bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of the in vivo genotoxicity of 2‐hydroxy 4‐methoxybenzophenone
Authors: Robison Steven H. , Odio Mauricio R. , Thompson Edward D. , Aardema Marilyn J. , Kraus Albert L. 
Published: February 2007

AbstractThe genotoxic potential of 2‐hydroxy 4‐methoxy‐benzophenone (benzophenone‐3, Bz‐3), a commonly used sunscreen, has been evaluated previously with in vitro systems. Data from Salmonella studies (with and without activation) have been predominantly negative, but two reports have shown weakly positive results in a single bacterial strain under conditions of metabolic activation. In addition, Bz‐3 has been reported to induce chromosome aberrations and equivocal results for sister chromatid exchange in Chinese hamster ovary (CHO) cells. We used the Drosopha somatic mutation and recombination test (SMART) and in vivo cytogenetics in rat bone marrow to define the potential for in vivo expression of this in vitro activity. For the SMART assay, larva from a mating of “multiple wing hair” (mwh) females with heterozygous “flare” (fir) males were exposed to 0,3000, or 3500 ppm Bz‐3 or 25 ppm dimethylnitrosamine (DMN, positive control) for 72 hr. A recombination between the mwh and flr genes produces twin wing spots, while events such as deletions produce single spots. None of the Bz‐3‐treated larva produced flies with significantly more single or multiple wing spots than controls. In contrast, DMN‐treated larva produced flies with significantly more single or multiple wing spots than controls. The in vivo cytogenetic assay in rat bone marrow cells was conducted to evaluate the clastogenicity of Bz‐3. Sprague‐Dawley rats were treated by oral gavage with a single administration of 0.0, 0.5, 1.67, or 5 gm/kg Bz‐3 or a single dose of 5 gm/kg/day Bz‐3 for 5 consecutive days. Cyclophosphamide (CP) was the positive control and was administered at 20 mg/kg with both treatment regimens. Colchicine growth‐arrested bone marrow cells were collected 8 and 12 hr after the single treatment and 12 hr after the last daily treatment. Under either treatment protocol none of the Bz‐3 concentrations caused any significant increase in chromosomal aberrations. Results from these two studies strongly support the conclusion that Bz‐3 is not genotoxic in vivo. © 1994 Wiley‐Liss, Inc.
Response of fibroblast cultures from ataxia‐telangiectasia patients to reactive oxygen species generated during inflammatory reactions
Authors: Ward A. J. , Olive P. L. , Burr A. H. , Rosin M. P. 
Published: February 2007

AbstractCells from patients with ataxia‐telangiectasia (AT) are more sensitive than cells from normal individuals to a number of compounds which induce DNA damage via oxygen‐derived free radical attack. We tested the hypothesis that AT cells would show a sensitivity to reactive oxygen species (ROS) generated by activated inflammatory cells. AT cells were exposed to neutro‐phils activated with 12‐O‐tetradecanoyl‐phor‐bol‐13‐acetate (TPA) or to xanthine/xanthine oxidase (X/XO), an enzyme system which generates superoxide and hydrogen peroxide. Induced micronuclei (MN) frequencies (corrected for spontaneous MN frequencies) were significantly higher in AT cell cultures than in cultures from normal individuals (comparison of MN frequencies of AT vs. normal cultures: for treatment with activated neutrophils, P = 0.003; for X/XO, P = 0.05). The comet assay was used to determine whether the elevated chromosomal damage in the treated AT cells was due to a difference in strand breakage or its rejoining. X/XO treatment was used in studies of single‐stranded (SS) DNA breakage, and X‐ray treatment for double‐stranded (DS) DNA damage. AT and normal cells showed no significant differences in the initial levels of SS (P = 0.29) or DS (P = 0.91) DNA damage. Likewise, they exhibited similar rejoining kinetics (rejoining half‐time for SS = 10 min, for DS = 30 min). These data support the involvement of the AT loci in determining a cell's ability to deal with oxidative stress, although the mechanism underlying this effect has yet to be resolved. The data also suggest that AT patients are at elevated risk of sustaining DNA damage in tissues undergoing inflammatory reactions. © 1994 Wiley‐Liss, Inc.
further studies with the somatic white‐ivory system of Drosophila melanogaster: Genotoxicity testing of ten carcinogens
Authors: Batiste‐Alentorn M. , Xamena N. , Creus A. , Marcos R. 
Published: February 2007

