bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutagenic activity of the 4,5‐ and 9,10‐dihydrodiols of benzo[J]fluoranthene and their syn‐ and anti‐dihydrodiol epoxides in salmonella typhimurium
Authors: Marshall Milton V. , He Zhen‐Min , Weyand Eric H. , Rice Joseph E. , Lavoie Edmond J. 
Published: February 2007

AbstractThe objective of this study was to determine the relative mutagenic activities of the major dihydrodiol metabolites of benzo[j]fluoranthene (B[j]F) and their corresponding syn‐ and anti‐dihydrodiol epoxides. Salmonella typhimurium tester strains TA97a, TA98, and TA100 were used to evaluate the mutagenic potencies of the parent hydrocarbon and these suspect proximate and ultimate mutagenic metabolites. B[j]F and the trans‐dihydrodiol metabolites were active only in the presence of an external metabolic activation system (S9) with the exception of the B[j]F‐4,5‐diol, which was weakly active in TA98 and TA100 in the absence of S9. The B[j]F‐4,5‐diol was more mutagenic than the B[j]F‐9,10‐diol in tester strains TA98 and TA100, whereas the opposite effect was observed in TA97a. In the absence of S9, the anti‐B[j]F‐4,5‐diol epoxide was more mutagenic than the syn‐B[j]F‐4,5‐diol epoxide and the syn‐ and anti‐B[j]F‐9,10‐diol epoxides in tester strains TA97a and TA100. The exceptional mutagenic potency of the anti‐B[j]F‐4,5‐diol epoxide in TA100 resembles that observed by epoxides located within a fjord, or by the anti‐diol epoxides of bay region methylated polycyclic aromatic hydrocarbons. In contrast, the mutagenicity of the pseudo bay region dihydrodiol epoxides arising from the B[j]F‐9,10‐diol more closely resembles that observed with the classical bay region dihydrodiol epoxides of chrysene. In summary, both dihydrodiol metabolites of B[j]F are mutagenic in S. typhimurium, and the relative potency varies among the tester strains. The highest mutagenic response was achieved in tester strain TA100, which detects base‐pair substitutions. The most potent direct‐acting dihydrodiol epoxide in this tester strain was the anti‐B[j]F‐4,5‐diol epoxide, which agrees with the results of mouse skin painting studies that indicate that the B[j]F‐4,5‐diol is more tumorigenic that the parent hydrocarbon or the B[j]F‐9,10‐diol. A cova‐lent DNA adduct formed between the anti‐B[j]F‐4,5‐diol epoxide and deoxyguanosine was the major species of DNA adduct formed in S. typhimurium. This adduct corresponds to the major DNA adduct formed in mouse skin following application B[j]F.
Micronucleus test and erythropoiesis: Effect of cobalt on the induction of micronuclei by mutagens
Authors: Suzuki Yuji , Shimizu Hidesuke , Nagae Yusuke , Fukumoto Masakatsu , Okonogi Hideo , Kadokura Makoto 
Published: February 2007

AbstractThe micronucleus test is used widely as an in vivo short‐term assay for potential carcinogens. In the present study, results of the micronucleus test were affected by cobalt dichloride pretreatment. Cobalt dichloride was used to induce erythropoietin, a growth factor for erythropoiesis. The increase in mutagen‐induced micronucleus response following cobalt pretreatment, therefore, may have been due to a change in the rate of erythropoiesis. The greatest interaction between cobalt pretreatment and mutagen treatment for the induction of micronucleated polychromatic erythrocytes (MPCE) occurred when mice were injected with 1,1‐dimethylhydrazine (DMH) 12–24 hr after pretreatment with cobalt dichloride and killed 30 hr later. Increased sensitivity of the micronucleus test was attributable to the administration of mutagen during the differentiation and multiplication of erythroblast, which is presumed to have been accelerated by pretreatment with cobalt dichloride. An increased induction of MPCE in the bone marrow by two chemicals—benzo(a)pyrene, 2‐naphthylamine—was also observed following pretreatment with cobalt dichloride. © 1993 Wiley‐Liss, Inc.
Comparative studies on cytotoxic and genotoxic effects of two organic mercury compounds in lymphocytes and gastric mucosa cells of sprague‐dawley rats
Authors: Betti C. , Barale R. , Pool‐Zobel B. L. 
Published: February 2007

