bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activity of aromatic amines in the eye: w/w+ somatic assay of drosophila melanogaster
Authors: Rodriguez‐Arnaiz Rosario , Aranda Judith Hernández 
Published: February 2007

AbstractAromatic amines represent a category of classical environmental hazards which require biotransformation in order to exert their mutagenic and carcinogenic effects. The mutagenic activity of several aromatic amines was tested by means of the w/w+ somatic assay of Drosophila melanogaster employing a wild‐type strain Leiden Standard (LS) and an insecticide‐resistant stock Hikone‐R (HK‐R). Four monocyclicortho‐anisidine (O‐AN), ortho‐toluidine (O‐TO), 2, 4‐diaminoanisole (2, 4‐DAA) and 4‐nitro‐o‐phenylenediamine (4‐N‐o‐PDA), and one bicyclic‐ 4, 4′‐oxidianiline (4, 4′‐ODA) aromatic amines were tested by chronic exposure. Two separate experiments were run, and concurrent controls were treated with the solvent mixture. Results show that the ortho‐anilines (O‐AN and O‐TO) were active in the assay, while the diamines containing a methoxy (2, 4‐DAA) or a nitro group (4‐N‐o‐PDA) were inactive. The bicyclic aromatic amine, 4, 4′‐ODA, was the most potent. The genotoxic responsiveness of both strains was very similar. © 1994 Wiley‐Liss, Inc.
Determination of genotoxic and other effects in mice following short term repeated‐dose and subchronic inhalation exposure to phosphine
Authors: Barbosa A. , Rosinova E. , Dempsey J. , Bonin A. M. 
Published: February 2007

AbstractPhosphine is an important fumigant in the grain industry and has been reported to be genotoxic in occupationally exposed fumigators. This study reports on the effects of phosphine inhalation exposure at up to, and exceeding, occupational relevant levels in a subchronic (0.3, 1.0 and 4.5 ppm, 13 weeks) and a short term repeated‐dose (5.5 ppm, 2 weeks) study in both sexes of Balb‐c mice. The following end‐points were examined: micronucleus induction in bone marrow, peripheral blood, spleen lymphocytes and skin keratinocytes, muat the hypox‐anthine‐guanine phosphoribosyl transferase locus in lymphocytes, and weight gain and relative organ weights (kidneys, lungs, liver, heart, brain and spleen). After subchronic exposure, there was a highly significant negative linear correlation between proportional weight gain and exposure in both sexes (multiple linear regression, r = −0.56, P < 0.0001), with female mice showing a greater effect. Females also showed an increase in relative organ weights at the highest test dose, in contrast to males where there was a slight decrease. A statistically significant increase in micronucleus frequency was seen in the bone marrow and spleen lymphocytes of both sexes, but only at the highest concentration. The short term repeated‐dose study revealed a slight decrease in weight gain in both sexes, with a greater effect in females.It is concluded that phosphine is weakly genotoxic in both sexes of mice, and has an effect on weight gain. However, the weak genotoxic effect may not be biologically significant as it was seen only in the subchronic study and only at the highest test concentration of 4.5 ± 0.8 ppm (approaching the LD50). Although such exposure conditions are unlikely to be encountered in an occupational environment, caution should continue to be exercised in the use of phosphine until more data become available. © 1994 Wiley‐Liss, Inc.
Centromere analysis of micronuclei induced by 2‐aminoanthraquinone in cultured mouse splenocytes using both a gamma‐satellite DNA probe and anti‐kinetochore antibody
Authors: Afshari Arash J. , McGregor Pamela W. , Allen James W. , Fuscoe James C. 
Published: February 2007

AbstractWe have tested 2‐aminoanthraquinone (2‐AAQ) as a potential aneugen in a cytokinesis‐blocked mouse splenocyte micronucleus (MN) assay. Bi‐nucleated cells (BNC) were evaluated for MN, and the MN were further probed with two indicators of centromere presence: an anti‐kineto‐chore autoantibody and a DNA probe for the mouse gamma‐satellite locus. A dose‐dependent increase in the frequency of BNC with MN was observed. At the highest 2‐AAQ concentration (10 μg/ml), the frequency of BNC containing MN was increased greater than 10‐fold over background. Both centromere‐positive and centromere‐negative MN were significantly increased. At least 62% of MN at all 2‐AAQ doses were positive for the gamma‐satellite DNA probe, while 30–53% were labeled with the anti‐kinetochore antibody. In contrast with the 2‐AAQ results, after treatment with the aneugen demecolcine (positive control), greater than 80% of MN labelled positive with both probes. This discordance in the results with the two probes after 2‐AAQ exposure suggests that the mode of action of this chemical may be as an aneugen by disruption of the kinetochore proteins, as a clastogen with a preferential cleavage site at or near the gamma‐satellite locus, or both. Our results also suggest that the use of either of these probes individually may not be an adequate measure of centromere presence. Nevertheless, positive results for both markers provides strong evidence that 2‐AAQ is aneugenic. © 1994 Wiley‐Liss, Inc.
Mutagenicity of trans, trans‐muconaldehyde and its metabolites in V79 cells
Authors: Chang R. L. , Wong C. Q. , Kline S. A. , Conney A. H. , Goldstein B. D. , Witz G. 
Published: February 2007

