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PubMed1986

Evaluation of eugenol for mutagenicity by the mouse micronucleus test.

Mutagenicity of eugenol (2-methoxy-4-allylphenol) was evaluated by an in vivo eukaryotic assay in mice. A 50% lethal dose (LD50) for intraperitoneal (IP) delivery of eugenol was found to be 1109.6 mg/kg body weight (7.5% eugenol-in-saline). Oral (PO) delivery via stainless-steel, esophageal cannulation was not lethal to 14,794 mg/kg body weight (100%) eugenol. Based upon recommended procedure, 80 and 25% LD50 doses were administered IP in 250 microliter volumes. Undiluted eugenol was administered PO in 100 microliter volumes. Delivery of eugenol by both regimes to male mice induced anaphase mutations in polychromatic erythrocytes as measured by the bone marrow micronucleus test. IP delivery of both doses induced the formation of micronuclei to significant levels (P less than 0.001) compared to saline controls. PO delivery of eugenol induced a much reduced frequency of micronuclei when compared to the IP route. However, a significant increase in micronuclei was evident when this test population was compared to its control group (P less than 0.003). These results suggest that eugenol presents some mutagenic capacity in eukaryotic hosts and should be evaluated for further toxicological effects.

Administration, Oral↗
PubMedDate not supplied

Detection of the cytogenetic effect of inhaled aerosols by the micronucleus test.

The induction of micronuclei in mice exposed to aerosols of the following 6 genotoxic chemicals by inhalation was examined: cyclophosphamide (CP), methyl methanesulfonate (MMS), mitomycin C (MMC), dimethylnitrosamine (DMN), ethylcarbamate and colchicine. Exposure of mice to CP aerosols at a theoretical concentration of 2426 mg/m3 for 29, 81 and 139 min induced 0.6, 1.0 and 2.3% micronucleated polychromatic erythrocytes (MNPCEs) in bone marrow 24 h after the termination of exposure. The other chemicals except for DMN showed a similar exposure-response relationship following in vivo exposures to their aerosols. The results obtained in this study suggest that the cytogenetic effect of inhaled aerosols can be detected by the micronucleus test, and the method described in the present report is useful as a rapid in vivo test for atmospheric aerosols.

Aerosols↗
PubMed1999

[Application of in vitro micronucleus tests using L5178Y mouse lymphoma and WTK1 human lymphoblastoid cell lines to antimutagenicity assay].

In the in vitro micronucleus (MN) tests using L5178Y mouse lymphoma and WTK1 human lymphoblastoid cell lines, 2 well-known antimutagens, Vitamin C (Vc) and the sodium and copper salt of chlorophyll (Chl), were tested to evaluate their ability to inhibit the mutagenicity of mitomycin C(MMC). Three kinds of treatment were designed, namely the simultaneous treatment with Vc (or Chl) and MMC, the use of Vc (or Chl) before the use of MMC, and the use of Vc (or Chl) after the use of MMC. The results showed that Vc and Chl had no MN inductivity in the two cell lines; that simultaneous treatment with Vc and MMC and pre-treatment with Vc effectively reduced MMC-induced MN cell frequencies; and that simultaneous treatment and pre-treatment with Chl at dose level of 0.12 mg/ml, significantly reduced MMC-induced MN cell frequencies of L5178Y cells. The antimutagenic effect of Chl on WTK1 cells was found in simultaneous and pre-treatment at dose levels of 0.12 and 0.06 mg/ml.

Animals↗
PubMed1996

Genotoxicity of selected pesticides in the mouse bone-marrow micronucleus test and in the sister-chromatid exchange test with human lymphocytes in vitro.

