bluuebunny/crossref_metadata_2025_split huggingface dataset:
Benzene metabolite, 1,2,4‐benzenetriol, induces micronuclei and oxidative DNA damage in human lymphocytes and HL60 cells
Authors: Zhang Luoping , Robertson Moire L. , Kolachana Prema , Davison Allan J. , Smith Martyn T. 
Published: February 2007

AbstractThe triphenolic metabolite of benzene, 1,2,4‐benzenetriol (BT), is readily oxidized to its corresponding quinone via a semiquinone radical. During this process, active oxygen species are formed that may damage DNA and other cellular macromolecules. The ability of BT to induce micronuclei (MN) and oxidative DNA damage has been investigated in both human lymphocytes and HL60 cells. An antikinetochore antibody based micronucleus assay was used to distinguish MN containing kinetochores and potentially entire chromosomes (kinetochore‐positive, K+) from those containing acentric chromosome fragments (kinetochore‐negative, K−). BT increased the frequency of MN formation twofold in lymphocytes and eightfold in HL60 cells with the MN being 62% and 82% K+, respectively. A linear dose‐related increase in total MN, mainly in K+‐MN, was observed in both HL60 cells and lymphocytes. Addition of copper ions (Cu2+) potentiated the effect of BT on MN induction threefold in HL60 cells and altered the pattern of MN formation from predominantly K+ to K−. BT also increased the level of 8‐hydroxy‐2′‐deoxyguanosine (8‐OH‐dG), a marker of active oxygen‐induced DNA damage. Cu2+ again enhanced this effect. Thus, BT has the potential to cause both numerical and structural chromosomal changes in human cells. Further, it may cause point mutations indirectly by generating oxygen radicals. BT may therefore play an important role in benzene‐induced leukemia. © 1993 Wiley‐Liss, Inc.
Genotoxicity analysis of N,N‐dimethylaniline and N,N‐dimethyl‐p‐toluidine
Authors: Taningher Maurizio , Pasquini Rossana , Bonatti Stefania 
Published: February 2007

AbstractN,N‐Dimethylaniline (DMA, CAS No. 121—69—7) and N,N‐dimethyl‐p‐toluidine (DMPT, CAS No. 99—97—8) belong to the N‐dialkylaminoaromatics, a chemical class structurally alerting to DNA reactivity. Their applications may be industrial (dye and pesticide intermediates, polymerizing agents) and surgical (polymerization accelerators for the manufacture of bone cements and prosthetic devices), thus implying heterogeneous types of human exposure. Findings of carcinogenicity in rodents and some nonexhaustive genotoxicity data are available for DMA, but to our knowledge no information is available on DMPT concerning either carcinogenicity or any kind of genetic toxicity. To investigate their mechanism cf action and mutagenic/carcinogenic potential, DMA and DMPT were analyzed for complementary genotoxicity end‐points, namely, gene mutation in Salmonella (Ames test), structural and numerical chromosome aberrations in hamster V79 cells (micronucleus test, matched with an immunofluorescent staining for kinetochore proteins), and in vivo DNA damage in mouse and rat liver (alkaline DNA elution test). The results essentially indicate that both chemicals are chromosome damaging agents. Indeed, at the maximum nontoxic doses, they proved nonmutagenic in Salmonella (although their toxicity did not allow concentrations > 70 μg/plate to be tested) and weakly positive in inducing DNA damage (increases in DNA elution rates at most ∼2.4 times control value). Conversely, they proved clearly positive in inducing numerical chromosome alterations, with dose‐dependent increases up to more than five times the control value for DMPT. At the highest dose tested, both chemicals also showed a significant clastogenic effect. © 1993 Wiley‐Liss, Inc.
Mutagenicity of soluble and insoluble nickel compounds at the gpt locus in G12 chinese hamster cells
Authors: Lee Y. W. , Pons C. , Tummolo D. M. , Klein C. B. , Rossman T. G. , Christie N. T. 
Published: February 2007