AbstractTrans, trans‐Muconaldehyde (MUC), a six‐car‐bon‐diene‐dialdehyde, is a microsomal, hema‐totoxic ring‐opened metabolite of benzene. MUC is metabolized to a variety of compounds which are formed by oxidation and/or reduction of the aldehyde group(s). In the present studies, MUC and its metabolites were examined for mutagenic activity at the hypoxanthine guanine phosphoribosyltransferase (HGPRT) locus in Chinese hamster V79 cells. Mutagenicity was scored by counting 8‐azaguanine‐resistant colonies. Of the 6 compounds tested, MUC and its aldehydic metabolites 6‐hydroxy‐trans, trans 2, 4‐hexadienal and 6‐oxo‐trans, trans‐hexadi‐enoic acid were mutagenic in that order of potency. The other MUC metabolites tested (1, 6‐dihydroxy‐trans, trans‐2, 4‐hexadiene, trans, trans‐muconic acid, and 6‐hydroxy‐trans, trans‐2, 4‐hexadienoic acid) had little or no activity in this system. The order of mutagenic activity of MUC and its aldehydic metabolites correlates with their reactivity towards glutathione, suggesting that alkylating potential is important in the genotoxicity of these compounds. © 1994 Wiley‐Liss, Inc.
Rapid DNA degradation in primary rat hepatocytes treated with diverse cytotoxic chemicals: Analysis by pulsed field gel electrophoresis and implications for alkaline elution assays
Authors: Elia Michael C. , Storer Richard D. , McKelvey Troy W. , Kraynak Andrew R. , Barnum John E. , Harmon Lori S. , Deluca John G. , Nichols Warren W. 
Published: February 2007

AbstractThe use of genetic toxicology tests for hazard identification is complicated by the fact that some in vitro tests using cultured mammalian cells are subject to potential artifacts that can make it difficult to distinguish between direct, chemically‐induced genotoxicity, and DNA damage that occurs secondary to chemically‐induced cytotoxicity (e.g., mediated by endogenous nucleases). Recently, we demonstrated that cytotoxicity‐induced DNA double strand breaks (dsb) can produce artifacts in the in vitro alkaline elution/rat hepatocyte assay [Elia et al., 1993]. To explore this further, we used pulsed field gel/DNA dsb assays to characterize the relationship between chemically‐induced cytotoxicity and the degradation of genomic DNA to high molecular weight fragments. Two sets of compounds were tested: 17 cytotoxic agents judged to be neither genotoxic nor carcinogenic, and 10 known genotoxic carcinogens. We found a close correlation between chemically‐induced cytotoxicity and the rapid degradation of DNA to high molecular weight, double‐stranded fragments. In contrast, the classic genotoxic chemicals tested generally did not trigger DNA dsb fragmentation at doses that were genotoxic but not immediately cytotoxic. These data indicate that pulsed field gel/DNA dsb assays can be used with in vitro genetic toxicology assays to help distinguish between genotoxic and cytotoxic mechanisms of DNA damage. © 1994 Wiley‐Liss, Inc.
Etoposide (VP‐16) is a potent inducer of micronuclei in male rat meiosis: Spermatid micronucleus test and DNA flow cytometry after etoposide treatment
Authors: Lähdetie J. , Keiski A. , Suutari A. , Toppari J. 
Published: February 2007

