bluuebunny/crossref_metadata_2025_split huggingface dataset:
potent clastogenicity of the human carcinogen etoposide to the mouse bone marrow and mouse lymphoma L5178Y cells: Comparison to salmonella responses
Authors: Ashby J. , Tinwell H. , Glover P. , Poorman‐Allen P. , Krehl R. , Callander R. D. , Clive D. 
Published: February 2007

AbstractThe suspect human carcinogen, etoposide, is known to be genotoxic, producing both gene and chromosomal mutations, probably by virtue of its ability to inhibit topoisomerase II activity. The present paper describes assays conducted using the Salmonella assay, the mouse lymphoma tk+/‐ assay (gene and chromosomal mutation analysis and molecular analysis of tk‐/‐ mutants) and the mouse bone marrow micronu‐cleus assay. Nonreproducible, weak, dose‐related increases in mutation frequency in strain TA98 (but not TA1538 or TA1537) of Salmonella typhimurium were observed. Etoposide was highly mutagenic at the heterozygous thymidine kinase (tk+/‐) locus of L5178Y mouse lymphoma cells at concentrations below 0.1 μg/ml. Mostly small colony mutants were induced, consistent with the potent clastogenicity also observed. Molecular analysis of mutants indicated that 83% and 92% of large and small colony mutants, respectively, had lost the entire target gene sequence. Chromosomally aberrant L5178Y cells were ˜2 to 600‐fold more prevalent than small tk‐/‐ mutant colonies. This suggests that the viable target for etoposide‐mediated clastogenesis in the selective assay is ˜one‐fifth of chromosome 11b, itself being ˜one‐fortieth of the mouse genome. An unusually potent response was observed for etoposide in the mouse bone marrow micronucleus assay (63.1 ± 18 MPE/1,000 PE 24 hours after an oral dose of 1 mg/kg). The minimum detectable dose level in the assay was between 0.01 and 0.1 mg/kg. At dose levels between 1 and 15 mg/kg, an inverse dose response was observed. This reduction in assay response was not due to the small concommitant decrease in the incidence of polychromatic erythrocytes, a conclusion based on studies with N‐methyl‐N‐ni‐trosourea. Animals sampled 48 hours after dosing with etoposide (10 mg/kg) had no polychromatic erythrocytes in the bone marrow. These observations for the micronucleus assay await explanation. The chemical structure of etoposide is displayed and discussed within the context of such strong mutagenic activity being associated with a nonelectrophilic agent. © 1994 Wiley‐Liss, Inc.
Comparison of sister chromatid exchange induction in murine germinal and somatic cells by gamma radiation exposure in vivo
Authors: Morales‐Ramírez P. , Mendiola‐Cruz M. T. , Vallarino‐Kelly T. , Rodríguez‐Reyes R. 
Published: February 2007

AbstractSister chromatid exchange (SCE) induction by gamma rays was determined in spermatogonia irradiated before or after BrdU incorporation. Furthermore, the comparison of responses obtained in spermatogonia, bone marrow and salivary gland cells was carried out in the cells irradiated after BrdU incorporation, a condition which permits a higher SCE induction. Results indicate that gamma ray exposure of spermatogonia could induce a significant increase in SCE frequency with doses as low as 0.27 Gy, either before or after BrdU incorporation. However, the increase caused by radiation exposure after BrdU incorporation in spermatogonia was nearly three times lower than that obtained in both bone marrow and salivary gland cells. These data suggest that spermatogonia are either more efficient in repairing the gamma ray‐induced lesions involved in SCE production or that these cells are less prone to the induction of Such lesions. © 1994 Wiley‐Liss, Inc.
Promutagen activation by fish liver as a biomarker of littoral pollution
Authors: Rodriguez‐Ariza A. , Dorado G. , Navas J. I. , Pueyo C. , López‐Barea J. 
Published: February 2007