AbstractNickel is an established human and animal carcinogen, but efforts to demonstrate its mutagenicity in a number of cell types have not been successful. In this report we describe the mutational response to nickel compounds in the G12 cell line, an hprt deficient V79 cell line containing a single copy of the E. coli gpt gene. This cell line has a low spontaneous background, making it suitable for assessment of mutagenic responses to environmental contaminants. When G12 cells were treated with insoluble particles of crystalline nickel sulfide < 5 μm in diameter, a strong, dose‐dependent mutagenic response was observed up to 80 times the spontaneous background. Of 48 mutant gpt(−) clones isolated that were induced by insoluble nickel, all were capable of DNA amplification of the gpt sequences by polymerase chain reaction (PCR). The ability to produce full‐length PCR products is an indication that large deletions of gene sequences have not occurred. When G12 cells were treated with soluble nickel sulfate, the mutational response was not significantly increased over the spontaneous background. This difference in mutagenic response reflects a large difference in the mutagenic potential of soluble and insoluble nickel compounds, which reflects the carcinogenic potential of these forms of nickel. © 1993 Wiley‐Liss, Inc.
Genetic toxicity of malathion: A review
Authors: Flessel Peter , Quintana P. J. E. , Hooper Kim 
Published: February 2007

AbstractMammalian in vivo and in vitro studies of technical or commercial grade malathion and its metabolite malaoxon show a pattern of induction of chromosome damage, as measured by chromosome aberrations, sister chromatid exchanges, and micronuclei. Experiments with purified (<99%) malathion gave weak or negative results. In contrast to the cytogenetic effects of technical grade malathion, responses in gene mutation assays were generally negative except for malaoxon, which was positive for mammalian gene mutations in both tested instances. This result also could be a consequence of chromosome level changes, however. Dermal exposure, a common human route, caused cytogenetic damage in test animals at doses near those producing positive results by intraperitoneal injection. Workers who apply technical grade malathion and other pesticides have higher levels of chromosomal damage than unexposed individuals. Because of the inactivity of malathion mixtures in gene mutation assays, malathion has been thought to be of little genotoxic concern. However, the pattern of chromosome damage in animals and mammalian cells in culture (including human) indicates that technical grade malathion and its components have not been adequately studied for genotoxic potential in humans. © 1993 Wiley‐Liss, Inc.
In vitro and in vivo assays of isopropanol for mutagenicity
Authors: Kapp Robert W. , Marino Dale J. , Gardiner Thomas H. , Masten Lawrence W. , McKee Richard H. , Tyler Tipton R. , Ivett James L. , Young Robert R. 
Published: February 2007

AbstractTo assess the mutagenic potential of isopropanol, an in vitro Chinese hamster ovary (CHO) cell/HGPRT gene mutation assay and a bone marrow micronucleus study in mice were conducted. In the CHO/HGPRT assay, concentration levels ranged from 0.5 to 5.0 mg/ml. No elevated mutant frequencies attributable to treatment were observed in the test under either activated or non‐activated conditions. In the micronucleus assay, mice were injected intraperitoneally (IP) with either 350, 1,173, or 2,500 mg/kg of isopropanol at constant volumes of 10 ml/kg. No increased incidence of micronuclei was observed in bone marrow polychromatic erythrocytes (PCEs) harvested at 24, 48, or 72 hr post‐dosing. In both assays, negative and positive control mutant frequencies were within historical control ranges. These results, in conjunction with previously published data, clearly demonstrate that isopropanol is not a mutagen. © 1993 Wiley‐Liss, Inc.
Use of fluorescence in situ hybridization to detect chromosome‐specific changes in exfoliated human bladder and oral mucosa cells
Authors: Moore Lee E. , Titenko‐Holland Nina , Smith Martyn T. 
Published: February 2007

AbstractChange in chromosome number, numerical aneuploidy, has been consistently linked with cancer development. Since 90% of cancers arise in epithelial tissues, techniques that measure aneuploidy in these tissues would be very useful. Here we describe methods of optimization and suggest use of fluorescent in situ hybridization (FISH) to detect aneuploidy in exfoliated epithelial cells collected from the mouth and bladder. A total of 10,383 urothelial cells and 4,691 buccal cells were scored in order to determine a baseline frequency of aneuploidy in human volunteers using a classical satellite probe for chromosome 9. Protein digestion with pepsin was found to be more efficient at removing the keratinized cell membrane and optimizing probe penetration than acid washes, detergent washes, or hypotonic treatments. A 20 min cellular digestion with 200 μg/ml and a 30 min digestion with 300 μg/ml of pepsin in 0.01 M HCI optimized probe penetration in urothelial and buccal cells, respectively. Average frequencies for 0, 1, 2, 3, and 4 hybridization regions were 10.3, 10.1, 78.4, 1.0, and 0.3% for urothelial cells and 8.8, 9.8, 79.4, 1.3, and 0.3% for buccal cells, respectively. These results are very similar to those previously described in lymphocytes. The urothelial cells of males had a lower frequency of diploid cells and a higher frequency of cells without hybridization regions than females (P < 0.02). No statistically significant variability was found between individuals or sex groups in buccal cells. Our data show that FISH is a useful tool to detect changes in frequency of aneuploidy in exfoliated epithelial cells and has good potential for monitoring human populations exposed to genotoxic agents. © 1993 Wiley‐Liss, Inc.
Spectrum of spontaneous HPRT mutations in TK6 human lymphoblasts
Authors: Giver Cynthia R. , Nelson Stephen L. , Grosovsky Andrew J. 
Published: February 2007