AbstractThe genotoxic and cytotoxic effects of etoposide (VP‐16), a topoisomerase II inhibitor, on male rat spermatogenic cells were studied by analysing induction of micronuclei during meiosis. Micronuclei (MN) were scored in early spermatids offer different time intervals corresponding to exposure of different stages of meiotic prophase. Etoposide had a strong effect on diplotene‐diakinesis I cells harvested 1 day after exposure, and a significant effect also on late pachytene cells harvested 3 days after exposure. The effect at 18 days corresponding to exposure of preleptotene stage of meiosis (S‐phase) was weaker but also statistically significant. Adriamycin was used as a positive control in this study. The results indicate a different mechanism of action of etoposide compared with adriamycin and other chemicals studied previously with the spermatid micronucleus test.DMA flow cytometry was carried out to assess cytotoxic damage at the same time intervals (1, 3, and 18 days after treatment) at stages I and VII of the seminiferous epithelial cycle allowing a study of cytotoxicity to different spermatogenic cell stages. Damage of differentiating sper‐matogonia was observed by a decrease in the cell numbers of the 2C peak 1 and 3 days after treatment and by a reduction of the number of 4C cells (primary spermatocytes) 18 d after etoposide treatment. Adriamycin also killed differentiating spermatogonia. Since the cell population which showed a high induction of MN by etoposide was not reduced in number, the genotoxic effect is remarkable. We conclude that etoposide is a potent inducer of genotoxicity and patients treated with this agent during cancer chemotherapy are at a risk of genetic damage. © 1994 Wiley‐Liss, Inc.
QSAR models for both mutagenic potency and activity: Application to nitroarenes and aromatic amines
Authors: Benigni R. , Andreoli C. , Giuliani A. 
Published: February 2007

AbstractWe studied the molecular determinants that discriminate between mutagenic and inactive compounds for: a) aromatic and heteroaromatic amines; b) nitroarenes. Mutagenic activity (data from literature) had been previously assessed in Salmonella typhimurium and Escherichia coli (SOS repair). The Quantitative Structure‐Activity Relationships (QSAR) found were compared with those obtained in the laboratory of Professor C. Hansch for the mutagenic potency of the same compounds. It appears that there is a dramatic difference between the QSARs for potency, and those for yes/no activity: hydrophobicity played a major role in determining the potency of the active compounds, whereas mainly electronic factors differentiated the actives from the inactives. The electronic factors were those expected on the basis of the hypothesized metabolic pathways of the chemicals. Our interpretation is that the electronic factors (together with size/shape, possibly) determine the minimum requirement for the chemicals to be metabolized, whereas the hydrophobicity determines the extent of activity of chemicals that can be metabolized (actives). Moreover, the different QSARs found for the Salmonella strains TA98 and TA100 were discussed in the light of recent progress in the understanding of the molecular mechanisms of mutagenicity in these organisms. It is concluded that the nonlinear relationship observed for these chemicals between the two types of QSAR should be taken into account both when planning QSAR studies, and when using mutagenicity data for risk assessment. © 1994 Wiley‐Liss, Inc.
Metabolic activation of carcinogenic aromatic amines by fish exposed to environmental pollutants
Authors: Rodríguez‐Ariza A. , Diaz‐Méndez F. M. , Navas J. I. , Pueyo C. , López‐Barea J. 
Published: February 2007

AbstractActivation of arylamines to mutagenic metabolites by hepatic S9 fractions has been evaluated as a biomaker of fish exposure to pollutants, using gilthead seabream (Sparus aurata), a valuable fish species from the Spanish South Atlantic littoral, as model organism. To obtain maximal sensitivity to the mutagenic action of aromatic amines, a strain of Salmonella typhimurium overproducing O‐acetyltransferase was used. Fish were treated with Aroclor 1254, pesticides (malathion and dieldrin), or cop‐per(ll), and compared to Aroclor 1254–treated rats. The promutagen activation capabilities of the S9 fractions were further characterized by studying the effect of two monooxygenase inhibitors, α‐naphthoflavone, a well known inhibitor of aromatic hydrocarbon‐inducible forms of cytochrome P450, and methimazole, a substrate for the flavin monooxygenase (FMO) system. This study shows that 2–aminoanthracene (2–AA) and 2–acetylaminofluorene (AAF) activation by gilthead liver is enhanced by treatment of fish with different xenobiotics. The catalyst responsible for this enhanced activation appears to be different for each promutagen and, at least for 2–AA, dependent on the type of xenobiotic. The data presented indicate further that treatment of gilthead with some compounds, such as malathion and dieldrin, enhances the activation of aromatic amines in liver, without inducing ethoxyresorufin‐O‐deethylase activity. The use of acetyltransferase‐overproducing bacteria appears to be a useful tool in the study of aryl‐amine activation by fish liver, where biotransformation capability is lower than in mammals. © 1995 Wiley‐Liss, Inc.
Metabolic reduction of novel 3,4–dichloro‐5‐nitrofurans in Salmonella typhimurium
Authors: Hatcher James F. , Yamamoto Katsumi , Ichikawa Masataka , Bryan George T. , Swaminathan Santhanam 
Published: February 2007