AbstractMetabolic activation of known promutagens by liver S9 fractions of Mugil sp. (grey mullet) from two zones of the South Atlantic Spanish littoral was determined and related to their pollution levels. Sediments from the putative contaminated area contained high concentrations of PAHs, PCBs and pesticides, and animals from the polluted site exhibited higher concentrations of metals than those from the reference area. Hepatic S9 fractions of mullets from the polluted site showed 5.1‐, 18.6‐ and 42.8‐fold higher capability to activate benzo(a)pyrene, 2‐acetyl‐aminofluorene and 2‐aminoanthracene, respectively, than those from reference animals. Cadmium, a highly toxic metal, was one of the pollutants detected in the contaminated area. Gilthead seabream (Sparus aurata) were exposed under controlled conditions to different Cd concentrations in order to investigate the effects of Cd on fish promutagen activation capability. A clear dose‐response relationship was observed between Cd concentration, EROD activity and metabolic activation of 2‐aminoanthracene and benzo(a)pyrene. Our data indicate that the enhanced promutagen activation by fish S9 fractions accompanying induction of EROD activity is a sensitive and reliable index of pollution in aquatic environments. © 1994 Wiley‐Liss, Inc.
Effects of light on the cytotoxicity and Genotoxicity of Benzo(a)pyrene and an oil refinery effluent in the newt
Authors: Fernandez Maria , I'Haridon Jacques 
Published: February 2007

AbstractThe genotoxicity and/or toxicity of benzo(a)pyrene (BOP) were evaluated under different light‐ ing conditions in larvae and embryos of the newt Pleurodeles walfl. Visible light alone 11,220 Ix; 2.1 mW/cm2), UVA alone (250 μW/cm ), or BOP alone (500,50,25,12.5 ppb) had no toxic effects on the larvae. Conversely, toxic effects were ob‐ served in animals exposed to BOP (500 ppb) + daylight, or BaP (≥25 ppb) + UVA. BOP solutions (50 or 12.5 ppb) were irradiated for 24 hr (Irr BaP) prior to being assayed in the dark. The genotoxicity of BOP (50ppb) as evaluated in the micronucleus test (on day 8) was halved by its previous exposure to UVA, and was abol‐ ished at the lowest concentration (12.5 ppb). In other experiments, the larvae were exposed al‐ ternatively to BaP or Irr BaP (18 hr in the dark) and UVA (6 hr in water), every day for 8 days. All animals that had accumulated non‐irradiated BOP (50 ppb) showed signs of severe toxicity, and 90% died before the end of the test. On the other hand, irradiated BOP (50 ppb) was 4‐fold less toxic and half as genotoxic as non‐irradi‐ oted BaP. In addition, exposure of the animals to UVA alone for 4 days prior to treatment with BaP did not affect the genotoxicity or toxicity of this hydrocarbon. In the dark, the embryotoxicity of BOP was markedly attenuated by the presence of the jelly coats (10% vs. 24%). With deiellied em‐ bryos, comparable mortality (24%) was ob‐ served after exposure to 25 ppb BOP for 54 or 312 hr. Although UVA alone did not affect growth of the embryos, the toxicity of BaP was enhanced by the combined action of the two agents together or in succession (BOP + UVA or BaP then UVA). Larvae were treated with an oil refinery effluent (EF). At the concentration em‐ ployed (125 mM), EF was not found to be geno‐ toxic in the dark. However, in animals exposed to both EF and UVA, there was a progressive increase in level of micronucleated erythrocytes with increasing duration of daily exposure to UVA (9,15,24 hr). Moreover, the genotoxic potential of irradiated EF + UVA was systematically below that of non‐irradiated EF + UVA for all durations of exposure to ultraviolet light. lrradiotion of this type of effluent might help reduce its harmful effects on aquatic species. Our results also suggest that metabolic activa‐ tion is not necessary for hydrocarbons to induce toxic effects. © 1994 Wiley‐Liss, Inc.
Protective effect of ethanol on X‐ray‐induced mitotic recombination in drosophila melanogaster
Authors: Palermo Ana M. , Rey Mónica , Muñoz Enzo R. 
Published: February 2007

AbstractThe effect of ethanol pretreatment on X‐ray‐induced mitotic recombination in D. melanogaster females was investigated by means of the white/white+ (w/w+) spot test. White females inseminated by yellow males were allowed to oviposit for 8 hr on medium containing 5%, 7.5% and 10% (v/v) ethanol and submitted to 10 Gy of X‐rays 52 hr after the beginning of the egg laying period (chronic treatments). For acute treatments 56 ± 4‐hr‐old larvae grown in regular medium were held in petri dishes containing filter paper soaked with 50% (v/v) ethanol for 30 min before being irradiated with 10 Gy. The emerging heterozygous w/w+ females were inspected for the presence of white spots (LS) in their eyes. Acute ethanol pretreatments lead to a significant reduction in the frequency of LS. This is suggested to be due to the scavenging by ethanol of free radicals originating during irradiation. If so, the contribution of the indirect action of radiation to mitotic recombination induced by X‐rays must be significant. Chronic ethanol pretreatments also resulted in a decrease of LS, though impairment of larval development by ethanol may have partly contributed to the effect observed. At the concentrations tested, ethanol by itself did not modify the frequency of LS observed in the control. © 1994 Wiley‐Liss, Inc.
Bacterial mutagenicity, metabolism, and DNA adduct formation by binary mixtures of benzo[a]pyrene and 1‐nitropyrene
Authors: Lee Huei , Cherng Shur‐Hueih , Liu Tsung‐Yun 
Published: February 2007

