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At least 145 records · Page 8Linked to original sources

PubMed2006

Air quality biomonitoring: assessment of air pollution genotoxicity in the Province of Novara (North Italy) by using Trifolium repens L. and molecular markers.

Mixed air pollutants are considered a major cause of DNA damage in living species. In this study Trifolium repens L. cv Regal was used as a bioindicator to assess the genotoxicity of air stressors in the Italian province of Novara. Two on-site biomonitoring experiments were performed during the spring and autumn of 2004. Test plants were exposed at 19 monitoring sites distributed homogeneously throughout the province, and each experiment lasted for a period of 6 weeks. Genotoxicity was evaluated with Amplified Fragment Length Polymorphism (AFLP) molecular markers. The results show the predominantly rural central-west region of the Novara Province to have the worst air quality with regard to genotoxicity. Analyses of geomorphology, land use and climatic factors suggest that the compromised air quality in the region could be attributed to wind strength and direction, transporting pollution from vehicular traffic on the A4 highway and from the urban/industrialized centres of Novara and Vercelli. Plant growth, changes in plant photochemical efficiency and the presence of ozone related leaf injuries were also measured to better interpret the results of genotoxicity. Statistical analyses show that although climatic factors such as light intensity and temperature influence plant growth, they do not contribute to atmospheric stressor-induced DNA damage. Further analyses indicated that, as expected, a mixture of genotoxic and non-genotoxic pollutants coexist in the Novara Province troposphere, and that the elevated ozone concentrations experienced during the study may have contributed to the DNA damage in the tested plants by enhancing genotoxicity via interaction with other air stressors.

Air Pollutants↗

PubMed2004

Failure of the standard battery of short-term tests in detecting some rodent and human genotoxic carcinogens.

Theoretical reasons and experimental evidence indicate that a no-effect level generally cannot be expected for genotoxic carcinogens; as a consequence, in quantitative risk assessment the capability of distinguishing genotoxic from non-genotoxic carcinogens is of fundamental importance in order to identify relevant levels of human exposure. According to generally accepted guidelines, the standard three-test battery for the detection of genotoxic compounds consists of: (i) an in vitro test for gene mutation in bacteria; (ii) an in vitro test in mammalian cells with cytogenetic evaluation of chromosomal damage and/or a test that detects gene mutations; (iii) an in vivo test for chromosomal damage using rodent hematopoietic cells. This test battery is designed to avoid the risk of false negative results for compounds with genotoxic potential, but it cannot be taken for granted that the risk is completely eliminated. As a matter of fact there are some chemicals, classified by the International Agency for Research on Cancer (IARC) as probably or possibly carcinogenic to humans, which gave consistent negative results in this test battery, and in contrast provided positive results in other not routinely employed genotoxicity assays. The failure of the standard test battery in detecting some genotoxic carcinogens is attributable to several causes, but the principal of them are the following ones: in vitro, the artificial metabolic activity of the liver S9-mix, and the different biotransformation of chemicals in cells of different type and from different animal species; in vivo, the pharmacokinetic behaviour of the test compound, and its possible species-, sex- and tissue-specificity.

Animals↗

PubMed2006

Genotoxic effects of myosmine in a human esophageal adenocarcinoma cell line.

The incidence of esophageal adenocarcinoma is rapidly rising in Western populations. Gastroesophageal reflux disease (GERD) is thought to be one of the most important risk factors. However, the mechanisms by which GERD enhances tumor formation at the gastroesophageal junction are not well understood. Myosmine is a tobacco alkaloid which has also a wide spread occurrence in human diet. It is readily activated by nitrosation and peroxidation giving rise to the same hydroxypyridylbutanone-releasing DNA adducts as the esophageal carcinogen N'-nitrosonornicotine. Therefore, the genotoxicity of myosmine was tested in a human esophageal adenocarcinoma cell line (OE33). DNA damage was assessed by single-cell gel electrophoresis (Comet assay). DNA strand breaks, alkali labile sites and incomplete excision repair were expressed using the Olive tail moment (OTM). The Fapy glycosylase (Fpg) enzyme was incorporated into the assay to reveal additional oxidative DNA damage. DNA migration was determined after incubation of the cells for 1-24h. Under neutral conditions high myosmine concentrations of 25-50mM were necessary to elicit a weak genotoxic effect. At pH 6 genotoxicity was clearly enhanced giving a significant increase of OTM values at 5mM myosmine. Lower pH values could not be tested because of massive cytotoxicity even in the absence of myosmine. Co-incubation of 25 mM myosmine with 1mM H(2)O(2) for 1h significantly enhanced the genotoxicity of H(2)O(2) but not the oxidative lesions additionally detected with the Fpg enzyme. In the presence of the peroxynitrite donor 3-morpholinosydnonimine (SIN-1) a dose-dependent significant genotoxic effect was obtained with 1-10mM myosmine after 4h incubation. NS-398, a selective inhibitor of cyclooxygenase 2, did not affect the SIN-1 stimulated genotoxicity of myosmine. Finally, the 23 h repair of N-methyl-N'-nitro-N-nitrosoguanidine-induced DNA lesions was significantly inhibited in the presence of 10mM myosmine. In conclusion, myosmine exerts significant genotoxic effects in esophageal cells under conditions which may prevail in GERD such as increased oxidative and nitrosative stress resulting from chronic inflammation.