AbstractTo gain insight on biochemical mechanisms of mutagenesis and carcinogenesis by the experimental carcinogens, 5–nitrofurans, a new series of 3,4‐dichloro‐5‐nitrofurans, comprised of 3,4‐dichloro‐5‐nitro‐2‐acetylfuran (I), 3,4‐dichloro‐5‐nitro‐2‐bromoacetylfuran (II), methyl 3,4‐dichloro‐5‐nitro‐2‐furoate (III), were synthesized and tested for their activation to mutagenic forms in the standard plate assay using Salmonella typhimurium TA98, TA100, and TA100NR, a derivative of TA100 deficient in nitroreductase activity. The mutagenic responses in TA98 were 2‐ to 6‐fold lower compared to TA100. Furthermore, I and II were less active in TA100NR, while compound Ill was about four times more mutagenic in TA100NR compared to the parent strain TA100. Incubation of Ill with NADPH and bacterial lysates showed that the extent of reduction was greater in TA100 compared to TA100NR. High‐pressure liquid chromatography analysis of the ethyl acetate extract obtained from incubation of Ill with lysates of TA100 revealed the formation of four metabolites with retention times of about 4.0, 5.7, 10.0, and 14.3 minutes. The spectroscopic and chromatographic properties of the components with retention times of 10.0 and 14.3 minutes were identical to two derivatives obtained by chemical reduction of Ill, and thus represent nitroreduction products. These derivatives have been identified as cisand frans‐oxime isomers of methyl 3,4‐dichloro‐2‐furoate, based on spectroscopic analyses. These oximes were not mutagenic for TA100. Furthermore, Ill was more mutagenic under anaerobic conditions, suggesting that secondary superoxide or nitroanion free radicals generated from nitroreduction are not responsible for the mutagenicity of Ill. In addition, the higher mutagenic response in TA100NR, and the lack of mutagenic activities of the amino and the oxime analogs of Ill suggest that the mutagenic activation of Ill might be due to the nitroso intermediate or involve mechanisms other than nitroreduction. © 1995 Wiley‐Liss, Inc.
Mutagenicity testing of nine herbicides and pesticides currently used in agriculture
Authors: Kale Purushottam G. , Petty Bobby T. , Walker Sophia , Ford Jeffery B. , Dehkordi Nahid , Tarasia Srikumar , Tasie Bertram O. , Kale Ranjini , Sohni Youvraj R. 
Published: February 2007

AbstractNine herbicides and pesticides were tested for their mutagenicity using the Drosophila sex‐linked recessive lethal mutation assay. These are Ambush, Treflan, Blazer, Roundup, 2,4‐D Amine, Crossbow, Galecron, Pramitol, and Pondmaster. All of these are in wide use at present. Unlike adult feeding and injection assays, the larvae were allowed to grow in medium with the test chemical, thereby providing long and chronic exposure to the sensitive and dividing diploid cells, i.e., mitotically active spermatogonia and sensitive spermatocytes. All chemicals induced significant numbers of mutations in at least one of the cell types tested. Some of these compounds were found to be negative in earlier studies. An explanation for the difference in results is provided. It is probable that different germ cell stages and treatment regimens are suitable for different types of chemicals. Larval treatment may still be valuable and can complement adult treatment in environmental mutagen testing. © 1995 Wiley‐Liss, Inc.
Increased frequency of mutations at A:T base pairs in the bone marrow of B6C3F1 lacl transgenic mice exposed to 1, 3‐butadiene
Authors: Recio Leslie , Meyer Kathy G. 
Published: February 2007

AbstractWe have examined the spectra of mutations in a collection of 74 lacl mutants isolated from the bone marrow of B6C3F1 lacl transgenic mice exposed to 1, 250 ppm 1, 3‐butadiene (BD). Of the 49 independent mutations analyzed in the present study, 30 of 49 (61%) were point mutations at G:C base pairs, and 10 of 49 (20%) were point mutations at A:T base pairs. The remaining mutations consisted of small deletions and insertions and a single tandem change. An analysis of variance (ANOVA) on the frequency of specific mutations observed in each animal in this mutagenicity experiment [present study; also Sisk SC et al. (1994): Carcinogenesis 15:471–477] indicated that the frequency of point mutations at A:T base pairs is significantlantly greater (P < 0.05) in BD‐exposed mice than in the air controls. In addition, there was a decrease (P < 0.05; Fisher's exact test) in the frequency of G:C→A:T transitions at 5′‐CpG‐3′ sites in BD‐exposed mice (27%) relative to air controls (51%). These data indicate that subchronic exposures to BD induces an increased frequency of in vivo mutation at A:T base pairs in the bone marrow of B6C3F1 lacl transgenic mice. © 1995 Wiley‐Liss, Inc.
In vivo DNA adduct formation by bisphenol A
Authors: Atkinson Alfonza , Roy Deodutta 
Published: February 2007