AbstractAir pollutants are a complex mixture containing polycyclic organic compounds. Among these are 1‐NP and B[a]P, which are important contributors to the mutagenicity of diesel exhaust and airborne particulate matters. To investigate the interaction of a complex mixture of airborne mutagens, the mutagenicity of 1‐NP was examined with S. typhimurium TA98 and TA98NR in the presence and absence of B[a]P. B[a]P exhibited a more antagonistic effect on the mutagenicity of 1‐NP in strain TA98 than in strain TA98NR. Also studied were (1) the inhibitory effects of B[a]P on the nitroreductive metabolism of 1‐NP and (2) DNA adduct formation by 1‐NP. Nitroreductase was associated with the metabolism of 1‐NP, and was reduced in a dose‐dependent manner in a binary mixture of 1‐NP and B[a]P. HPLC analysis showed that the amounts of 1‐AP and NAAP, the metabolites of 1‐NP, were significantly decreased by the addition of B[a]P in mixtures. The results indicate that the antagonistic effect of B[a]P on the mutagenicity of 1‐NP is mediated through altering its nitroreductive metabolism. © 1994 Wiley‐Liss, Inc.
Topoisomerase II enzymes and mutagenicity
Authors: Ferguson Lynnette R. , Baguley Bruce C. 
Published: February 2007

AbstractTopoisomerase II (topo II) enzymes maintain DNA structure by relieving torsional stress occurring in double‐strand DNA during transcription and replication. Topo II causes transient breaks in both strands of DNA, allowing passage of one double helix through another, and probably acts as a structural protein in inter‐phase cells, playing a role in the organisation of mitotic and meiotic chromosomes. A number of clinical anticancer drugs are thought to act on topo II enzymes to stabilise DNA‐drug‐topo II ternary complexes known as “cleavable complexes.” These complexes may lead to illegitimate recombination events, as well as to the formation of other DNA lesions. Topo II‐mediated genotoxicity is strongly dependent on the cell cycle status of the target cells. It is now apparent that some dietary components and environmental chemicals may act on topo II. Since the structural features of chemicals that lead to topo II interaction are not clear, it is currently not possible to predict such activity from chemical structure. For many years, the central dogma of chemical carcinogenesis has been that the most carcinogenic chemicals are those that can form a covalent bond with DNA, either directly or after metabolic activation. Topo II‐directed drugs are not usually capable of forming covalent bonds with DNA and tend to have low mutagenicity in microbial assays. However, topo II‐directed agents are potent cancerogens, inducing characteristic cytogenetic modifications. It is important to define the most sensitive tests to identify topo II‐directed mutagens and to develop appropriate strategies for genotoxicity testing of such chemicals. © 1994 Wiley‐Liss, Inc.
Role of oxygen radicals in the chromosomal loss and breakage induced by the quinone‐forming compounds, hydroquinone and tert‐butylhydroquinone
Authors: Dobo Krista L. , Eastmond David A. 
Published: February 2007

AbstractThe mechanisms by which two quinone‐forming compounds, hydroquinone (HQ) and tert‐butyl‐hydroquinone (tBHQ), induce chromosomal loss and breakage in a prostaglandin H synthase‐containing V79 cell line have been investigated using the cytokinesis‐block micronucleus assay with CREST antibody staining. Increased frequencies of CREST‐positive micronuclei (indicating chromosome loss) and CREST‐negative micronuclei (indicating chromosome breakage) were observed following exposure of cells to HQ and tBHQ. The formation of micronuclei by HQ, but not tBHQ, was dependent on arachi‐donic acid supplementation, indicating activation by prostaglandin H synthase. Since the oxidation of hydroquinones can result in the generation of oxygen radicals, the contribution of oxygen radicals to the formation of chromosomal alterations induced by HQ and tBHQ was investigated. In the presence of a superoxide‐generating system consisting of hypoxanthine and xanthine oxidase, a significant increase in micronucleated cells was observed. These induced micronuclei consisted exclusively of CREST‐negative micronuclei and their formation was completely inhibited by pretreatment with catalase. Catalase also significantly inhibited the CREST‐negative micronuclei induced by HQ and tBHQ. In addition, glutathione treatment inhibited both CREST‐positive and negative micro‐nuclei induced by these phenolic compounds. These results indicate that both chromosome loss and breakage are induced by these two quinone‐forming agents. Reactive oxygen species contribute to the chromosomal breakage induced by HQ and tBHQ but the observed chromosomal loss appears to result from other mechanisms such as an interference of quinone metabolites with spindle formation. © 1994 Wiley‐Liss, Inc.
Induction of genotoxic effects by chlorohydroxyfuranones, byproducts of water disinfection, in E. coli K‐12 cells recovered from various organs of mice
Authors: Fekadu Kassie , Parzefall Wolfram , Kronberg Leif , Franzen Robert , Schulte‐Hermann Rolf , Knasmüller Siegfried 
Published: February 2007