Adenocarcinoma↗

PubMed2004

Genotoxicity of hormonal steroids.

Hormonal steroids have a widespread use in medicine and their side effects are continuously debated. The possible genotoxic activity of steroids has been the subject of many investigations. The natural estrogens estradiol, estrone and estriol are generally negative in the ICH core battery of tests, but several positive results have been obtained when using additional endpoints of genotoxicity. The genotoxic activity of the 4-hydroxy metabolites of estradiol and estrone is well established. The synthetic steroidal estrogens have a comparable profile of negative and positive test results. Cyproterone acetate and some of its analogues have a special position within the group of progestins. Their genotoxic potential has been established. Other progestins are generally negative in the routine tests. Anti-glucocorticoids, anti-progestins, corticosteroids, androgens, anabolics and anti-androgens appear to be devoid of genotoxic activities. The genotoxic potential of estradiol, estrone and cyproterone acetate with its analogues may play no role under normal physiological and therapeutic conditions. The metabolic conditions that are needed for the formation of DNA-reactive metabolites and oxygen radicals may not be present in humans. Epidemiological cancer data seem to support this view. The importance of thresholds in the dose-effect-relationship of genotoxicity data and their use in risk assessment is discussed.

Androgens↗

PubMed1999

Anti-genotoxicity and glutathione S-transferase activity in mice pretreated with caffeinated and decaffeinated coffee.

In vivo anti-genotoxic effects of caffeinated and decaffeinated instant coffee were compared in mice after pretreatment either by gavage for 10 consecutive days or in the drinking water for 2 weeks. Changes in hepatic sulfhydryl (-SH) content and glutathione S-transferase (GST) activity were evaluated in pretreated animals. Both caffeinated and decaffeinated instant coffee induced a moderate increase in -SH content and GST activity following pretreatment (with 70, 140 and 280 mg/kg body weight) by gavage for 10 days. This enhancement was not always dose dependent. The maximum effect on GST activity was observed at a dose of 140 mg/kg body weight/day. However, such an effect was not observed after administration of drinking water containing 2% caffeinated/decaffeinated instant coffee for 2 weeks. Results of the bone marrow micronucleus test for evaluating genotoxic effects revealed that both caffeinated and decaffeinated instant coffee (140 mg/kg body weight/day) could exert significant anti-genotoxic effects against ip injected benzo[a]pyrene (BP), cyclophosphamide (CPH), 7,12-dimethylbenz[a]anthracene (DMBA), mitomycin C (MMC) and procarbazine (PCB) in animals pretreated by gavage. Anti-genotoxic effects against BP, DMBA and urethane (URE) were evaluated in animals that received drinking water containing 2% caffeinated/decaffeinated instant coffee for 2 weeks. With the exception of the anti-genotoxic effect of decaffeinated coffee against DMBA, there was no significant change in genotoxicity after the above pretreatment. From this work, there is no evidence for any significant difference in the in vivo anti-genotoxicity of caffeinated and decaffeinated instant coffee.

Animals↗

PubMed2002

The Bacillus subtilis rec-assay: a powerful tool for the detection of genotoxic substances in the water environment. Prospect for assessing potential impact of pollutants from stabilized wastes.