AbstractTo provide further background data for the white‐ivory somatic mutation Drosophila assay, ten selected carcinogens (acetamide, acrylamide, benzo(α)pyrene, cyclophosphamide, diethylstilbestrol, 4‐nitroquinoline N‐oxide, propyleneimine, safrole, thiourea, and o‐toluidine) have been tested in this system. Seventy‐two hours after egg laying, larvae were fed with different concentrations of each carcinogen during the rest of their development until pupation, and the genotoxic effects were measured as significant increases in the appearance of visible mutant clones of ommatidia in the eyes of the emerging adult flies. Our results indicate that three of the ten carcinogens tested (cyclophosphamide, 4‐nitroquinoline N‐oxide, and propyleneimine) were strong genotoxic agents, two (diethylstilbestrol and acrylamide) induced significant positive results but without a dose‐response relationship, and safrole was weakly positive. On the other hand, acetamide, benzo(α)pyrene, thiourea, and o‐toluidine were unable to increase the frequency of mutant clones. © 1994 Wiley‐Liss, Inc.
Induction of DNA strand breaks by ethylene oxide in human diploid fibroblasts
Authors: Nygren Jonas , Cedervall Björn , Eriksson Stefan , Duškinská Mária , Kolman Ada 
Published: February 2007

AbstractIn vitro exposure of normal human diploid fibro‐blasts (strain VH‐10) to ethylene oxide (EtO) induced DNA strand breaks in the dose range of 2.5–30 mMh of EtO. Alkaline DNA unwinding (ADU), neutral filter elution (NFE), pulsed field gel electrophoresis (PFGE), and the comet assay were used to measure DNA single (SSBs) and double strand breaks (DSBs).Different induction rates of SSBs and DSBs, depending on applied method and also on treatment conditions (cells in monolayer or in suspension were used), were found. A dose‐dependent increase of DNA strand breaks was found by the ADU method in the dose range of 2.5–20 mMh of EtO when treatment was performed in monolayer and in suspension. DSBs were detected by NFE only when the cells were treated with EtO in suspension (doses 10–30 mMh). The highest induction rate of DSBs (about 4 DSBs per 100 Mbp per 1 mMh of EtO) was detected in suspension with PFGE applied. We have shown that heat‐labile sites are formed by EtO. Presumably, the different DSB levels detected by PFGE and NFE result from the conversion of these sites to DSBs during cell lysis at elevated temperature in the PFGE method. The results of the comet assay confirmed that apoptotic processes are not involved in the formation of DSBs in our experimental conditions (less than 1% of apoptotic cells were observed at all doses studied). Possible mechanisms for the induction of DNA strand breaks by EtO‐treatment are discussed. The capacity to repair DSBs in EtO‐exposed (5–7.5 mMh) cells was studied, and it was found that a considerable part of the damage (about 50%) could be repaired during 18 hr of incubation. © 1994 Wiley‐Liss, Inc.
Evidence that SCEs induced by mutagens do not occur at the same locus in successive cell cycles: Lack of cancellation in three‐way stained CHO chromosomes
Authors: Cortés F. , Daza P. , Piñero J. , Escalza P. 
Published: February 2007

AbstractAn approach based on the synchronization of CHO cells after a first cell cycle incorporating a relatively low amount of bromodeoxyuridine (BrdUrd) into DNA, followed by mutagenic treatment and subsequent culture for second and third generations of BrdUrd incorporation for the scoring of sister chromatid exchanges (SCEs) per cell cycle in three‐way differentially (TWD) stained chromosomes, has been used to investigate the possible concellation of SCEs. Cancellation is expected to occur if two mutagen‐induced SCEs occur at exactly the same site in subsequent rounds of replication. Lesions in DNA seem to persist and are able to induce SCE throughout two cell cycles after treatment with the three mutagens tested—mitomycin C (MMC), ethyl methanesulfonate (EMS) and ultraviolet (UV) light—though this latter agent was shown as only moderately persistent. Our results seem to indicate that SCEs induced by these mutagens do not take place at the same locus in successive cell generations, as assessed by a lack of SCE cancellation. © 1994 Wiley‐Liss, Inc.
Ascorbic acid (vitamin C) modulates the mutagenic effects produced by an alkylating agent in vivo
Authors: Aidoo Anane , Lyn‐Cook Lascelles E. , Lensing Shelly , Wamer Wayne 
Published: February 2007

