2007

AbstractIt is known that high levels of DNA precursors can be both clastogenic and mutagenic in cultured cell lines and in vivo. The purpose of the present study was to examine at an observational level the cytogenetic effects of adenine and adenosine in primary human cell cultures. Human peripheral blood lymphocytes from four donors were cultured and treated with a range of concentrations of adenine and adenosine. Although no increase in sister chromatid exchange (SCE) frequency was observed with either compound, there was a statistically significant, dose‐related increase in the proportion of polyploid cells in cultures treated with adenine, but not in those treated with adenosine. Some of the polyploid metaphases found after adenine treatment contained diplochromosomes, suggesting that endoreduplication might have been involved in polyploid formation in these cells. It is concluded that a high level of adenine can cause genetic changes in human lymphocytes by interfering with mitosis, perhaps by disturbing the balance of DNA precursor pools. © 1995 Wiley‐liss, Inc.
Interaction of 7H‐dibenzo[c, g]carbazole and its organspecific derivatives with hepatic mitochondrial and nuclear DNA in the mouse
Authors: Périn‐Roussel Odette , Périn François , Barat Nicole , Plessis Marie‐José , Zajdela François 
Published: February 2007

AbstractThe recent observation of a high level of adducts in mitochondrial DNA (mtDNA) of cells exposed to chemical carcinogens aroused new interest in the hypothesis that carcinogen‐induced damage in mitochondria plays a role in one or more stages of carcinogenesis. In order to investigate whether differences in the metabolic activation of carcinogens have qualitative and quantitative effects on mt‐ and nuclear DNA (nuDNA) adduct formation, mice were exposed to the potent hepatocarcinogenic and sarcomagenic polycyclic hydrocarbon 7H‐dibenzo[c, g]carbazole (DBC) and to three of its derivatives that show large differences in enzymatic activation: N‐acetyl‐DBC (N‐AcDBC), which is carcinogenic for several tissues; 5,9‐dimethyl‐DBC (DiMeDBC), which is exclusively hepatocarcinogenic; and N‐methyl‐DBC (N‐MeDBC), which is exclusively sarcomagenic. Adduct formation and toxic effects were measured over 48 hr. With a moderate 5 μmol/kg dose of DBC, the adduct level in liver 24 hr after treatment was always higher in nuDNA than in mtDNA; after 48 hr a substantial increase in the level of adducts in mtDNA was observed, with a parallel decrease in the level in nuDNA. With DiMeDBC, a 4.9‐fold increase in mtDNA was seen at 48 hr, whereas, at the same dose, the non‐hepatocarcinogenic N‐MeDBC induced a very small number of adducts. In order to obtain a nearly identical level of adducts in nu‐ and mtDNA at 24 hr, the dose of DBC must be three times higher (15 μmol/kg); this and higher dose levels had a strong cytotoxic effect in liver cells. Qualitative differences in adduct distribution were observed on chromatograms of mtDNA and nuDNA, showing that the access to mtDNA is a complex process. Our results confirm that mouse liver mtDNA is a major target for DBC and its hepatocarcinogenic derivatives. The possible interference of genotoxic alterations in mtDNA with carcinogenic mechanisms is discussed. © 1995 Wiley‐Liss, Inc.
Induction of delayed mutations by benzene and ethylene dibromide in drosophila
Authors: Kale Purushottam , Kale Ranjini 
Published: February 2007

AbstractTwo carcinogens, ethylene dibromide and benzene, were used to induce delayed (germinal mosaic) sex‐linked recessive lethal mutations in spermatozoa and spermatids of adult Drosophila males. Significant numbers of delayed mutations (in F3) were scored in absence of conventional (in F2) mutations. A large proportion of nonlethal F2 cultures carried delayed mutations, so much so that, in some cultures, all F2 females were carriers of mutations. The mechanism through which single strand damage to treated X chromosomes can result in such delayed lethals is discussed. These observations indicate that the delayed mutation test should be used for testing the mutagenicity of environmental compounds, especially carcinogens, which tested negative in the conventional sex‐linked recessive lethal mutation test. The data will support the relationship between mutagenesis and carcinogenesis and, also will further enhance the sensitivity of the Drosophila mutation assay. © 1995 Wiley‐Liss, Inc.
Statistical design and analysis of mutation studies in transgenic mice
Authors: Carr G. J. , Gorelick N. J. 
Published: February 2007