The Bacillus subtilis rec-assay has been specially developed to detect genotoxicity in environmental water samples. The rationale of the B. subtilis rec-assay is based on the relative difference of survival of a DNA repair-recombination proficient strain and its deficient strain, which is interpreted as genotoxicity. This assay method can be very powerful in that it has higher sensitivity for the detection of mutagens in highly polluted waters than other bacterial mutation assays. Hydrophobic fractions from various environmental waters were fractionated by using XAD-2 resins and assayed, targeting the detection of organic genotoxic substances. Genotoxic response was detected in most of them, which revealed that many unknown micropollutants with genotoxicity occur in public water bodies. Positive response was also detected from a treated municipal solid waste (MSW) landfill leachate. Genotoxicity remaining in the treated effluent suggests that genotoxic micropollutants may pass through conventional water treatment processes such as activated sludge treatment process. Without proper control of waste quality and landfill facilities, waste landfill could be a heavy pollution source.

Bacillus subtilis↗

PubMed2004

Genotoxicity of benzene and its metabolites.

The potential role of genotoxicity in human leukemias associated with benzene (BZ) exposures was investigated by a systematic review of over 1400 genotoxicity test results for BZ and its metabolites. Studies of rodents exposed to radiolabeled BZ found a low level of radiolabel in isolated DNA with no preferential binding in target tissues of neoplasia. Adducts were not identified by 32P-postlabeling (equivalent to a covalent binding index <0.002) under the dosage conditions producing neoplasia in the rodent bioassays, and this method would have detected adducts at 1/10,000th the levels reported in the DNA-binding studies. Adducts were detected by 32P-postlabeling in vitro and following high acute BZ doses in vivo, but levels were about 100-fold less than those found by DNA binding. These findings suggest that DNA-adduct formation may not be a significant mechanism for BZ-induced neoplasia in rodents. The evaluation of other genotoxicity test results revealed that BZ and its metabolites did not produce reverse mutations in Salmonella typhimurium but were clastogenic and aneugenic, producing micronuclei, chromosomal aberrations, sister chromatid exchanges and DNA strand breaks. Rodent and human data were compared, and BZ genotoxicity results in both were similar for the available tests. Also, the biotransformation of BZ was qualitatively similar in rodents, humans and non-human primates, further indicating that rodent and human genotoxicity data were compatible. The genotoxicity test results for BZ and its metabolites were the most similar to those of topoisomerase II inhibitors and provided less support for proposed mechanisms involving DNA reactivity, mitotic spindle poisoning or oxidative DNA damage as genotoxic mechanisms; all of which have been demonstrated experimentally for BZ or its metabolites. Studies of the chromosomal translocations found in BZ-exposed persons and secondary human leukemias produced by topoisomerase II inhibitors provide some additional support for this mechanism being potentially operative in BZ-induced leukemia.

Animals↗

PubMed2002

Soil genotoxicity assessment: a new stategy based on biomolecular tools and plant bioindicators.

The setting up of efficient early warning systems is a challenge to research for preventing environmental alteration and human disease. In this paper, we report the development and the field application of a new biomonitoring methodology for assessing soil genotoxicity. In the first part, the use of amplified fragment length polymorphism and flow cytometry techniques to detect DNA damage induced by soils artificially contaminated with heavy metals as potentially genotoxic compounds is explained. Results show that the combination of the two techniques leads to efficient detection of the sublethal genotoxic effect induced in the plant bioindicator by contaminated soil. By contrast, the classic mortality, root, and shoot growth vegetative endpoints prove inappropriate for assessing soil genotoxicity because, although they cause genotoxic damage, some heavy metals do not affect sentinel plant development negatively. The statistical elaboration of the data obtained led to the development of a statistical predictive model which differentiates four different levels of soil genotoxic pollution and can be used everywhere. The second part deals with the application of the biomonitoring protocol in the genotoxic assessment of two areas surrounding a steelworks in northern Italy and the effectiveness of this methodology. In this particular case, in these areas, the predictive model reveals a pollution level strictly correlated to the heavy metal concentrations revealed by traditional chemical analysis.

DNA Damage↗

PubMed1997

Roles of DT diaphorase in the genotoxicity of nitroaromatic compounds in human and fish cell lines.