AbstractRecent reports suggest that ascorbic acid (vitamin C) inhibits tumorigenesis as well as exerts a protective effect against mutagenesis in vitro; however, there is no information on its ability to affect gene mutations induced in vivo. In this study, we have investigated the antimutagenic effects of ascorbic acid on the frequency of 6‐thioguanine‐resistant (6‐TGr) T‐lymphocytes produced in Fischer 344 rats dosed with the direct‐acting alkylating agent, N‐ethyl‐N‐nitrosourea (ENU). The freqeuncy of 6‐TGr T‐lymphocytes from the spleen measured five weeks after ENU treatment indicated that ENU produced a substantial mutagenic response. Pretreatment and/or post‐treatment of rats with ascorbic acid administered in the drinking water appeared to inhibit the response, but the inhibition was statistically significant only when data from the various dosing schedules were pooled. In addition, there was no clear dose‐dependency to the inhibitory effect of ascorbic acid. To further evaluate the time effects of the vitamin supplement on ENU mutagenicity, rats were exposed to the mutagen together with ascorbic acid, which was given continuously for the entire duration of the experiment. At specific times after ENU treatment, the frequency of 6‐TGr T‐cells was determined in lymphocytes isolated from the spleen and the thymus. Time‐dependent increases in the frequency of 6‐TGr T‐cells were observed with ENU treatment; ascorbic acid significantly reduced the ENU‐mediated mutagenic responses, most dramatically in the spleen at weeks 6 and 8 (P < 0.0001), and to a lesser extent in the thymus (P < 0.01 at week 6 and P < 0.006 at week 8). Our data suggest that ascorbic acid intake affects the in vivo mutagenicity of ENU, a direct‐acting mutagen/carcinogen, and that the reported inhibitory effects of the antioxidant on carcinogenesis may be partially mediated by its effects on mutagenesis. Although it is difficult to extrapolate from rodent studies to humans, the results presented suggest an explanation for epidemiological data that link vitamin C ingestion with decreased cancer risk. © 1994 Wiley‐Liss, Inc.
mutation spectra in salmonella of complex mixtures: Comparison of urban air to benzo[a]pyrene
Authors: Demarini David M. , Shelton Melissa L. , Bell Douglas A. 
Published: February 2007

AbstractWe used an ion‐exchange procedure coupled to the Salmonella assay to fractionate the dichlo‐romethane‐extractable particulate organics from an urban air sample collected in Boise, ldaho. A resulting base/neutral fraction contained 81% of the mutagenic activity but only 36% of the mass of the unfractionated sample. Chemical analysis showed that polycyclic aromatic hydrocarbons (PAHs) accounted for much of the mutagenic activity of the air sample. Colony probe hybridization, PCR, and DNA sequence analysis were then used to determine the mutations induced by the complex mixtures and a model PAH, benzo[a]pyrene (BAP) in ∼900 revertants of the frameshift hisD3052 allele and ∼400 revertants of the base‐substitution hisG46 allele. The majority (93–94%) of the mutations induced at the frameshift allele in strain TA98 by the whole or base/neutral fraction of the urban air sample was a hotspot 2‐base deletion of a CG or GC within the sequence CGCGCGCG. The remaining mutations were complex frame‐shifts that consisted of −2 or +1 frameshifts associated with a flanking base substitution. BAP induced a somewhat similar pattern of mutations, with 70% being the hotspot mutation, 23% being complex frameshifts, and the remaining being deletions. The inferred base‐substitution specificity associated with the complex frame‐shifts at the hisD3052 allele (primarily G · C→T · A transversions) was consistent with the observation that this same transversion was the primary mutation induced by the whole urban air sample and BAP at the base‐substitution allele in strain TA100. At the frameshift allele, adducts that promote correct incorporation/slippage could account for hotspot mutations, whereas those that promote misincorporation/slippage could account for complex frameshifts. At the base‐substitution allele, a mixture of adducts or of adducts with multiple conformations could account for the observed proportion of transitions and transversions. Combined with the bioassay‐directed chemical analysis, these results from the first mutation spectra of a complex mixture suggest that such spectra reflect the dominance of particular classes of chemical mutagens within the mixture. © 1994 Wiley‐Liss, Inc.
cytogenetic and germ cell effects of phosphine inhalation by rodents: II. subacute exposures to rats and mice
Authors: Kligerman A. D. , Bishop J. B. , Erexson G. L. , Price H. C. , O'Connor R. W. , Morgan D. L. , Zeiger E. 
Published: February 2007