AbstractWe have been working on identifying sources of variability in data from transgenic mouse mutation assays in order to develop appropriate statistical methods and designs for routine studies. Data from our lab and elsewhere point to the presence of significant animal‐to‐animal variability, which must be taken into account in statistical hypothesis tests. Here, the usual Cochran‐Armitage (CA) test for trend in mutant frequencies, which takes the transgene as the experimental unit, and a generalized Cochran‐Armitage test (GCA), which takes the animal as the experimental unit, are contrasted in computer simulations that help to quantify the differences between these statistical tests. The simulations report the statistical power of each test to detect treatment group differences, and their type I error rates. We find in general that the GCA test performs poorly compared to the CA test when it is appropriate to take the transgene as the experimental unit, and the study also uses a small number of animals. However, the CA test performs poorly in small group‐size studies when the animal is the appropriate experimental unit. Extensions of the computer simulations allow for identification of cost‐effective experimental designs. The results emphasize that the benefits of using additional animals in these mutation studies can be realized without substantial increases in costs. Here we illustrate the methods for liver studies in our lab. These methods can be used to derive optimal experimental designs for any combination of spontaneous mutant frequency and animal‐to‐animal variability. © 1995 Wiley‐Liss, Inc.
Induction of micronuclei in murine lymphocytes by morphine
Authors: Sawant Satin G. , Couch David B. 
Published: February 2007

AbstractAlthough individuals who abuse drugs are prone to an increased risk of malignancy, the mutagenic and carcinogenic potential of these agents has received relatively little attention. We report here on the potential of morphine to induce micronuclei in murine lymphocytes. Following a single intraperitoneal injection of 20 mg/kg morphine, the frequency of micronucleated binuclear (cytochalasin‐blocked) murine T‐ and B‐splenocytes was elevated from 1 2–36 hr after treatment. The maximum frequencies seen 24 hr after injection were 6.3– and 4.9–fold greater than the respective controls. A dose‐dependent induction of micronuclei was observed from 5–20 mg/kg morphine, with no further increases in frequency produced by higher doses. In contrast, incubation of mitogen‐stimulated splenocytes with 10‐7‐10‐4 M morphine in vitro produced no change in frequency of micronucleated cells relative to controls. Treatment with the narcotic antagonist naloxone (5 mg/kg) alone had no effect on the frequency of micronuclei, but reduced the clasto‐genic response of a subsequently administered dose of morphine (20 mg/kg). Thus, in murine lymphocytes morphine indirectly produces genetic damage, which is at least in part opioid receptor‐mediated. © 1995 Wiley‐Liss, Inc.
Mutagenicity in vitro of 3,4‐dichloro‐5‐hydroxy‐2(5H)‐furanone (mucochloric acid), a chlorine disinfection by‐product in drinking water
Authors: Jansson Kristian , Hyttinen Juha M. T. , Niittykoski Minna , Mäki‐Paakkanen Jorma 
Published: February 2007

AbstractThe mutagenicity of chlorinated humic drinking waters is accounted for mainly by a single contaminant, 3‐chloro‐4‐(dichloromethyl)‐5‐hydroxy‐2(5H)‐furanone (MX), as assessed in Salmonella typhimurium strain TA100. In the present study, 3,4‐dichl‐oro‐5‐hydroxy‐2(5H)‐furanone (mucochloric acid, MA), another drinking water contaminant much less potent as a mutagen in TA100 than MX, was tested in Chinese hamster ovary (CHO) cells for the induction of mutation at the hypoxanthine phosphoribosyl transferase (hprl) locus to 6‐thioguanine resistance (TG'). Unexpectedly, MA induced TG mutants in CHO cells with a potency comparable to that reported previously for MX. In subsequent experiments with S. typhimurium, the presence of pKM1O1 plasmid in strain TA100 increased susceptibility to the mutagenicity of MA, but much less than to that of MX, relative to the parental strain TA1535 lacking pKMlOl. The difference between the two compounds in TA100 thus appears to be due to a higher enhancement of the mutagenicity of MX than that of MA by pKM101 mediated error‐prone DNA repair. © 1995 Wiley‐Liss, Inc.
Genotoxicity of two arsenic compounds in germ cells and somatic cells of Drosophila melanogaster
Authors: Ramos‐Morales Patricia , Rodriguez‐Arnaiz Rosario 
Published: February 2007