The genotoxicity of nitroaromatic compounds was examined in two cultured cell lines, namely, a human hepatoma cell line, HepG2, and a brown bullhead fibroblast cell line, BB. Furthermore, the role of the quinone-reducing enzyme DT diaphorase [NAD(P)H:(quinone acceptor) oxidoreductase] was examined with respect to its influence on the genotoxic effects of model nitroaromatic pollutants. The nitroreductive characteristics of these two cell lines were examined using an acetylated cytochrome c reduction assay for enzymatic nitroreductase activity. Subsequently, the influence of DT diaphorase on the genotoxicity of two model nitroaromatics, 4-nitroquinoline 1-oxide (4NQ) and nitrofurantoin (NF), revealed that DT diaphorase was the predominant 4NQ reductase in cytosols of both cell lines, but played a lesser role in NF reduction in both species. Despite these interspecific similarities, results revealed marked qualitative differences between the two species in terms of the influence of DT diaphorase on quinone-mediated genotoxicity. When pretreated with the DT diaphorase inhibitor dicoumarol, HepG2 cells exhibited an exacerbation of genotoxicity in the presence of 4NQ, indicating a protective influence of the enzyme. In contrast, 4NQ genotoxicity in BB cells was reduced in the presence of dicoumarol, indicating a deleterious effect of DT diaphorase activity. Conversely, dicoumarol pretreatment was moderately protective against NF-mediated genotoxicity in HepG2 cells but exacerbated NF toxicity in BB cells. This study illustrates the manner in which functionally analogous enzymes may have markedly distinct influences on xenobiotic toxicity in different cellular systems.

4-Nitroquinoline-1-oxide↗

PubMedDate not supplied

A review of the genotoxicity of triallate.

Triallate is a selective herbicidal chemical used for control of wild oats in wheat. It has an extensive genotoxicity database that includes a variety of in vitro and in vivo studies. The chemical has produced mixed results in in vitro assay systems. It was genotoxic in bacterial mutation Ames assays, predominantly in Salmonella typhimurium strains TA100 and TA1535 in the presence of S9. Weaker responses have been observed in TA100 and TA1535 in the absence of S9. Mixed results have been observed in strain TA98, whereas no genotoxicity has been observed in strains TA1537 and TA1538. The presence and absence of S9 and its source seem to play a role in the bacterial response to the chemical. There have also been conflicting results in other test systems using other bacterial genera, yeast, and mammalian cells. Chromosome effects assays (sister-chromatid exchange and cytogenetics assays) have produced mixed results with S9 but no genotoxicity without S9. Triallate has not produced any genotoxicity in in vitro DNA damage or unscheduled DNA synthesis assays using EUE cells, human lymphocytes, and rat and mouse hepatocytes. In a series of in vivo genotoxicity assays (cytogenetics, micronucleus, dominant lethal, and unscheduled DNA synthesis), there has been no indication of any adverse genotoxic effect. Metabolism data indicate that the probable explanation for the differences observed between the in vitro studies with S9 and without S9 and between the in vitro and the in vivo studies is the production of a mutagenic intermediate in vitro at high doses of triallate is expected to be at most only transiently present in in vivo studies. The weight of evidence strongly suggests that triallate is not likely to exert mutagenic activity in vivo due to toxicokinetics and metabolic processes leading to detoxification.

Animals↗

PubMed2005

Biomonitoring of the genotoxic potential of draining water from dredged sediments, using the comet and micronucleus tests on amphibian (Xenopus laevis) larvae and bacterial assays (Mutatox and Ames tests).

Management of contaminated dredged sediments is a matter of great human concern. The present investigation evaluates the genotoxic potential of aqueous extracts of five sediments from French channels (draining water from dredged sediments), using larvae of the frog Xenopus laevis. Two genotoxic endpoints were analyzed in larvae: clastogenic and/or aneugenic effects (micronucleus induction after 12 d of exposure) and DNA-strand breaking potency (comet assay after 1 and 12 d of exposure) in the circulating blood. Additionally, in vitro bacterial assays (Microtox and Ames tests) were carried out and the results were compared with those obtained with larvae. Physicochemical analyses were also taken into account. Analytical analyses highlighted in the five draining waters a heavy load of contaminants such as metals and hydrocarbons. The results obtained with the micronucleus test established the genotoxicity of three draining waters. The comet assay showed that all 5 draining waters were genotoxic after 1 d of exposure. Although 3 of them were still genotoxic after 12 d of exposure, DNA damage globally decreased between d 1 and 12. The comet assay can be considered as a genotoxicity-screening tool. Data indicate that both tests should be used in conjunction in Xenopus. Bacterial tests (Ames) revealed genotoxicity for only one draining water. The results confirm the relevance of the amphibian model and the need to resort to bioassays in vivo such as the Xenopus micronucleus and comet assays for evaluation of the ecotoxicological impact, an essential complement to the physicochemical data.