AbstractHuman lymphocytes (HL) as well as lymphocytes (RL), hepatocytes (RH), and gastric mucosa cells (GM) of Sprague‐Dawley rats were treated in vitro for 1 h with methylmercury chloride (MMC, 0.5–4 μg/ml) and dimethylmercury (DMM, 5–40 μg/ml). The cytotoxicity of the two organic mercury compounds was assessed by dye exclusion, and the extent of induced DNA fragmentation was measured with a single‐cell microgel electrophoresis assay. Both MMC and DMM induced DNA damage and cytotoxicity in a dose‐related manner in HL, RL, and GM. MMC was more effective in causing a significant increase in median DNA migration than DMM at doses yielding approximately the same degree of cytotoxicity. In rat hepatocytes the MMC‐induced DNA damage was, however, lower than in the other cells. An analysis of repair kinetics following exposure to 2 μg/ml MMC was carried out in human lymphocytes obtained from an adult male donor. The bulk of DNA repair occurred 90 min after in vitro exposure, and it was about complete by 120 min following cessation of exposure. Finally, in order to have a basis for extrapolating to the human situation, in vivo studies were performed with Sprague‐Dawley rats, also assessing the DNA damage and cytotoxicity in the lymphocytes and gastric mucosa cells. These in vivo results after oral exposure may be directly compared to the in vitro data obtained in the same cells. © 1993 Wiley‐Liss, Inc.
Update on target theory as applied to chromosomal aberrations
Authors: Savage John R. K. 
Published: February 2007

AbstractThe early radiobiologists, who developed target theory to explain their results, considered the chromosome “target” as a visible thread that could be physically broken by ionizing radiation. Most of the broken ends restituted, but those that did not were free to wander about and, within limits, could rejoin with any other broken end they happened to contact to form structural aberrations. Failing this, they could remain to be seen as “open” breaks at the subsequent metaphase.These ideas, and their inevitable consequences, still form the basis for much modern thinking, even though we now know that the structure of the chromosome, and of the interphase nucleus, are very much more complicated than the originators of the theory envisaged. Current understanding of chromosomes of the molecular level and the varied responses a cell can mobilize when damage is introduced, raise again the question, Can we still think in terms of simple targets?Some of the experimental observations and suggestions made since those early days are reviewed, and the application of target theory to the three theories of aberration origins (Classic, Exchange, Recombination) is briefly discussed. © 1993 Wiley‐Liss, Inc.
Mechanism of hyperoxia‐induced chromosomal breakage in chinese hamster cells
Authors: Gille Johan J. P. , Van Berkel Carola G. M. , Joenje Hans 
Published: February 2007

AbstractExposure of cell cultures to hyperoxia, i.e., an atmosphere containing more than 20% O2, results in various genotoxic effects. The most prominent effect of hyperoxia is its clastogenicity. In this paper, earlier published data, obtained from research devoted to the mechanism of hyperoxia‐induced clastogenesis, are reviewed. In addition, new data are presented concerning the hyperoxia‐sensitivity of the DNA‐repair deficient Chinese hamster cell lines xrs1, irs1, and EM9. None of these ionizing radiation‐sensitive mutants showed hypersensitivity to hyperoxia, as measured by chromosomal aberration induction and loss of clonogenic cell survival. From the normal hyperoxia‐sensitivity of xrs1, it may be concluded that DNA double strand breaks, of the type that are induced by ionizing radiation, do not play a role in chromosomal aberration formation by hyperoxia. In addition, since xrs1 is hypersensitive to drugs that inhibit topoisomerase II, it seems rather unlikely that exposure to hyperoxia affects topoisomerase II activity. Based on circumstantial evidence we hypothesize that perturbation of poly(ADP‐ribose) metabolism may play a critical role in the mechanism of hyperoxia‐induced clastogenesis. © 1993 Wiley‐Liss, Inc.
Mutagenicity of methyl methanesulfonate (MMS) in vivo at the Dlb‐1 native locus and a lacl transgene
Authors: Tao K. S. , Urlando Cesare , Heddle John A. 
Published: February 2007

AbstractMethyl methanesulfonate (MMS) is an extraordinarily poor mutagen compared to ethylnitrosourea (ENU) or even X‐rays. In lung fibroblasts in vivo, MMS has been shown to induce many micronuclei but few, if any, mutations at the hpt locus. We wondered if the lack of mutations might be due to the lack of division and DNA synthesis in fibroblasts in vivo, which would permit substantial time for differential repair of DNA lesions. This idea was tested in the small intestine, a tissue in which the cells are actively dividing. Two loci were examined: a native locus (Dlb‐1) which determines the presence or absence of a lectin binding site on the surface of the epithelial cells, and a lacl transgene which controls β‐galactosidase synthesis. Lacl mutations were detected after in vitro packaging of DNA isolated from the intestinal epithelium into lambda phage and expression in suitable bacteria.Although the epithelial cells are proliferating, acute treatments produced no significant increase in mutations at either locus. Subacute treatments produced low but significant increases in mutation frequency at both loci. The results confirm that MMS is a far more potent clastogen than it is a mutagen and should be regarded as a super‐clastogen in the same manner as ENU is a super‐mutagen. The carcinogenicity of MMS is probably the result of its potent clastogenicity rather than its weak activity as a point mutagen.
Transcription by T7 RNA polymerase of DNA containing abasic sites
Authors: Sanchez Giselle , Mamet‐Bratley Margaret D. 
Published: February 2007