AbstractTwo arsenic compounds, sodium arsenite (NaAsO2) and sodium arsenate (Na2HAsO4), were tested for their possible genotoxicity in germinal and somatic cells of Drosophila melanogaster. For germinal cells, the sex‐linked recessive lethal test (SLRLT) and the sex chromosome loss test (SCLT) were used. In both tests, a brood scheme of 2–3–3 days was employed. Two routes of administration were used for the SLRLT: adult male injection (0.38, 0.77 mM for sodium arsenite; and 0.54, 1.08 mM for sodium arsenate) and larval feeding (0.008, 0.01, 0.02 mM for sodium arsenite; and 0.01, 0.02 mM for sodium arsenate). For the SCLT the compounds were injected into males. Controls were treated with a solution of 5% sucrose which was employed as solvent. The somatic mutation and recombination test (SMART) was run in the w+/w eye assay as well as in the mwh +/+ flr3 wing test, employing the standard and insecticide‐resistant strains. In both tests, third instar larvae were treated for 6 hr with sodium arsenite (0.38, 0.77, 1.15 mM), and sodium arsenate (0.54, 1.34, 2.69 mM). In the SLRLT, both compounds were positive, but they were negative in the SCLT. The genotoxicity of both compounds was localized mainly in somatic cells, in agreement with reports on the carcinogenic potential of arsenical compounds. Sodium arsenite was an order of magnitude more toxic and mutagenic than sodium arsenate. This study confirms the reliability of the Drosophila in vivo system to test the genotoxicity of environmental compounds. © 1995 Wiley‐Liss, Inc.
Concurrent analysis of cytogenetic damage in vivo: A multiple endpoint‐multiple tissue approach
Authors: Krishna G. , Theiss J. C. 
Published: February 2007

AbstractSimultaneous assessment of in vivo micronucleus and chromosome aberration endpoints has been described in the rat and the mouse. Bone marrow and spleen cells were utilized for genotoxicity assessment. A cellulose column methodology was used in the micronucleus assay (where applicable) to eliminate nucleated cells and facilitate cytogenetic scoring. The test agents–cyclophosphamide, chlorambucil, and acrylamide–produced qualitatively comparable results between micronucleus and chromosome aberration endpoints and varied slightly on a quantitative basis depending on the type of test agent and tissue studied. The results from test agents such as cyclophosphamide, chlorambucil, acrylamide, dimethylnitrosamine, vincristine, and x‐rays indicated that bone marrow cytogenetic results are similar to spleen and that the spleen tissue is at least as sensitive as the bone marrow. The concurrent analysis of cytogenetic damage in vivo using a multiple endpoint‐multiple tissue approach described here has the following advantages: a) reducing the overall animal usage, b) clarifying marginal micronucleus and/or chromosome aberration data, c) correlating cytogenetic results from multiple endpoints and multiple tissues, and d) helping the investigation of the mechanism of action of test agents and their potential target organs. Also, the multiple endpoint‐multiple tissue approach can be extended to other endpoints, tissues, and species (where appropriate and practical) to obtain detailed genotoxicity information. © 1995 Wiley‐Liss, Inc.
Effect of lsopropyl‐β‐D‐thiogalactopyranosid induction of the lac operon on the specificity of spontaneous and doxorubicin‐induced mutations in Escherichia coli
Authors: Veigl M. L. , Donover S. P. , Anderson R. D. , Akst L. , Sedwick C. E. , Sedwick W. D. 
Published: February 2007

AbstractPrevious studies of doxorubicin‐induced mutations employing F lacl/lacO as an endogenous gene target have focused on properties of large deletions with 3′ endpoints residing in the lacO region of the target gene. This study considers the influence of Lac represser binding on the distribution of these deletions. Results of the DNA sequence level analysis of spontaneous and doxorubicin‐induced i−d and lacO mutations in Escherichia coli uvrB− are reported for mutants isolated under conditions where Lac repression is relieved by isopropyl‐β‐D‐thioga‐lactopyranosid (IPTG; an inducer that prevents represser binding to lacO). The location of deletions isolated from doxorubicin‐treated cultures in the presence and absence of IPTG suggests that doxoru‐bicin preferentially focuses deletion endpoints adjacent to its binding sites in lacO and that the distribution of these deletion endpoints is not modulated by Lac represser binding. In contrast, spontaneous deletion endpoints are preferentially clustered in the loop away from the palindromic sequences under conditions of repression. However, when the Lac repressor/lacO binding complex is dissociated by IPTG, the spontaneous 3′‐deletion endpoints distribute proportionally between the putative stem and loop of the lacO palindrome.The single most striking effect of IPTG induction of the Lac operon was elimination of a “hot spot” for T:A→C:G transitions at position +6 in lacO. This base substitution “hot spot,” which accounted for 17.6% of total doxorubicin‐induced mutants and 16.4% of spontaneous mutants in repressed bacterial cultures, accounted for approximately 1% of total mutations in similar experiments carried out in the presence of IPTG. A large number of mutations at the +6 position are induced only by doxorubicin in the absence of IPTG, however, suggesting that both doxorubicin‐induced and spontaneous mutation at this transition “hot spot” are mediated by Lac represser binding to lacO. © 1995 Wiley‐Liss, Inc.
Use of multicolour chromosome painting to identify chromosomal rearrangements in human lymphocytes exposed to bleomycin: A comparison with conventional cytogenetic analysis of giemsa‐stained chromosomes
Authors: Ellard Sian , Parry Elizabeth M. , Parry James M. 
Published: February 2007