AbstractThe occurrence of deletions, coding sequence alterations, and intronic changes leading to aberrant splicing has been characterized among 33 spontaneous HPRT− mutants in TK6 human lymphoblasts. Deletions detectable by multiplex PCR amplification accounted for 45% (15/33) of the mutant collection. Base substitutions represented 30% (10/33) of the total, and were predominated by changes at G:C base pairs. The remaining mutants were distributed among frameshifts (9%, 3/33), small deletions (6%, 2/33), and compound alterations (9%, 3/33). Five mutants (15%) demonstrated aberrant splicing of the hprt transcript. A cluster of 4 deletion/insertion events was identified in hprt exon 6. A nearly perfect 13 bp duplication differed from the original sequence only by an A:T to G:C transition, which was observed as a unique alteration in another HPRT− mutant. A model involving correction of a mismatch in a secondary structure formed by the duplicated sequence may account for these results. © 1993 Wiley‐Liss, Inc.
Induction of sister chromatid exchange in spleen and bone marrow cells of rats exposed by inhalation to different dose rates of ethylene oxide
Authors: Ong T. , Bi H.‐K. , Xing S. , Stewart J. , Moorman W. 
Published: February 2007

AbstractWe investigated the effects of dose rate on the frequency of sister chromatid exchange (SCE) in bone marrow and spleen cells of rats exposed to ethylene oxide (EtO). Four groups (18/group) of male Fischer 344 rats were exposed to EtO by inhalation. The exposures consisted of 100 ppm for 6 hr/day, 300 ppm for 2 hr/day, 600 ppm for 1 hr/day, and clean air control. All EtO treated rats were given a total exposure dose of 600 ppm‐hr daily, 5 days/week for 3, 6, or 9 months. Six rats per group were sacrificed at each time point, and SCEs were measured in cultured spleen and bone marrow cells. A statistically significant increase was found in SCEs in both bone marrow and spleen cells for all treated groups and at each time point when compared to the control, except at the 3‐month exposure for the middle and high dose‐rate groups in bone marrow cells. In the spleen, the increases in SCEs were similar among the three experimental groups. In bone marrow, the lowest dose rate (100 ppm) resulted in higher SCE frequencies than the medium and high dose‐rate group after 3 and 6 month exposures. The overall frequencies of SCEs in the spleen cells were higher than in the bone marrow cells. The increase in SCE frequencies and decrease in the replicative index in spleen cells were also dependent on the duration of exposure. These results indicate that (1) EtO, by inhalation, can cause SCEs both in spleen and bone marrow cells of Fischer 344 rats, (2) spleen cells are more sensitive to EtO than bone marrow cells, and (3) in bone marrow cells the lowest dose‐rate (longest) exposure causes more SCEs than the highest dose‐rate (shortest) exposures. © 1993 Wiley‐Liss, Inc.
Antimutagenic potency of chlorophyllin in the salmonella assay and its correlation with binding constants of mutagen‐inhibitor complexes
Authors: Dashwood Roderick , Guo Dexin 
Published: February 2007

AbstractChlorophyllin (CHL) is a water‐soluble salt of chlorophyll that exhibits antimutagenic activity in short‐term genotoxicity assays and inhibits carcinogen‐DNA binding in vivo. The antimutagenic potency of CHL was studied against several structurally related heterocyclic amines using the Salmonella assay. The mutagens included 2‐amino‐3‐methylimidazo[4,5,‐f]‐quinoline (IQ) and seven related IQ‐type compounds, and 3‐amino‐1‐methyl‐5H‐pyrido[4,3‐b]indole (Trp‐P‐2) and three additional non‐IQ‐type compounds. No relationship was observed between mutagenic potency (revertants/ng mutagen) and antimutagenic potency when expressed in terms of the CHL dose/plateinhibiting mutagenicity by 50 percent (l50). However, a correlation was observed between mutagenic potency and the mole ratio of CHL to mutagen giving 50% inhibition (MR50), with most mutagens requiring several hundredfold to several thousandfold molar excess of CHL for inhibition. In spectrophotometric studies, CHL formed noncovalent molecular complexes with the heterocyclic amines, with binding constants in the range 3–13 x 103 M−1. Binding constants were inversely correlated with l50 and MR50 values, i.e., with increasing strength of complex formation less CHL/plate and a lower mole ratio of CHL to mutagen was required to inhibit mutagenicity. The results support an inhibitory mechanism in which chlorophylls operate as “interceptor molecules,” interacting with carcinogens and mutagens directly and limiting their bioavailability. © 1993 Wiley‐Liss, Inc.
Test of chiral recognition in the salmonella typhimurium (TA100) mutagenicity of mucochloric acid‐cysteine adducts
Authors: Lalonde Robert T. , Xie Shan , Bu Lin 
Published: February 2007