AbstractThe effects of abasic (AP) sites on RNA synthesis were studied in vitro, using T7 RNA polymerase and a plasmid template containing a T7 promoter. The presence of increasing numbers of AP sites caused a progressive decline in RNA synthesis. The average RNA chain length, calculated from the ratio of initiation to chain elongation, decreased with increasing numbers of AP sites, revealing that complete blocks must occur during synthesis. The probability that RNA polymerase would be blocked at an AP site in the DNA template strand was estimated to be 0.3 in our experimental conditions. These results demonstrate that RNA synthesis by T7 RNA polymerase is inhibited by AP sites and that readthrough of the lesion occurs more frequently than premature chain termination. Chemical reduction of AP sites in the template did not change the block/bypass pattern. © 1994 Wiley‐Liss, Inc.
Mutant alleles of tRNAThr genes suppress the hisG46 missense mutation in Salmonella typhimurium
Authors: Kupchella Eugene , Koch Walter H. , Cebula Thomas A. 
Published: February 2007

AbstractExtragenic suppressors of the hisG46 missense mutation were mapped to the 71 and 88 min regions of the Salmonella typhimurium chromosome, positions that in Escherichia coli contain the thrV (tRNAThr1) and thrT (tRNAThr3) genes, respectively. The suppressor loci were identified as mutant alleles of thrV and thrT, using allelespecific colony hybridization. An oligomer, based on the conserved 5′ sequence of the thrT and thrV genes in E. coli and designed to contain the putative mutant anticodon, discriminated between suppressor‐containing and wild‐type strains. Similarly, probes specific for the thrV‐[SuGGG] and thrT[SuGGG] were used to differentiate the two suppressors. To date, all extragenic suppressors of hisG46 have been identified as either thrV[SuGGG] or thrT[SuGGG]. A near equal distribution of thrV[SuGGG] and thrT[SuGGG] suppressors was found among 29 spontaneous and 43 mutagen‐induced hisG46 extragenic suppressor revertants. It was concluded, therefore, that mutant alleles of thrV and thrT are predominantly, if not solely, responsible for intergenic suppression of the hisG46 mutation. © 1994 Wiley‐Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United States of America.
Multiplex PCR analysis of in vivo‐arising deletion mutations in the hprt gene of human T‐lymphocytes
Authors: Fuscoe James C. , Zimmerman Lisa J. , Harrington‐Brock Karen , Moore Martha M. 
Published: February 2007

AbstractA multiplex polymerase chain reaction (PCR) procedure was adapted for the rapid and efficient evaluation of deletions of the hypoxanthine guanine phosphoribosyltransferase (hprt) gene in human T‐lymphocytes. The hprt clonal assay was used to isolate in vivo‐arising hprt‐deficient T‐cells from six healthy males. Mutant frequencies ranged from 9‐27 × 10−6. Simple crude cellular extracts from 223 mutants were analyzed for hprt gene deletion. Sixteen (7.2%) were found to be due to total gene deletion and 22 (9.9%) were due to partial gene deletion. The relatively high frequency of total gene deletions was caused by replicate isolates of a single mutational event as shown by single‐strand conformation polymorphism (SSCP) analysis of rearranged T‐cell receptor (TCR)‐γ genes. Eighteen of the 22 partial hprt gene deletion mutants were determined to be of independent origin based on a unique hprt mutation or SSCP‐TCR‐γ pattern. One‐half (9/18) of the partial deletion mutants involved all or part of exon 4 alone, suggesting that this region of the hprt gene is prone to deletion. The small deletions effecting exon 1 (1 mutant), exon 2 (2 mutants), and exon 4 (6 mutants) would not have been detected by conventional Southern blot analysis and may represent a new, previously unrecognized class of mutations. The ready isolation of such intragenic deletions will allow the characterization of breakpoint junctions and may provide insights into the important processes of DNA breakage and rejoining. © 1994 Wiley‐Liss, Inc.
Lack of chloroform‐induced DNA repair in vitro and in vivo in hepatocytes of female B6C3F1 mice
Authors: Larson Jeffrey L. , Sprankle Catherine S. , Butterworth Byron E. 
Published: February 2007