AbstractThe genotoxic effects of three chlorohydroxy‐furanones (CHFs), 3‐chloro‐4‐(dichloromethyl)‐5‐hydroxy‐2[5H]‐furanone (MX), 3‐chloro‐4‐(chloromethyl)‐5‐hydroxy‐2[5H] furanone (CMCF) and 3, 4,‐dichloro‐5‐hydroxy‐2[5H]furanone (MCA), which are formed as byproducts of water disinfection with chlorine, were investigated in bacterial differential DNA repair assays in vitro and in animal‐mediated assays in vivo. As indicators of DNA damage, E. coli K‐12 strains were used that differ in their repair capacity (uvrB/recA vs. uvr+/rec+). Liquid incubation of the compounds without metabolic activation caused a pronounced reduction of the viability of the repair‐deficient strain relative to the repair‐proficient wild‐type strain. The order of potency of genotoxic activity in vitro (dose range 0.004–10 μg/ml) was MX > CMCF > MCA. Addition of mouse S‐9 mix or bovine serum albumin to the incubation mixtures resulted in an almost complete loss of the activity of all three test compounds. In the animal‐mediated assays, mixtures of the indicator bacteria were injected intravenously into mice which were subsequently treated with the test compounds (200 mg/kg b.w.). Two hours later, the cells were recovered from various organs and the relative survival frequencies determined. Under these conditions, all three compounds caused pronounced genotoxic effects, MX and CMCF being stronger genotoxins than MCA. The strongest effects were consistently found in the gastrointestinal tract, but statistically significant DNA damage was also observed in indicator cells recovered from lungs, liver, spleen and kidneys. In a further experiment, the effects of lower doses of MX (4.3, 13 and 40 mg/kg) were investigated. In these experiments dose‐dependent effects were measured in all organs. CMCF and MA caused only marginal effects at 40 mg/kg except in the stomach where approximately a 50% reduction of relative survival frequency was observed with CMCF. The results of these animal‐mediated assays indicate that (i) all three CHFs cause genotoxic effects in the living animal, and (ii) the potencies of the three compounds observed under in vivo conditions are not commensurate with their extremely high activities measured in vitro. One possible explanation for the weaker responses observed in the animal‐mediated assays might be that CHFs are inactivated by nonspecific protein binding. © 1994 wiley‐Liss, Inc.
Genomic DNA sequencing of mRNA splicing mutants in the hprt gene of chinese hamster ovary cells
Authors: Valentine Carrie R. , Heflich Robert H. 
Published: February 2007

AbstractWe have analyzed 41 mRNA‐splicing mutants from the hypoxanthine‐guanine phosphoribo‐syl‐transferase (hprt) gene of Chinese hamster ovary (CHO) cells. Twenty‐two of these mutants produced single cDNA PCR products with a partial or complete exon deletion; 19 mutants produced multiple cDNA PCR products, and most of these products contained one or more deleted exons. The affected exons and surrounding in‐trons were amplified from genomic DNA and sequenced in order to identify mutations causing aberrant splicing. We found acceptor site mutations in 14 mutants, donor site mutations in 10 mutan's, exonic mutations in 8 mutants, and no mutations in 5 mutants. Four mutants from solvent controls did not amplify the appropriate exons and were considered genomic deletion mutants. Our previous work [Manjanatha MG et al. (1994): Mutat Res 308;65–75] showed that nonsense mutants in the hprt gene of CHO cells are associated with multiple cDNA PCR products containing deleted exons and a low abundance of hprt mRNA if the mutation is found in an internal exon. The present results are consistent with these associations being facilitated by instability of mRNA after ribosome termination at nonsense codons. © 1995 Wiley‐Liss, Inc.
Somatic reversion of some copia‐like induced mutations, at the white locus of drosophila melanogaster, after treatment with alkylating agents
Authors: Soriano S. , Creus A. , Marcos R. , Xamena N. 
Published: February 2007