AbstractExchange aberrations induced by bleomycin were identified by multicolour fluorescence in situ hybridisation (FISH) with probes for chromosomes 1, 2, and 3. The frequency and distribution of aberration types were compared to conventional metaphase analysis of Giemsa‐stained chromosomes from the same human lymphocyte cultures. The total percentage of exchanges detectable by painting three pairs of chromosomes with separate colours was calculated as 40%. Giemsa staining revealed predominantly asymmetric chromosome exchanges, which are expected to comprise 50% of the total induced exchanges. Genomic exchange frequencies were, therefore, determined by multiplying the observed frequencies from FISH analysis by 2.5 and the number of asymmetric exchanges identified in Giemsa‐stained slides by 2.0. By these calculations, the genomic exchange frequency calculated from chromosome painting exceeded that estimated by Giemsa‐staining. This difference was due to the identification by chromosome painting of a unique class of cells in which chromosomes had undergone complex exchanges (nonreciprocal exchanges involving multiple mutual sites). The percentage of cells exhibiting exchanges was similar for both methods. © 1995 Wiley‐Liss, Inc.
Role of classical nitroreductase and O‐acetyltransferase on the mutagenicity of nifurtimox and eight derivatives in Salmonella typhimurium
Authors: Jurado Juan , Pueyo Carmen 
Published: February 2007

AbstractThis study investigates the mutagenicity of nifurtimox (NFX) and eight analogues in Salmonella typhimurium indicator strains that possess different levels of classical nitroreductase or O‐acetyltransferase activities. The NFX analogues tested replace the 3‐methyl‐4‐yl‐tetrahydro‐1,4‐thiazine‐1,1 ‐dioxide group of the parent compound with the following other groups: indazol‐l‐yl (1G); pyrazol‐1‐yl (1B); benzimidazol‐1‐yl (lE); 1,2,4‐triazol‐4‐yl (1D); 1‐methyl‐3‐methylthio‐1,2,4‐triazol‐4‐yl‐5‐thione (11); 3,5‐bis(methylthio)‐1,2,4‐triazol‐4‐yl (1H); 1‐ada‐mantyl (ADA); and 4,6‐diphenylpyridin‐1‐yl‐2‐one (1K). In the genetic backgrounds of the standard Ames tester strains TA98 and TA100, these bacteria combine the L‐arabinose resistance forward mutation assay (Ara test) with a deficiency or overproduction of either nitroreduction or O‐acetylation. The Ara test revealed, in agreement with previous findings, important differences between TA98 and TA100 and demonstrated, moreover, that these genetic differences are of significance in mutagenicity testing with nitrofuran compounds. The Ara test also indicated dissimilarities between the metabolic activation of NFX and its analogues, these compounds being classified in three different groups according to their mutagenicity toward strain BA14 (genetic background of TA98) and its derivatives. The first group included analogues (1G, 1E, 11, and ADA) that showed similar mutagenic potency in all bacterial strains. These compounds are considered not to be substrates for both classical nitroreductase and O‐acetyltransferase. The second group included compounds (analogues 1 B and 1K, and the reference drug NFX) with increased mutagenicity toward the strain overproducing the classical nitroreductase, and/or reduced mutagenicity toward the corresponding deficient bacteria. These compounds are considered to be activated by the classical nitroreductase. The third group (analogues 1D and 1H) was activated by bacterial O‐acetyltransferase, and consequently showed increased and decreased mutagenicity with the particular overproducer or deficient bacterial strain, as compared to their isogenic parentals. Previous reports have pointed out interest in NFX analogue 1H as a promising candidate for the replacement of NFX. The present study further enhances the putative interest of compound 1H, based on the different metabolic activation pathway exhibited by this analogue as compared to the parental drug, NFX. © 1995 Wiley‐Liss, Inc.
Clastogenic effects of 1, 3‐butadiene and its metabolites 1,2‐epoxybutene and 1,2,3,4‐diepoxybutane in splenocytes and germ cells of rats and mice in vivo
Authors: Xiao Y. , Tates A. D. 
Published: February 2007