AbstractChloroform has been shown to induce hepatocellular carcinomas in female B6C3F1 mice when administered by gavage, but not when given in drinking water. When administered in corn oil at the carcinogenic doses of 238 and 477 mg/kg, chloroform induced necrosis and sustained regenerative cell proliferation in the liver. To investigate the mode of action of tumor induction in the target cells, the ability of chloroform to induce unscheduled DNA synthesis (UDS) was examined in the in vitro and in vivo hepatocyte DNA repair assays. In the in vitro assay, primary hepatocyte cultures from female B6C3F1 mice were incubated with concentrations from 0.01 to 10 mM chloroform in the presence of 3H‐thymidine. UDS was assessed by quantitative autoradiography. No induction of DNA repair was observed at any concentration. In the in vivo assay, animals were treated by gavage with 238 and 477 mg/kg chloroform in corn oil. Primary hepatocyte cultures were prepared 2 and 12 hr later, incubated with 3H‐thymidine, and assessed for induction of UDS as above. No DNA repair activity was seen at either dose or at either timepoint. These negative results in the target organ are consistent with the concept that neither chloroform nor its metabolites are directly DNA reactive and that the carcinogenicity of chloroform is secondary to induced cytolethality and regenerative cell proliferation. © 1994 Wiley‐Liss, Inc.
Relationship between benzo(a)pyrene‐DNA adducts and somatic mutation and recombination in drosophila melanogaster
Authors: Zordan M. , Osti M. , Pavanello S. , Costa R. , Levis A. G. 
Published: February 2007

AbstractThe evaluation of the relationship between the dose to DNA of a mutagen/carcinogen and in vivo somatic cell mutagenesis may provide information on the mechanisms leading to induced mutational events. This can be achieved, for example, by coupling test systems that permit the detection of somatic mutation and recombination on the basis of phenotypic changes in cuticular structures of Drosophila melanogaster, with methods for the quantitation of carcinogen‐DNA adducts such as the 32P‐postlabeling technique. In this article, we evaluate the quantitative relationship between BaP‐DNA adduct formation, determined by 32P‐postlabeling, and the induction of mutant cells in the wing marker version of the somatic mutation and recombination test (SMART) in Drosophila melanogaster. The total single clones in the trans‐heterozygous mwh/flr3 flies show a linear relationship with the BaP‐DNA adduct levels, suggesting a single hit mechanism for the genetic damage giving rise to this type of clones. In contrast, the twin clones (which are of recombinational origin) display a linear‐quadratic relationship with the adduct levels, suggesting that multiple hits may be involved in generating these clones. The total single clones in the mwh/TM3, Ser flies (in which mitotic recombination is suppressed) show a logarithmic relationship with the adduct levels. The discussion of these data in terms of the pathways that may be involved in the repair of the BaP‐DNA adducts leads to the suggestion that in Drosophila melanogaster the repair of Bap metabolite‐DNA adducts in somatic cells may proceed, in large part, via post‐replicative recombinational repair. © 1994 Wiley‐Liss, Inc.
Cytogenetic effects of phosphine inhalation by rodents. I: Acute 6‐hour exposure of mice
Authors: Kligerman A. D. , Bryant M. F. , Doerr C. L. , Erexson G. L. , Kwanyuen P. , McGee J. K. 
Published: February 2007

AbstractPhosphine (PH3) is a highly toxic grain fumigant that can be produced from the reaction of metal phosphides with water. To determine the in vivo cytogenetic effects of inhalation of PH3, male CD‐1 mice were exposed to either 0, 5, 10, or 15 ppm target concentrations of PH3 for 6 hr. Twenty hours after the termination of exposure, the spleens of the mice were removed, macerated, and the splenocytes cultured for analyses of sister chromatid exchanges, chromosome aberrations, and micronuclei in cytochalasin B‐in‐duced binucleated cells. In addition, bone marrow smears were made for the analysis of micronuclei in polychromatic erythrocytes. No increase in any of the cytogenetic endpoints was found at any of the concentrations examined. The only statistically significant response was a concentration‐related slowing of the cell cycle in the splenocytes. © 1994 Wiley‐Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United States of America.
Chemical mutagenesis testing in Drosophila. X. Results of 70 coded chemicals tested for the national toxicology‐program
Authors: Foureman P. , Mason J. M. , Valencia R. , Zimmering S. 
Published: February 2007