AbstractIt has been suggested that transposable elements can be associated with different types of genotoxic effects. For this reason it seems appropriate to outline suitable systems to detect changes in the phenotypic expression of the loci containing transposable elements, as well as those agents that induce such changes. The sex‐linked white locus offers a suitable experimental system for studying such events because most of the spontaneous mutations at the white locus are the result of insertions of repeated mobile sequences, and it is easy to follow mutational changes of the locus due to the possibility of detecting even slight changes in eye color. Here we report the results obtained in different strains of Drosophila melanogaster with copia‐like induced mutations at the white locus, after treatment with three alkylating agents: ethyl meth‐anesulfonate (EMS), methyl methanesulfonate (MMS), and N‐nitroso‐N‐ethylurea (ENU). The three insertional white mutants used in this work were w04, wbf, and wsp55, with the wa2 mutation used as control because its mutant phenotype is the result of a point mutation instead of the insertion of a DNA fragment.Our data constitute evidence that EMS, MMS, and ENU induce a clear increase in the frequencies of somatic‐revertant sectors in the three strains carrying a white allele with an inserted copia‐like element. For the wa2 strain, whose mutant phenotype is the result of a point mutation, only ENU at the highest concentration tested is able to induce a significant increase in the somatic reversion frequency. In addition, cur results indicate that the use of D. melanogaster strains with transposable elements in the white locus is suitable for detecting genotoxic damage induced by chemicals. © 1995 Wiley‐Liss, Inc.
Characterization of mutagenic activity in instant hot beverage powders
Authors: Johansson Maria A. E. , Knize Mark G. , Jägerstad Margaretha , Felton James S. 
Published: February 2007

AbstractExtracts of several grain‐based coffee‐substitute blends and instant coffees were mutagenic in the Ames/Salmonella test using TA98, YG1024, and YG1029 with metabolic activation. The beverage powders induced 150 to 500 TA98 and 1,150 to 4,050 YG1024 revertant colonies/g, respectively. Increased sensitivity was achieved using strain YG1024. No mutagenic activity was found in instant hot cocoa products. The mutagenic activity in the beverage powders was shown to be stable to heat and the products varied in resistance to acid nitrite treatment. Differential bacterial strain specificity, and a requirement for metabolic activation suggest that aromatic amines are present. Characterization of the mutagenic activity, using HPLC and the Ames test of the collected fractions, showed the coffee‐substitute blends and instant coffees contain several mutagenic compounds. Known heterocyclic amines are not responsible for the major part of the mutagenic activity. The main mutagenic activity in grain‐based coffee‐substitute blends and instant coffees is due to several unidentified compounds, which are most likely aromatic amines. © 1995 Wiley‐Liss, Inc.
Determination of hprt mutant and mutation frequencies and the molecular characterization of human derived in vivo T‐lymphocyte mutants
Authors: Curry John , Rowley Gabriella T. , Saddi Vera , Beare David , Cole Jane , Glickman Barry W. 
Published: February 2007

AbstractUsing a T‐lymphocyte clonal assay, 73 6‐thiogua‐nine resistant T‐lymphocytes were isolated from two blood samples obtained 4 months apart from a 50‐year‐old male subject. Sixty‐six of these mutants were characterized at the DNA sequence level using cDNA. One particular single base substitution was recovered a total of 23 times. The majority of T‐cell receptors (TCR) of these mutants all share a common γ‐TCR rearrangement, and thus likely represent a single mutational event that underwent clonal expansion in vivo. Siblings of this clone were recovered in both collections. Three other single base substitutions were also recovered more than once. In two of the three cases, the mutants were also found to be clonally related, while in one case they were not. A number of identical exon loss events were also recovered, yet none of these were clonally related. This probably reflects the multiple pathways by which these mutations can arise. The TCR data was used to correct the observed mutant frequency to produce an estimate of the actual mutation frequency. The two mutant frequencies, 18 × 10−6 and 19 × 10−6, obtained from the first and second sampling periods, respectively, can thus be corrected to yield true mutation frequency's of 12 × 10−6 each © 1995 Wiley‐Liss, Inc.