AbstractPhosphine (PH3) is a highly toxic grain fumigant to which there is significant human workplace exposure. To determine the in vivo cytogenetic effects of inhalation of PH3, male F344/N rats and B6C3F1 mice were exposed to target concentrations of 0, 1.25, 2.5, or 5 ppm PH3 for 6 hr/day for 9 days over an 11 ‐day period. Approximately 20 hr after the termination of exposures, blood was removed from the mice and rats by cardiac puncture and the lymphocytes cultured for analyses of sister chromatid exchanges and chromosome aberrations in rats and mice, and micronuclei (MN) in cytochalasin B‐induced binucleated lymphocytes from mice. In addition, bone marrow (rats) and peripheral blood (mice) smears were made for the analysis of MN in polychromatic and normochromatic erythrocytes. No significant increase in any of the cytogenetic endpoints was found at any of the concentrations examined. These results indicate that concentrations of PH3 up to 5 ppm are not genotoxic to rodents when administered by inhalation for 9 days during an 11 ‐day period as measured by several cytogenetic assays. To evaluate the effects of PH3 on male germ cells, a dominant lethal test was conducted in male mice exposed to 5 ppm PH3 for 10 days over a 12‐day period and mated to groups of untreated females (2 females/male) on each of 6 consecutive 4‐day mating intervals. None of the 6 groups of females exhibited a significant increase in percent resorptions. These results indicate that exposure to 5 ppm PH3 by inhalation does not induce dominant lethality in male mouse germ cells at steps in spermatogenesis ranging from late differentiating spermatogonia/early primary spermatocytes through mature sperm. © 1994 Wiley‐Liss, Inc.
Reciprocal mitotic recombination is the predominant mechanism for the loss of a heterozygous gene in saccharomyces cerevisiae
Authors: Acuña Gonzalo , Würgler Friedrich E. , Sengstag Christian 
Published: February 2007

AbstractThe loss of a functional copy of a heterozygous tumor suppressor gene represents an important step during neoplastic transformation. In order to learn more about the genetic events that lead to spontaneous and drug‐induced loss of heterozygosity, a diploid Saccharomyces cerevisiae strain was constructed that allows the detection of the loss of a heterozygous gene by means of direct selection. The strain contains a single functional URA3 gene copy inserted at the ADE2 locus located on the right arm of chromosome 15. In addition, the chromosome contains two other phenotypic marker genes, HIS3 which is located distal from URA3, and PHO80 which is closely linked to the centromere. The homologous chromosome lacks all three marker genes. Loss of the heterozygous copy of URA3 can easily be detected by 5‐fluoro‐orotic acid resistance of the resulting clones. Simple phenotypic tests of the resistant clones further allows one to distinguish whether the loss of the URA3 gene copy occurred by crossing over, chromosomal loss, or point mutation and gene conversion. Loss of heterozygosity was found to be induced in a dose‐dependent fashion by UV radiation and by several chemical agents. All the tested mutagens induced loss of heterozygosity predominantly by crossing over. © 1994 Wiley‐Liss, Inc.
Excision repair and gene orientation modulate the strand specificity of UV mutagenesis in a plasmid‐borne yeast tRNA gene
Authors: Armstrong John D. , Kunz Bernard A. 
Published: February 2007

AbstractUltraviolet (UV) mutagenesis in a plasmid‐borne Saccharomyces cerevisiae tRNA gene (SUP4‐o) occurs preferentially at sites where the pyrimidine in the base pair is part of a dipyrimidine sequence on the transcribed strand. In this study, we examined whether excision repair, or strand identity with respect to DNA replication, influences this strand bias. The specificity of UV mutagenesis was determined for a wild type (RAD) strain and an isogenic excision repair‐deficient (rad1) derivative, each carrying SUP4‐O on the vector YCpMP2, or another vector (YCpJA1) that differed only in the orientation of SUP4‐O with respect to a unique origin of replication. Most (≧ 90%) of the SUP4‐O mutations induced by UV in these strains were single base pair substitutions, predominantly (> 87%) transitions. The rad1 defect and inversion of SUP4‐O in the RAD strain eliminated the strand preference, whereas inversion of SUP4‐O in the rad1 strain caused it to reappear. Both conditions also altered the distribution of frequently mutated sites and the relative fraction of transitions at TT sequences. These results suggest that excision repair and gene orientation can be important determinants for the strand and site specificities of UV mutagenesis in SUP4‐O on YCpMP2 and YCpJA1. We consider several possible explanations for our observations, including potential roles for transcription by RNA polymerase II, sequence context effects on the efficiency of excision repair, and inherent differences in strand mutability or translesion synthesis by the leading and lagging strand DNA replication complexes. © 1995 Wiley‐Liss, Inc.
Effects of X‐irradiation on mouse testicular cells and sperm chromatin structure
Authors: Sailer B. L. , Jost L. K. , Erickson K. R. , Tajiran M. A. , Evenson D. P. 
Published: February 2007