AbstractA difference in biological response to enantiomers is not an uncommon observation and is, therefore, to be expected in various manifestations of genotoxicity. The bacterial mutagen mucochloric acid (2,3‐dichloro‐5‐hydroxy‐2(5H)‐furanone) has one chiral center, at C‐5, but this mutagen exists in racemic form because of the facile stereoisomerization occurring by the mechanism of ring‐chain tautomerism. Two readily synthesized enantiomeric analogs of mucochloric acid, as well as the racemic form of the two, were prepared from mucochloric acid and (R)‐(+)‐, (S)‐(‐)‐, and (R,S)‐(+/‐)‐cysteine. Using Salmonella typhimurium (TA100), the enantiomeric compounds were assayed together in four dose/response assays along with mucochloric acid, the reference mutagen. In three of the same four assays, the racemic form was also assayed. Neither statistically significant differences in mutagenicity, as determined in slope responses, nor distinctions from the plotted curves were observed among the two enantiomers and their racemic form. Therefore, no enantiospecific interaction between enantiomers and chiral DNA or enzymes involved in repair or replication could be concluded. © 1993 Wiley‐Liss, Inc.
Evidence for excision repair‐dependent and independent processes in ara C‐induced chromosome rearrangements in G1 human lymphocytes
Authors: Kishi Kunikazu , Sekizawa Koichi 
Published: February 2007

Abstract1‐β‐D‐arabinofuranosylcytosine (ara C) enhances the formation of chromosome rearrangements such as translocations or dicentric chromosomes in G1 cells containing DNA lesions. The formation of rearrangements is hypothesized to be the result of inhibition of excision repair. Ara C has also been known to lead to the formation of chromosome rearrangements in G1 cells in the absence of induced DNA lesions. It is not known whether a common mechanism is involved in these two processes. In the present study, we used excision repair‐deficient XP cells to investigate whether excision repair is involved in the formation of chromosome rearrangements in G1 cells which do not contain induced DNA lesions.G0 Lymphocytes from an XP patient were either treated with 4‐nitroquinoline‐1‐oxide (4NQO) or left untreated. Cells were then cultured in the presence of ara C for about 18 h. Aphidicolin (APC), which induces chromosome rearrangements in cells containing 4NQO‐induced DNA lesions, was used for comparison. The resulting frequency of dicentrics and rings (dic & ring) was determined at the first mitoses after culture initiation. In 4NQO‐pretreated XP cells, the frequency of dic & ring was not increased by post‐treatment with ara C or with APC. This result is thought to reflect the absence of excision repair in XP cells. However, normal induction of dic & ring was observed in XP cells not pretreated with 4NQO but treated with ara C.Thus, there seems to be two different processes involved in the induction of G1 rearrangements: excision repair‐dependent and excision repair‐independent. UV‐endonuclease is not involved in excision repair‐independent rearrangements.
Contribution of O6‐alkylguanine and N‐alkylpurines to the formation of sister chromatid exchanges, chromosomal aberrations, and gene mutations: New insights gained from studies of genetically engineered mammalian cell lines
Authors: Kaina Bernd , Fritz Gerhard , Coquerelle Therese 
Published: February 2007