Selected pesticides (aldicarb, 1,3-dichloropropene, methidathion, parathion, triadimefon, vinclozolin) were tested for their clastogenic and aneugenic activities in the mouse bone-marrow micronucleus (MN) test in vivo and for their sister-chromatid exchange-inducing activities in human lymphocytes in vitro in the presence and absence of an exogenous metabolizing system from rat-liver S9. 1,3-Dichloropropene significantly increased the frequencies of micronucleated polychromatic erythrocytes (PCE) in bone-marrow cells of female mice from 3.3 MN/1000 PCE to 15.3 MN/1000 PCE (187 mg per kg body weight). 1,3-Dichloropropene (100 microM) induced 16.0 SCE/metaphase after 24 h of incubation as compared with the basal rate of 11.2 SCE/metaphase (-S9) and of 15.4 SCE/metaphase as compared with 10.5 SCE/metaphase of the control (+S9). These values were statistically significantly different from each other. The other pesticides tested did neither increase the rate of micronuclei significantly in polychromatic erythrocytes in male nor in female animals. Aldicarb and methidathion induced a significant increase in SCEs in human lymphocytes in vitro only without the metabolic activating system: aldicarb, 5 microM, 24 h incubation: 15.5 SCE/metaphase; control: 12.6 SCE/metaphase; methidathion, 100 microM, 24 h incubation: 15.8 SCE/metaphase, control: 11.1 SCE/metaphase. Parathion, triadimefon and vinclozolin did not have any SCE-inducing effects.

Adult↗
PubMed2000

The importance of lymphocyte micronucleus test for the detection of genotoxic events.

DNA lesion induced by xenobiotics is implemented either through direct interaction of the chemical with DNA through covalent binding or intercalation, or indirectly, through interference with the processes of DNA replication and repair, interaction with proteins, nuclease release from lysosomes etc. The present study emphasizes that the assessment of genotoxic risk arising from xenogenous substances demands the development of sensitive, direct and more exact genotoxic testing methods. One of them is micronucleus assay. It is a simple and quick test for investigating of cytogenic damage with the advantage that exposure to both clastogens and aneugens may be detected.

Animals↗
PubMed1984

Density-gradient enrichment of newly-formed mouse erythrocytes. Application to the micronucleus test.

To facilitate scoring micronuclei in peripheral blood erythrocytes, we have developed a centrifugation method to concentrate polychromatic and newly-formed normochromatic erythrocytes from microliter quantities of blood in a Percoll density gradient. Erythrocytes were separated into two discrete bands in a continuous gradient generated in situ in a microhematocrit capillary tube. The upper band contained white blood cells and a mixture of polychromatic and young normochromatic erythrocytes with a density of 1.080-1.082 g/ml. More than 75% of the polychromatic erythrocytes in samples of normal blood were recovered in the upper band. Older normochromatic erythrocytes migrated to the lower band. The frequency of polychromatic erythrocytes was increased from approximately 2% in whole blood to 60-80% in the upper band. After clastogen treatments, the elevated frequencies of micronuclei in the upper band polychromatic erythrocytes were similar to those in unfractionated blood. The frequencies of micronucleated normochromatic erythrocytes in the upper band were higher than those in whole blood at 48, 72 and 96 h after clastogen treatment, consistent with the expectation that the low-density normochromatic cells are newly derived from polychromatic erythrocytes. This density-gradient centrifugation technique enhances the efficiency of scoring micronuclei in the acute peripheral blood micronucleus test.

Animals↗
PubMed1982

Application of the micronucleus test to exfoliated cells of high cancer risk groups: tobacco chewers.

Powdered tobacco (Khaini tobacco) with the addition of lime is commonly used by the residents of Bihar, India. The tobacco/lime mixture is usually placed on the inner side of the lower lip within the gingivolabial groove. About 42% of the users keep it at the front, the rest move the tobacco towards the left or right side within the oral cavity. Carcinomas (so-called "Khaini cancers") develop mainly at the site where the tobacco is in close contact with the mucosa. Scrapings of the mucosa were taken at sites where the tobacco is kept, then smears were prepared, stained with the Feulgen reaction and fast green, and screened for micronuclei which indicate the occurrence of chromosome aberrations in the dividing cell population of the basal layer. An elevated frequency of cells with micronuclei was found in the oral mucosa of all 27 examined Khaini tobacco users (Munda and Santal tribes) compared to that of non-chewers of similar ethnic background and dietary habits. The induction of micronucleated mucosa cells seems to be due to genotoxic agents released from the tobacco/lime mixture. In vitro, an aqueous extract of the Khaini tobacco elicits chromosome aberrations and micronuclei in cultured human fibroblasts and Chinese hamster ovary (CHO) cells. No chromosome-damaging effect was observed following the application of lime or calcium hydroxide (Ca(OH)2). The micronucleus test on exfoliated cells can provide evidence of carcinogen exposure in the tissue from which cancers will develop. This approach combines all the advantages of in vitro short-term tests for genotoxic and carcinogenic agents with those of using an intact organism with all its defence mechanisms.