AbstractThe testicular regions of male mice were exposed to x‐ray doses ranging from 0 to 400 rads. Forty days after exposure the mice were killed and the testes and cauda epididymal sperm removed surgically. Flow cytometric measurements of acridine orange stained testicular samples indicated a repopulation of testicular cell types following x‐ray killing of stem cells. Cauda epididymal sperm were analyzed by the sperm chromatin structure assay (SCSA), a flow cytometric measurement of the susceptibility of the sperm nuclear DNA to in situ acid denaturation. The SCSA detected increased susceptibility to DNA denaturation in situ after 12.5 rods of x‐ray exposure, with significant increases following 25 rads. Abnormal sperm head morphology was not significantly increased until the testes were exposed to 60 rads of x‐rays. These data suggest that the SCSA is currently the most sensitive, non‐invasive method of detecting x‐ray damage to testicular stem spermatogonia. © 1995 Wiley‐Liss, Inc.
Bleomycin sulfate‐induced micronuclei in human, rat, and mouse peripheral blood lymphocytes
Authors: Erexson Gregory L , Bryant Miriam F. , Kwanyuen Puntipa , Kligerman Andrew D. 
Published: February 2007

AbstractThe sensitivity to micronucleus (MN) induction of human, mouse, and rat peripheral blood lymphocytes (PBLs) exposed to bleomycin sulfate (BLM) in vitro was compared in cytochalasin B‐induced binucleated (BN) cells. For the PBLs of each species, either 0, 5, 10, 20, 40, 60, 80, or 160 μg/ml BLM was added to 5 ml aliquots of whole blood for 4 hr at 37°C in a 5% CO2 atmosphere. Leukocytes were isolated on a density gradient and cultured in the presence of phytohemagglutinin to stimulate blastogenesis, and cytochalasin B was added to each culture at 21 hr postinitiation to prevent cytokinesis. A total of 4,000 BNs/concentration/species was analyzed for MN in two independent experiments. In addition, multiple‐MN‐BNs were quantitated, and the nucleation index was determined. Significant increases both in total MN‐BNs and multiple‐MN‐BNs were observed at all concentrations in all species. All three species concentration‐response curves gave good fits (r2 values from 0.87 to 0.95) to either a linear or a square root model (y = mx + b or y = m[x]0.5 + b, respectively; where y = the percentage of MN‐BN, m is the slope, and b is the y‐intercept). The MN induction in the human and rat PBLs was not statistically different, but both were significantly less sensitive than the response shown by the BLM‐exposed mouse PBLs. This difference in MN susceptibility was observed only at BLM test concentrations ≧ 20 μg/ml. The nucleation index was significantly decreased in all species at either 80 or 160 μg/ml. © 1995 Wiley‐Liss, Inc.
Effects of asbestos and man‐made vitreous fibers on cell division in cultured human mesothelial cells in comparison to rodent cells
Authors: Pelin K. , Kivipensas P. , Linnainmaa K. 
Published: February 2007

AbstractWe report the effects of chrysotile and crocidol‐ite asbestos, and glass and rock wool fibers (man‐made vitreous fibers, MMVF) on the induction of binucleate cells in vitro. The response of human mesothelial cells (target cells in fiber carcinogenesis) and rodent cells was compared. Human primary mesothelial cells, MeT‐5A cells (an immortalized human mesothelial cell line), and rat liver epithelial (RLE) cells were exposed to asbestos and MMVF samples of similar size range. Milled glass wool, milled rock wool, and titanium dioxide were used as non‐fibrous particle controls. All four fiber types caused statistically significant increases in the amount of binucleate cells in human primary mesothelial cells and MeT‐5A cells (in the dose range 0.5–5.0 ug/ cm2). Chrysotile and crocidolite asbestos were more effective (1.3–3.0‐fold increases) than thin glass wool and thin rock wool fibers (1.3–2.2–fold increases). However, when the fiber doses were expressed as the number of fibers per culture area, the asbestos and MMVF appeared equally effective in human mesothelial cells. In RLE cells, chrysotile was the most potent inducer of binucleation (2.9–5.0‐fold increases), but the response of the RLE cells to crocidolite, thin glass wool, and thin rock wool fibers was similar to the response of the human mesothelial cells. No statistically significant increases in the number of bi‐ or multinucleate cells were observed in human primary mesothelial cells or RLE cells exposed to the non‐fibrous dusts. In MeT‐5A cells exposed to 5 ug/cm2of milled glass wool and milled rock wool, as well as in cultures exposed to 2 and 5 ug/cm2of TiO2, significant increases were, however, observed. Our results show that rodent cells respond differently to mineral fibers than human cells. The results also add evidence to the suggested importance of disturbed cell division in fiber carcinogenesis. © 1995 Wiley‐Liss, Inc.