Animals↗

PubMed2005

Hospital wastewater genotoxicity.

Hospitals represent an incontestable release source of many chemicals compounds in their wastewaters, and which may have an impact on the environment and human health. Indeed, some of the substances found in wastewaters are genotoxic and are suspected to be a possible cause of the cancers observed in the last decades. To study the toxicity and the risk associated with these releases biological tests, such as genotoxicity tests, can be used. An evaluation of the genotoxic potential of the wastewaters from a university hospital was performed with the SOS chromotest and the Salmonella fluctuation test. The samples were taken for six 1-week periods between May 2001 and April 2003. Out of a total of 38 samples tested, 31 were positive in at least one assay (82%). Distribution, proportion and intensity of the genotoxic response were different among the six sampling periods. The two genotoxicity tests had different sensitivities. It must be emphasized that whatever the sampling period, Monday samples were always genotoxic in at least one assay. This work shows that this hospital wastewaters samples are very often genotoxic, the response intensity being inflected by rain levels. Efforts must be undertaken by hospitals to integrate the knowledge and the control of their wastewaters in infection and environmental control programs.

DNA Damage↗

PubMed1995

Genotoxicity of 17 gyrase- and four mammalian topoisomerase II-poisons in prokaryotic and eukaryotic test systems.

The genotoxic potency of certain classes of topoisomerase II poisons is correlated with their affinity to the topoisomerase protein rather than with the presence of 'classical' structural alerts for DNA reactivity: bacterial topoisomerase II poisons (specifically named gyrase inhibitors) are highly genotoxic in prokaryotic systems; mammalian topoisomerase II poisons are potent mutagens/clastogens in eukaryotic systems. Studies with bacterial, lower eukaryotic and mammalian genotoxicity tests were performed to draw structure-activity conclusions and address risk-benefit considerations for the class of quinolone gyrase inhibitors. All 17 gyrase inhibitors investigated in this study showed genotoxic activity in Salmonella typhimurium strain TA102 and the SOS test. The genotoxic and the toxic activities increased in a highly parallel fashion from the parent compounds, nalidixic acid and oxolinic acid, to the new generation fluoroquinolones. Generally, the most potent fluoroquinolones also show clear-cut positive effects in eukaryotic test systems, although at concentrations 100-1000-fold higher than those effective in bacteria and also 100-1000-fold higher than the minimal genotoxic concentrations of antitumour topoisomerase II inhibitors (ellipticine, teniposide, mAMSA) used as reference compounds. However, subtle structural modifications of the quinolones can strongly diminish the preferential genotoxicity in the prokaryotic test systems.

Animals↗

PubMed1999

Modulation of genotoxic and related effects by carotenoids and vitamin A in experimental models: mechanistic issues.

The mechanisms involved in the modulation of genotoxic and related effects by carotenoids and vitamin A were inferred from a critical review of an ad hoc constructed database. Almost 500 results were generated in experimental models evaluating the activity of 32 structurally, metabolically and functionally related nutrients, including beta-carotene and 26 other carotenoids, retinol, retinal, all-trans-retinoic acid and retinyl esters. As many as 67 experimental test systems, either in vitro or in vivo, used a variety of cellular targets and/or end-points suggestive of distinctive mechanisms of action. The bulk of available data support the view that carotenoids and vitamin A do not induce genotoxic effects per se. Even in the absence of any genotoxic agent, these nutrients appeared, on the contrary, to display some mechanisms which play protective roles in tumor promotion and progression, such as inhibition of N-myc gene expression resulting in antiproliferative effects, up-regulation of cell-to-cell communication, an increase in connexin 43 gene expression, a decrease in the 'spontaneous' cell transformation frequency and induction of differentiation in vitro. A large number of studies investigated the modulation by carotenoids and vitamin A of genotoxic and related effects produced by 69 genotoxicants, including biological agents, physical agents, chemical compounds and complex mixtures. In spite of some discrepant data, the general trend was that both carotenoids and vitamin A are poorly effective in acting as nucleophiles, nor do they appear to substantially interfere with the induction or repair of DNA damage produced by direct-acting agents. In contrast vitamin A and carotenoids, irrespective of their provitamin A role, in most studies inhibited those genotoxicants which require metabolic activation to electrophilic derivatives in either bacterial or mammalian cells. Coupled with biochemical data, the distinctive patterns observed with genotoxic agents belonging to different chemical classes suggest a complex modulation of both phase I and phase II enzymes involved in the metabolism of xenobiotics. Furthermore, carotenoids and vitamin A shared other protective mechanisms, such as scavenging of genotoxic oxygen species, modulation of signal transduction pathways, inhibition of cell transformation induced by physical and chemical agents, and facilitation of intercellular communication inhibited by genotoxic compounds. Therefore, carotenoids and vitamin A appear to work via multiple mechanisms, which would support a potential protective role in cancer initiation and in the pathogenesis of other mutation-related diseases. These conclusions are consistent with the recognized cancer-preventive activity of these nutrients in certain animal models and with the evidence provided by observational epidemiological studies, which suggested cancer-protective effects at many sites as related to their dietary intake or plasma levels. However, all these lines of evidence and mechanistically based premises contrast with the unexpected outcome of recent clinical intervention trials, which raised the concern that supplemental use of beta-carotene and vitamin A may increase the risk of lung cancer amongst high risk individuals such as tobacco smokers and asbestos-exposed workers.