Adolescent↗
PubMed1991

Mouse micronucleus tests with known and suspect spindle poisons: results from two laboratories.

Micronucleus assays were carried out independently in two laboratories with 10 chemicals selected for aneuploidy studies in a coordinated project supported by the CEC. All chemicals were distributed from a single batch by the project coordinator. Male and female mice were treated by single i.p. injections, bone marrow was sampled 6, 24 and 48 h after treatment. Polychromatic and normochromatic erythrocytes were evaluated for the presence of micronuclei after May--Grünwald/Giemsa or Wright staining. The results from both laboratories are in close agreement even though different stocks of mice and different sample sizes were employed in the two laboratories. Only three of the 10 compounds induced micronuclei in mouse erythrocytes: colchicine, hydroquinone and vinblastine. The other seven chemicals gave negative results: econazole, chloralhydrate, diazepam, thiabendazole, cadmium chloride, thimerosal and pyrimethamine. The negative results for econazole and chloralhydrate were unexpected in light of the fact that these two chemicals were previously shown to increase the mitotic index and to induce c-mitotic effects in mouse bone marrow cells. The need for further investigations of these compounds by chromosome counting in second post-treatment metaphases is emphasized to determine their ability to induce aneuploidy.

Aneuploidy↗
PubMed2002

Further evaluation of an in vivo micronucleus test on rat and mouse skin: results with five skin carcinogens.

In a previous paper, we presented a practical in vivo micronucleus (MN) test that used rat skin as the target organ. To evaluate the test, as well as to determine the reproducibility and applicability of the method to mice, we used it to test the effect of five skin carcinogens (N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), 4-nitroquinoline 1-oxide (4NQO), 7,12-dimethylbenz[a]anthracene (DMBA), and benzo[a]pyrene (B[a]P)) on rat and mouse skin. All five compounds significantly and dose-dependently increased the MN frequencies in the basal cells of the chemical-treated skin. These results indicated the reproducibility of the test results and also the applicability of the test to mice as well as rats.

4-Nitroquinoline-1-oxide↗
PubMed1985

Mutagenicity of drinking water detected by the Tradescantia micronucleus test.

Spring Lake reservoir of Macomb, Illinois, is a typical model of the drinking water supply of some midwestern towns of the United States. Water samples collected periodically in 1980 and 1981 from this lake were tested for mutagenicity using the Tradescantia micronucleus (Trad-MCN) test, a highly sensitive mutagen-detecting bioassay. Water samples from 1981 were also analyzed chemically. The micronucleus (MCN) frequency peaked (12-14 MCN/100 tetrads) in mid-July in both years, as compared with the average frequency (5 MCN/100 tetrads) of the base-line control that was maintained in nutrient solution (prepared with distilled water and pure chemicals). Drinking water from the tap was tested in parallel with lake water, and its mutagenicity tended to fluctuate with the mutagenicity of the lake water.

Cell Nucleus↗
PubMed2005

Micronucleus test in mussels Perna perna fed with the toxic dinoflagellate Prorocentrum lima.

Micronucleus (MN) and other nuclear abnormalities have been measured in the hemocytes of mussels Perna perna to verify whether feeding mussels with different concentrations of Prorocentrum lima results in accumulation of levels of okadaic acid (OA) capable of inducing genotoxic effects at the chromosome level, as evidenced by micronuclei and nuclear abnormalities. Four groups of 12 mussels housed individually in aquaria containing filtered seawater were fed with different concentrations of P. lima. Another group collected directly from the production area served as outdoor control. A significantly higher frequency of MN and nuclear lesions was observed in hemocytes from the groups fed P. lima.