AbstractClastogenicity of 1,3‐butadiene (BD), 1,2‐epoxybutene (EB), and 1,2,3,4‐diepoxybutane (DEB) was studied in splenocytes and germ cells of rats and mice by means of micronucleus assays (cytokinesis‐block method for splenocytes, suspension method for germ cells). Inhalation exposure of mice to 200, 500, or 1,300 ppm BD (6 h/d; 5 days) induced significant chromosome damage in spermatocytes at the preleptotene stage. EB and DEB induced significant amounts of clastogenic damage in splenocytes and spermatocytes of rats and mice. The lowest tested effective doses for mice and rats were, respectively, 40 and 80 mg/kg for EB, and 15 and 30 mg/kg for DEB. In splenocytes, 80 mg EB/kg induced 3.6 times more MN in mice than in rats, whereas 30 mg DEB/kg induced the same amount of damage in both species. Damage in germ cells of mice was induced in early spermatocytes treated with 40 and 80 mg EB/kg, and in late spermatocytes exposed to 30 mg DEB/kg. In rats, 40 mg EB/kg induced damage in early spermatocytes, whereas 80 mg EB/kg induced chromosomal damage in early and late spermatocytes. In rats treated with DEB, clastogenic damage was induced in spermatocytes at preleptotene, zygotene, diplotene, and diakinesis stages. When the clastogenic potential of EB and DEB in splenocytes and germ cells of mice and rats was compared, DEB always showed a stronger effect than EB. Body weight, testis weight, ratio of testis weight to body weight, and ratio of Golgi to Golgi + cap phase spermatids were used as parameters for toxicity. Exposures to 500 and 1,300 ppm BD were somewhat toxic to mice. Doses of 80 mg EB/kg and 30 mg DEB/kg exhibited toxic effects in mice and rats. © 1995 Wiley‐Liss, Inc.
Southern blot analysis of T‐cell receptor gene rearrangements in cynomolgus monkeys, and identification of a progenitor cell HPRT mutation
Authors: Mattano S. S. , Zimmer D. M. , Harbach P. R. , Hunter T. C. , Aaron C. S. 
Published: February 2007

AbstractIncreases in peripheral blood T‐lymphocyte HPRT mutant frequency may reflect either a number of independent HPRT gene mutational events or clonal proliferation of a single HPRT mutant. Sequence analysis of HPRT mutations in conjunction with T‐cell receptor (TCR) gene rearrangement pattern analysis can distinguish these possibilities. Our laboratory previously characterized a nonhuman primate model for in vivo mutation studies using the clonal HPRT mutation assay. In the present study we report the use of probes for human TCR B and y genes to characterize TCR rearrangements in cynomolgus monkeys. Together, these methods were used to examine a monkey which exhibited a mean spontaneous HPRT mutant frequency (MF) of 16.4 × 10−6, compared to the normal mean MF of 3.03 × 10−6. The elevated MF resulted from the occurrence of a single HPRT mutation in a lymphocyte progenitor cell or stem cell, since T‐cell clones isolated from the monkey exhibited a G to T transversion at base pair 539 in the HPRT coding region, and had unique rearrangements of TCR y along with an apparent germline TCR B configuration. In a preliminary in vivo mutation study, the animal was treated with the investigational potent mutagen and antitumor agent adozelesin (U‐73975). No increase in HPRT mutant frequency was observed. The HPRT mutant clones isolated after treatment showed rearrangement of both TCR y and B genes. Possible explanations for these findings are discussed. © 1995 Wiley‐Liss, Inc.
Genotoxicity of m‐phenylenediamine and 2‐aminofluorene in Salmonella typhimurium and human lymphocytes with and without plant activation
Authors: Plewa Michael J. , Wagner Elizabeth D. , Yu T.‐W. , Anderson Diana 
Published: February 2007

AbstractThe promutagenic arylamines, m‐phenylenediamine (mPDA) and 2‐aminofluorene (2‐AF), were evaluated for their genotoxicity in Salmonella typhimurium strain YG 1024 and in human lymphocytes. These agents were assayed with and without TX1MX plant activation mix. Both arylamines without activation were refractory in S. typhimurium, demonstrating that plant activation was required for the generation of their ultimate mutagenic metabolites. However, using the alkaline single‐cell gel/ Comet assay, both mPDA and 2‐AF directly induced DNA damage in human lymphocytes. This effect was reduced when the human cells were treated with the arylamine plus TXIMX. mPDA with or without plant activation was not toxic to the exposed cells. However, at concentrations over 80 μM, 2‐AF was toxic to lymphocytes. This toxic response was eliminated by incubation with TX1MX. mPDA and 2‐AF were plant‐activated into mutagens for S. typhimurium. However, these plant‐activated products had a reduced genotoxic potency in human lymphocytes. © 1995 Wiley‐Liss, Inc.