AbstractO6‐methyl‐ and O6‐ethylguanine are the major premutagenic and precarcinogenic lesions induced in DNA by monofunctional alkyiating agents, albeit formed in minor amounts. The involvement of these lesions in SCE and aberration formation is less clear. We have analyzed the contribution of O6‐alkylguanine to SCE and aberration formation, as well as its toxic and point mutation inducing effect in transgenic Chinese hamster ovary (CHO) cell lines that express variable amounts of human O6‐methylguanine‐DNA methyltransferase (MGMT). Cells that overexpress MGMT (or the bacterial Ada protein) gained resistance to the formation of alkylation‐induced SCEs and aberrations, as compared to MGMT deficient cells. A correlation was apparent between the level of protection for SCEs and cell killing, indicating that both phenomena are interrelated. The protective effects were dependent on the level of MGMT expression, the agent used for alkylation, and cell cycle progression. Our data suggest that at least 2 kinds of lesions are responsible for SCE and aberration formation, namely, O6‐alkylguanine and one or various N‐alkylation products. The probability that O6‐methylguanine is converted into cytogenetic effects has been estimated to be about 1:30 for SCEs, and 1:147,000 and 1:22,000 for chromosomal aberrations in the first and second post‐treatment mitosis, respectively. The induction of SCEs and likely also of aberrations by O6‐methylguanine requires two replication cycles and is supposed to involve the formation of secondary DNA lesions. Increased repair of 3‐methyladenine and 7‐methylguanine in CHO cells that overexpress the N‐methylpurine‐DNA glycosylase (MPG) after transfection with the human MPG‐cDNA did not give rise to protection against methylation‐induced SCEs and aberrations, probably because of incomplete excision repair. MPG overexpressing cells reacted even more sensitively to methylating agents, suggesting apurinic sites formed as a result of MPG action to be SCE and aberration‐inducing lesions. © 1993 Wiley‐Liss, Inc.
Predominant induction of kinetochore‐containing micronuclei by extracts of diesel exhaust particulates in cultured human lymphocytes
Authors: Odagiri Youichi , Zhang Jian‐Xin , Uchida Hiroyuki , Kawamura Ken , Adachi Shuichi , Takemoto Kazuo 
Published: February 2007

AbstractThe aneuploidy‐inducing activity of extracts of diesel exhaust particulates from light duty (LD) and heavy duty (HD) engines was investigated in cultured peripheral blood lymphocytes of 8 healthy donors using the cytokinesis‐block micronucleus test with the kinetochore labelling modification. A majority of the subjects tested showed a significant kinetochore‐positive micronucleus induction after treatment with the highest dose (150 μg/ml) of LD extract, although some subjects also showed induction of kinetochore‐negative micronuclei. Only one subject had significantly increased numbers of kinetochore‐positive micronuclei at a dose of 400 μg/ml of HD extract. These results suggest that diesel extract, at least LD extract, possesses the ability to induce whole chromosome loss (aneuploidy) preferentially, although there are also chromosome breaks. © 1994 Wiley‐Liss, Inc.
Absence of formation of benzo[a]pyrene/DNA adducts in the cuttlefish (sepia officinalis, mollusca: Cephalopoda)
Authors: Lee Phillip G. , Lu Lee‐Jane W. , Salazar James J. , Holoubek Viktor 
Published: February 2007

AbstractBenzo[a]pyrene (B[a]P) injected intramuscularly into the base of the arms of cuttlefish was released continuously from the injection site and removed from the organism. Only a portion of the compound accumulated in the body. Twenty‐four hr after its injection, 75% of B[a]P applied in olive oil was removed from the cuttlefish, and 1.2% was found in the body outside the head, the site of injection. If the carcinogen was dissolved in dimethylformamide, the removal of B[a]P was slower, so that only 18% of the injected B[a]P was removed from the organism and 0.36% accumulated in the body outside the head 24 hr after injection. The high level of B[a]P in gills and hemolymph 4 hr after injection and the kinetics of the decrease of its concentration with time indicate that these two organs could be involved in the excretion of B[a]P from the body. The B[a]P/DNA adducts characteristic for vertebrates could not be demonstrated in gills, skin, brain, hepatopancreas, and lymphocytes of the cuttlefish 24 hr after injection of B[a]P. The dose of the carcinogen injected into the cuttlefish was 2—4 times higher than the dose resulting in the formation of a high level of B[a]P/DNA adducts in the vertebrates. A different metabolism of B[a]P in the tissue of cephalopods, compared to vertebrates, could be less favorable to the process leading to malignant transformation and could explain the absence from the literature of reports of tumors in cephalopods. © 1994 Wiley‐Liss, Inc.
Negative dose‐response relationship for radiation‐induced micronuclei in polychromatic erythrocytes of mice
Authors: McFee A. F. , Cook S. B. , Abbott M. G. 
Published: February 2007

AbstractMicronuclei were assessed among the bone marrow PCEs of mice 28 hr after exposures to 1 to 8 Gy of X‐rays and at 6‐hr intervals from 12‐60 hr after exposures to 2 or 6 Gy. At 28 hr, the frequency of micronuclei declined as the exposure level increased from 1 to 8 Gy. The peak proportion of micronucleated PCEs appeared much later following 6 Gy than after 2 Gy exposures, implicating cell cycle delay as the cause of the negative dose‐response relationship.