Animals↗
PubMed1996

The centromere as a target for the induction of chromosome damage in resting and proliferating mammalian cells: assessment of mitomycin C-induced genetic damage at kinetochores and centromeres by a micronucleus test in mouse splenocytes.

The cytokinesis-block micronucleus assay (MN) on murine splenocytes was used for the estimation of chromosome damage in a resting cell population in vivo that can be induced to proliferate in vitro. Mitomycin C at different doses (10(-8), 6 x 10(-8), 10(-7), 6 x 10(-7) and 10(-6)M) was used to induce cytogenetic damage in resting and cycling splenocytes. Antikinetochore antibodies (CREST) and two-colour fluorescence in situ hybridization (FISH) with minor and major satellite DNA were applied. These approaches allowed the detailed characterization of the mechanisms by which MN originates, since it was possible to identify breaks induced in pericentric heterochromatic (resulting in MN containing the major but not the minor satellite DNA) or detachment/disruption of kinetochore (resulting in different frequencies of MN containing kinetochore or both probes). Based on the evidence that resting and cycling mouse splenocytes are characterized by different spatial distribution of centromeric regions, the hypothesis was tested that the damage induced by mutagens at centromeres is influenced by the phase of the cell cycle in which the cells are treated. Data presented here show that resting and cycling splenocytes are both sensitive to mitomycin C action, and indicate that this compound has an aneugenic potential, besides its strong clastogenic activity. In particular, results obtained after CREST and FISH characterization of MN differed when cells were treated during proliferation, suggesting a disruption/detachment of kinetochores induced by mitomycin C at this cell stage. Furthermore, under the same treatment condition the proportion of MN containing the major satellite DNA only was greater than expected on the basis of random breakage at this site. Treatment of resting cells produced aneugenic damage, but without evidence of disruption/detachment of kinetochores or preferential breakage at the centromere. These results indicate that the amount and type of chromosome damage induced by mitomycin C in mouse splenocytes differ in relation to the proliferative status of treated cells.

Animals↗
PubMed2002

A protocol for the in vitro micronucleus test. I. Contributions to the development of a protocol suitable for regulatory submissions from an examination of 16 chemicals with different mechanisms of action and different levels of activity.

The in vitro micronucleus (IVM) test is currently used as a screen during the early stages of pharmaceutical development to identify chemicals likely to produce positive outcomes in the in vitro chromosome aberration assay. For several reasons, the assay is being considered as an alternative to the aberration assay, but the current screening protocols are not rigorous enough to fully satisfy concerns about genotoxic safety. This manuscript describes the investigation of several protocol parameters to assist with the development of a regulatory guideline for the IVM test. The parameters investigated are: the effect of cytochalasin B on the outcome of the assay when conducted with continually growing cell lines; the need for an extended exposure in the absence of metabolic activation; and the number of cells to be counted for a valid assay. In addition, two statistical procedures for the analysis of data from the test are described. The results of the investigation indicate that cytochalasin B does not effect the outcome of the test, that the extended exposure treatment is not necessary, that counting 2000 cells is preferable to counting 1000, and that the data can be appropriately analyzed using a trend test.

Animals↗
PubMed1998

In vitro mutagenicity and genotoxicity study of a number of short-chain chlorinated hydrocarbons using the micronucleus test and the alkaline single cell gel electrophoresis technique (Comet assay) in human lymphocytes: a structure-activity relationship (QSAR) analysis of the genotoxic and cytotoxic potential.