AbstractSeventy chemicals were tested for the ability to induce sex‐linked recessive lethal (SLRL) mutations in postmeiotic and meiotic germ cells of male Drosophila melanogaster. As in the previous studies in this series, adult feeding was chosen as the first route of administration. If the compound failed to induce mutations by this route, injection exposure was used. Two chemicals, n‐butane and propylene, were gaseous and therefore tested only by inhalation. One chemical (dimethylcar‐bamoyl chloride) was tested only by injection. Those chemicals that were mutagenic in the SLRL assay were further tested for the ability to induce reciprocal translocations.Sixteen of the 70 chemicals tested were mutagenic in the SLRL assay: 3‐chloro‐2‐methylpropene, 3‐(chloromethyl)pyridine HCI, dimethyl‐carbamoyl chloride, HC blue 1,3‐iodo‐1,2‐propanediol, malaoxon, N,N′‐methylene‐bisacrylamide, 4,4′‐methylenedianiline 2HCI, ziram, cis‐dichlorodiaminoplatinum II, 1,2‐dibromo‐ethane, dibromomannitol, 1,2‐epoxypropane, glycidol, myleran, and toluene diisocyanate. The last seven also induced reciprocal translocations. A comparison of the results from the SLRL assay with other assays for mutagens and carcinogens suggests that the SLRL assay is highly specific, but poorly sensitive, both for mutagens and potential carcinogens. © 1994 Wiley‐Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United States of America.
Genetic toxicology testing of Di(2‐ethylhexyl) terephthalate
Authors: Barber Eugene D. 
Published: February 2007

AbstractDi(2‐ethylhexyl) terephthalate (DEHT) is a commercially produced chemical (Kodaflex® DOTP) that is used as a general purpose, low‐volatility plasticizer for polyvinyl chloride and other polymeric materials. Less than 30 million kilograms of DEHT are produced annually. DEHT is isomeric with di(2‐ethylhexyl) phthalate (DEHP), a nongenotoxic rodent carcinogen whose mode of action has been suggested to derive from its ability to produce hepatocellular proliferation and/or hepatic peroxisome proliferation. Thus it is important to know the behavior of DEHT in genotoxicity assays in order to compare it with that of DEHP and other phthalate ester plasticizers. It is known from previously published studies that rats fed DEHT in the diet at 2,000 mg/kg produce urine that is negative in the Ames Salmonella bacterial mutagenicity assay in the presence and absence of induced rat liver S‐9 and in the presence and obsence of β‐glucuronidase/aryl sulfatase. Reported here are the results of direct testing of DEHT in the Ames plate incorporation assay, the Chinese hamster ovary/hypoxanthine guanine phosphoribosyl transferase (CHO/HGPRT) in vitro mammalian cell mutagenicity assay, and an in vitro chromosome aberrations assay using CHO cells. The results for mono(ethylhexyl) terephthalate (MEHT), a metabolite of DEHT, in the Ames Salmonella bacterial mutagenicity assay are also presented. All test results for both DEHT and MEHT were found to be negative, and it is therefore concluded that DEHT, like its isomeric relative DEHP, is not genotoxic. © 1994 Wiley‐Liss, Inc.
Propylene oxide mutagenesis at template cytosine residues
Authors: Snow Elizabeth T. , Singh Jatinder , Koenig Karen L. , Solomon Jerome J. 
Published: February 2007

AbstractPropylene oxide (PO) is a widely used industrial reagent which is mutagenic and carcinogenic. We have recently shown that a variety of aliphatic epoxides, including propylene oxide, can react with DNA to form hydroxyalkyl adducts at N‐3 of cytosine which rapidly undergo hydrolytic deamination to produce uracil adducts. These 3‐hydroxyalkyl uracil adducts are stable in DNA and are postulated to be an important class of potentially mutagenic lesions. Mutagenesis at cytosine residues due to PO modification of single‐stranded M13mp2/C141 DNA was studied by transfection of modified DNA into SOS and non‐SOS induced E. coli host cells. Mutations of the proline (CCC) codon at C141 which result in reversion of the lacZ phenotype (blue plaques) were scored. It was found that PO treatment of single‐stranded DNA results in dose‐dependent mutagenesis that is highly SOS dependent. The spectrum of base‐substitution mutations found at this site differed when PO‐modified DNA was transfected into E. coli with different DNA repair backgrounds. These results indicate that propylene oxide induced DNA adducts at template cytosine residues are mutagenic in E. coli and that this mutagenesis is greatly increased by SOS processing. They also show that these lesions may be repaired by one or more mechanisms.