Animals↗

PubMed1999

Genotoxic effects of benzyl isothiocyanate, a natural chemopreventive agent.

Benzyl isothiocyanate (BITC) is contained in cruciferous plants which are part of the human diet. Numerous reports indicate that BITC prevents chemically induced cancer in laboratory animals and it has been postulated that BITC might also be chemoprotective in humans. On the other hand, evidence is accumulating that this compound is a potent genotoxin in mammalian cells by itself. To further elucidate the potential hazards of BITC, we investigated its genotoxic effects in different in vitro genotoxicity tests and in animal models. In in vitro experiments [differential DNA repair assay with Escherichia coli, micronucleus assay with human HepG2 cells and single cell gel electrophoresis (SCGE) assay with hepatocytes and gastrointestinal tract cells] pronounced dose-dependent genotoxic effects were found at low dose levels (</=5 microg/ml). In contrast, substantially weaker effects were obtained in in vivo experiments with laboratory rodents: in the differential DNA repair assay with E.coli cells, only moderate genotoxic effects were seen in indicator cells recovered from various organs of mice after treatment with high doses (between 90 and 270 mg/kg), while in SCGE assay with rats a change in the DNA migration pattern was seen at a dose level of 220 mg/kg body wt. These findings indicate that BITC is detoxified under in vivo test conditions. This assumption was supported by the results of in vitro experiments which showed that the genotoxic effects of BITC are markedly reduced by bovine serum albumin and human body fluids such as saliva and gastric juice. Additional experiments carried out on the mechanistic aspects of the genotoxicity of BITC showed that this compound causes formation of thiobarbituric acid-reactive substances in HepG2 cells and that its DNA damaging properties are diminished by alpha-tocopherol, vitamin C, sodium benzoate and beta-carotene, indicating the possible involvement of free radicals in the genotoxicity of BITC. The doses of BITC required to cause measurable DNA damage in laboratory rodents exceeded by far the dietary exposure levels of humans, but are similar to those which were required to inhibit chemically induced cancer in earlier animal experiments.

Adult↗

PubMed1990

Involvement of different pathways in the genotoxicity of nitropropanes in cultured mammalian cells.

The metabolic pathways leading to genotoxicity of nitropropanes in mammalian cells were investigated by measuring the effects of 2-nitropropane (2-NP) and 1-nitropropane (1-NP) on various cell lines characterized for their expression of cytochrome P450-dependent mono-oxygenases. Cells used were the rat hepatoma cell lines 2sFou, H4IIEC3/G- and C2Rev7, which express various forms of cytochrome P450-dependent mono-oxygenases, and V79 Chinese hamster cells which lack these enzyme activities. Induction of DNA repair synthesis, micronuclei and, where assessable, mutations to 6-thioguanine (TG) resistance served as indicators of genotoxic effects. 2-NP elicited a positive response at all endpoints measured in the hepatoma lines after pretreatment of the cells with dexamethasone, an inducer of various liver-specific cytochrome P450 forms. Genotoxicity was much weaker or not detectable in cells not pretreated with the inducer. 1-NP was not genotoxic in the hepatoma cells irrespective of whether the cells were pretreated or not. Neither isomer elicited DNA repair synthesis in V79 cells, but both isomers caused mutations to TG resistance, and 1-NP increased the number of micronucleated and multinucleated cells. The findings show that there are different pathways in mammalian cells by which nitropropanes can be converted to genotoxic products. Presumably the induction of liver tumours by 2-NP is linked to the metabolic pathway which is characterized by the formation of genotoxic metabolites from 2-NP but not 1-NP. This pathway appears to depend on the presence of liver-specific, dexamethasone-inducible, cytochrome P450 forms. The relevance of the genotoxic effects of the nitropropanes observed in V79 cells for the situation in vivo is open to question.