Using the micronucleus (MN) test and the alkaline single cell gel electrophoresis (Comet) assay, potential mutagenicity (MN formation), genotoxicity (DNA breakage capacity) and cytotoxicity (cell proliferation reduction) of five chlorinated hydrocarbons (carbon tetrachloride, hexachloroethane, 1,2-dichloroethane, 1-chlorohexane and 2,3-dichlorobutane) have been evaluated in isolated human lymphocytes. With the MN test a low but statistically significant mutagenic activity was detected for all tested substances (except 2,3-dichlorobutane) with one out of the two donors and in the presence or absence of an exogenous metabolic activation system (S9 mix). However, at the concentration ranges tested none of the positive compounds induced a clear dose-dependent mutagenic effect. The Comet assay detected a strong DNA damaging effect for 1-chlorohexane, 2,3-dichlorobutane and 1,2-dichloroethane, but not for carbon tetrachloride and hexachloroethane. The influence of metabolism on the genotoxic activity of the chemicals was more clear in the Comet assay than in the MN test. The experimental genotoxicity and cytotoxicity data obtained in this study, together with data on five more related chemicals previously investigated, and their physico-chemical descriptors or electronic parameters have been used for QSAR analysis. The QSAR analysis high-lighted that the toxicity of the tested compounds was influenced by different parameters, like lipophilicity (logP), electron donor ability (charge) and longest carbon-chlorine (LBC-Cl) bond length. In addition, steric parameters, like molar refractivity (MR) and LBC-Cl, and electronic parameters, like ELUMO (energy of the lowest unoccupied molecular orbital, indicating electrophilicity), were predominant factors discriminating genotoxins from non-genotoxins in the presence but not in the absence of S9 mix. Although a limited number of compounds have been examined and cytotoxicity and genotoxicity were identified in two different bioassay tests, the data set was obtained by the same experimentor, strengthening the reliability of the QSAR.

Adult↗
PubMed2005

A study on the investigation of cadmium chloride genotoxicity in rat bone marrow using micronucleus test and chromosome aberration analysis.

In this study, we investigated the genotoxic and cytotoxic potential of cadmium chloride (CdCl2) in Wistar rat tibia bone marrow cells, using the structural chromosomal aberration (SCA) and micronucleus (MN) test systems. CdCl2 was administered to adult female rats as repeated i.p. doses of 0.5 mg/kg b.w. for 18 week (four months) at 48 h intervals. Mitomycin C (MMC) was used as a positive control (2 mg/kg b.w.). This study shows that cadmium chloride treatment significantly induced the frequency of micronucleus in polychromatic erythrocytes in tibia bone marrow. This increase in micronucleus frequency shows that cadmium has a genotoxic effect on bone marrow at this level. Also, in order to determine cytotoxicity in bone marrow, the ratio of polychromatic erythrocytes to normochromatic erythrocytes was calculated in bone marrow. The results of this study indicate that CdCl2 decreased this ratio. The decrease of this ratio in bone marrow shows CdCl2 may lead to cytotoxicity. We have reported that 0.5 mg/kg-level chronic exposure to cadmium (Cd) has an injurious effect on bone marrow. Our findings indicate that CdCl2 has a cytotoxic and genotoxic effect on rat bone marrow at chronic exposure.

Analysis of Variance↗
PubMed2000

Comet assay and cytokinesis-blocked micronucleus test for monitoring the genotoxic effects of X-ray radiation in humans.

OBJECTIVE: To assess the genotoxic effects of X-ray radiation on human populations. METHODS: The single cell gel electrophoresis (SCGE) and cytokinesis-blocked micronucleus (CBMN) test were applied as biological dosimeters to detect DNA damage and abnormalities in human peripheral lymphocytes of subpopulation exposed to X-ray radiation. The subjects were divided into four groups: 12 radiation-patients; 13 intervention-radiation-therapy doctors; 32 radiation-diagnostians; 28 controls. RESULTS: The average comet lengths of the four groups were 128.17 +/- 4.49 microns, 88.09 +/- 5.39 microns, 72.68 +/- 2.57 microns and 32.87 +/- 0.57 microns, respectively. The difference in average comet length between any two groups was highly significant (P < 0.01). The average micronucleated cell (MNC) rates (@1000) of the four groups were 12.33 +/- 0.85, 9.75 +/- 1.02, 8.48 +/- 0.66 and 3.18 +/- 0.36, respectively. The difference of MNC rates of Group 1 vs 3, 1 vs 4, 2 vs 4 and 3 vs 4 was highly significant (P < 0.01), and the difference of Group 1 vs 2 was significant (P < 0.05), but there was no difference of MNC rate in Group 2 vs 3 (P > 0.05). CONCLUSIONS: This study showed that both the comet assay and the CBMN test could be used to monitor populations exposed to X-ray radiation, but the comet assay seems to be more sensitive than the CBMN test.

Adult↗