AbstractWe have previously shown that bisphenol A (BPA) is oxidized to bisphenol‐o‐quinone in the presence of activation system and that the chemical reaction of DNA or deoxyguanosine 3′‐monophosphate (dGMP) with bisphenol‐o‐quinone produces adducts. In the present study, using the 32P‐postlabeling technique, we have investigated the in vivo DNA adduct formation by BPA by examining covalent modification in DNA. Administration of a single or multiple dose of 200 mg/kg of BPA to CD1 male rats produced two major and several minor adducts in liver DNA. The two major in vivo adducts matched the adduct profile of DNA or dGMP‐bis‐phenol‐o‐quinone. To determine how BPA may be converted to DNA‐binding metabolites, adducts were examined after incubation of DNA with BPA in the presence of a microsomal activation system. The in vitro incubation of BPA with DNA in the presence of a microsomal activation system revealed one major adduct and several minor adducts. The formation of adducts in DNA by BPA in the presence of a microsomal activation system was drastically decreased by known inhibitors of cytochrome P450. Adduct formation in DNA when cumene hydroperoxide or NADPH was used as a cofactor showed adducts with similar chromatographic mobilities as those from the reaction of dGMP‐bisphenol‐o‐quinone. These data demonstrate that BPA is capable of binding covalently to DNA. DNA binding can be inhibited by the inhibitors of cytochrome P450. One of the DNA‐binding metabolite(s) both in vitro and in vivo may be bisphenol‐o‐quinone. Covalent modifications in DNA by in vivo exposure of BPA may be a factor in the induction of hepatotoxicity. © 1995 Wiley‐Liss, Inc.
Reconsideration of the genetic risk assessment for ethylene oxide exposures
Authors: Preston R. Julian , Fennell Timothy R. , Leber A. Philip , Sielken Robert L. , Swenberg James A. 
Published: February 2007

AbstractThe US Environmental Protection Agency (EPA) developed a genetic risk assessment model for exposures to ethylene oxide utilizing data on the induction of reciprocal translocations in male germ cells [Rhomberg et al. 1990]. This particular approach served as a reasonable initial attempt, albeit somewhat limited with regard to endpoint and only partially attentive to the mechanisms of induction of genetic alterations and the behavior of chromosomes during meiosis. The present paper discusses the scientific basis for a reassessment of the EPA model, providing data and hypotheses related to effective dose to the target cells and shape of the dose‐response relationship at low doses, and dose rates. While the present genetic risk assessment approach is discussed in terms of ethylene oxide, it would be applicable to most mutagenic chemicals. The outcome of the discussion is that the genetic risk for exposed males from reciprocal translocation induction will be negligible at low doses since the dose‐response curve is likely to be a function of the square of the dose. In addition, the proportion of genetically unbalanced live born offspring in humans arising from reciprocal translocation carriers is less than 10% of the frequency formed through meiotic segregation and fertilization for such carriers. Simply from a consideration of mechanism—namely, the very high probability of DNA repair prior to the next S‐phase for a resting oocyte—it would be predicted that there would be a very low to negligible frequency of translocations in female germ cells from ethylene oxide exposure. It is further stressed that additional components of a genetic risk model require a consideration of all germ cell stages in the male, and the inclusion of calculations for point and deletion mutations. Some indications of likely response are presented with these points in mind. © 1995 Wiley‐Liss, Inc.
Aflatoxin b1, 2‐aminoanthracene, and 7,12‐dimethylbenz[a]anthracene‐induced frameshift mutations in human APRT
Authors: Zhu Yuan , Bye Steven , Stambrook Peter J. , Tischfield Jay A. 
Published: February 2007

AbstractAflatoxin BI, 2‐aminoanthracene, and 7,12‐dimethylbenz[a]anthracene have been implicated in the etiology of human cancers. In this study, we demonstrate that these three chemicals can be activated by rat liver homogenate S9 coupled with NADPH coenzymes to produce a dose‐dependent increase in the frequency of APRT reversion in the APRT‐deficient human cell line HTD114. HTD114 contains single nucleotide insertions at different positions in each APRT allele and the spontaneous reversion frequency is < 10−8. However, the highest reversion frequency induced by these chemicals is 1.2–2.0 × 10−5, at least a 103‐fold increase over the frequency of spontaneous reversion. Reversion of either mutant allele was observed to be a consequence of a frame‐restoring loss of a single nucleotide, which indicates that these three chemicals can function as frameshift mutagens in human cells. © 1995 Wiley‐Liss, Inc.