Alkanes↗

PubMed1996

Simultaneous measurement of unscheduled and replicating DNA synthesis by means of a new cell culture insert DNA retention method: rapid induction of replicating DNA synthesis in response to genotoxic carcinogens.

In order to measure simultaneously replicating DNA synthesis (RDS) and unscheduled DNA synthesis (UDS) in rat hepatocytes responding to exposure to carcinogens, a new method, namely the "cell culture insert DNA retention (CDR)" method, was developed. All CDR procedures for cell culture, digestion of cytoplasm and retention of DNA were performed on membranes attached to cell culture containers. Four subgroups of primary cultures of hepatocytes prepared from rats were exposed to a genotoxic or non-genotoxic carcinogen with or without 10 mM hydroxyurea and incubated for 4 h with 10 microCi/ml [3H]thymidine. The membranes were then processed for both liquid scintillation and autoradiography. Among seven tested chemicals, three genotoxic agents, 3,2'-dimethyl-4-aminobiphenyl, 2-acetylaminofluorene and diethylnitrosamine, and two non-genotoxic carcinogens, nafenopin and phenobarbital, induced RDS within 4 h after the exposure, indicating that these carcinogenic agents induce cell proliferation is non-proliferating rat hepatocytes prior to the emergence of genotoxic changes. Several indices were devised to characterize the genotoxicity of the tested chemicals. The induction patterns obtained showed a wide variation in the individual characteristics of carcinogen-induced genotoxicity and mitogenicity in the early phase of initiation. This is the first report of simultaneous measurement, by using a combination of autoradiography and liquid scintillation, of UDS and RDS induced in rat hepatocytes. The described CDR approach will be useful for risk assessment and characterization of carcinogenic and tumor-promoting agents.

2-Acetylaminofluorene↗

PubMed2001

Comparative efficacy of two microdoses of a potentized homoeopathic drug, Cadmium Sulphoricum, in reducing genotoxic effects produced by cadmium chloride in mice: a time course study.

BACKGROUND: Cadmium poisoning in the environment has assumed an alarming problem in recent years. Effective antimutagenic agents which can reverse or combat cadmium induced genotoxicity in mice have not yet been reported. Therefore, in the present study, following the homeopathic principle of "like cures like", we tested the efficacy of two potencies of a homeopathic drug, Cadmium Sulphoricum (Cad Sulph), in reducing the genotoxic effects of Cadmium chloride in mice. Another objective was to determine the relative efficacy of three administrative modes, i.e. pre-, post- and combined pre and post-feeding of the homeopathic drugs. For this, healthy mice, Mus musculus, were intraperitoneally injected with 0.008% solution of CdCl2 @ 1 ml/100 gm of body wt (i.e. 0.8 mcg/gm of bw), and assessed for the genotoxic effects through such studies as chromosome aberrations (CA), micronucleated erythrocytes (MNE), mitotic index (MI) and sperm head anomaly (SHA), keeping suitable succussed alcohol fed (positive) and CdCl2 untreated normal (negative) controls. The CdCl2 treated mice were divided into 3 subgroups, which were orally administered with the drug prior to, after and both prior to and after injection of CdCl2 at specific fixation intervals and their genotoxic effects were analyzed. RESULTS: While the CA, MNE and SHA were reduced in the drug fed series as compared to their respective controls, the MI showed an apparent increase. The combined pre- and post-feeding of Cad Sulph showed maximum reduction of the genotoxic effects. CONCLUSIONS: Both Cad Sulph-30 and 200 were able to combat cadmium induced genotoxic effects in mice and that combined pre- and post-feeding mode of administration was found to be most effective in reducing the genotoxic effect of CdCl2 followed by the post-feeding mode.

Administration, Oral↗