The genotoxic and cytotoxic effects of nicotine in the mouse bone marrow
15 Aug 2007-Mutation Research-genetic Toxicology and Environmental Mutagenesis (Elsevier)-Vol. 632, Iss: 1, pp 29-36
TL;DR: The findings suggest that nicotine at high doses and after prolonged time intervals is genotoxic and cytotoxic for mouse bone marrow.
Abstract: The objective of the present study was to investigate the potential of nicotine to induce micronucleated polychromatic erythrocytes (MNPCE) in bone marrow of male and female mice. Cyclophosphamide at 40 mg/kg was used as positive control clastogen. Single doses of 4, 8 or 16 mg/kg nicotine were given via oral intubation and bone marrow was sampled at 18, 24, 30, 36 and 48 h after treatment. Cyclophosphamide yielded the expected positive results. Despite the evident signs of acute toxicity shown by the animals, mainly at the 8 and 16 mg/kg doses of nicotine, and the reduction in the % PCE, the results show that the MNPCE frequency in male and female mice was not affected by treatment with any of the selected doses of nicotine, in either of the sampling times 18 or 24 h. However, at 30 and 36 h after treatment, the MNPCE showed significant increases in both genders after doses of 8 and 16 mg/kg. A sex-dependent response was recorded, with males having more MNPCE than females after treatment with 8 or 16 mg/kg nicotine and sampling at 30 h. However, at 36 h more MNPCE were induced in females than in males, suggesting different degrees of dose interaction in the sexes under the conditions of the assay. The response was directly correlated with bone-marrow toxicity, as greater bone-marrow suppression was noted in females than in males when 36 h samples were examined. By 48 h recovery was observed even though the cytotoxicity was high. These findings suggest that nicotine at high doses and after prolonged time intervals is genotoxic and cytotoxic for mouse bone marrow. © 2007 Elsevier B.V. All rights reserved.
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TL;DR: The findings suggest that nicotine potentially protects cells against DNA reactive carcinogens contained in tobacco smoke although earlier in vitro and animal studies showed that the alkaloid induces DNA damage per se.
Abstract: The primary aim of the study was to investigate the impact of tar and nicotine contents of cigarettes on chromosomal damage in oral mucosa cells of smokers. We monitored the effect of smoking different cigarette types (i.e., of ultralight filter, light filter, medium filter and unfiltered cigarettes) on induction of nuclear anomalies including micronuclei (MN), broken eggs (BE), binucleates (BN), condensed chromatin (CC), karyorrhexis (KR), karyolysis (KL) and pyknosis (P) in exfoliated buccal cells. The cells were collected from 83 healthy heavy smokers (n=15-25/group) consuming a similar number of cigarettes (26-33) per day and from never smokers as controls (n=20). The frequencies of KR, CC, KL, BE and BN were increased significantly only in smokers of medium (MF) and non-filtered (NF) types of cigarettes while MN levels were only elevated (p < 0.0001) in the group that smoked NF cigarettes. Since BN and BE were increased (p < 00001) as a consequence of exposure to lower levels of toxic constituents in tobacco, it suggests that these endpoints, which both reflect DNA damage, are more sensitive than MN, which is the only parameter scored in most earlier studies. The induction of MN, BN, KR and KL increased significantly with daily tar exposure and decreased simultaneously with daily nicotine uptake (in all cases, P was < 0.0001). These findings also suggest that nicotine potentially protects cells against DNA reactive carcinogens contained in tobacco smoke although earlier in vitro and animal studies showed that the alkaloid induces DNA damage per se. A significant inverse correlation between the frequencies of endpoints such as cells with MN (- 1.56), MN (-1.69), BN (-1.36), KR (-1.10) and KL (-1.87) with the nicotine levels in cigarettes was found. However, this observation requires further verification by a controlled intervention study. In case it can be substantiated it will have an impact on the ongoing discussion of the health risks associated with nicotine replacement therapy.
73 citations
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Abstract: Cisplatin is a potent chemotherapeutic agent that has gained widespread use against various malignant tumours in a variety of human malignancies. Like other chemotherapeutic agents, cisplatin is genotoxic and apoptogenic in non-tumour cells and the formation of reactive oxygen species appears to be responsible for these toxicities. The anti-genotoxic and anti-apoptotic effects of resveratrol, a polyphenol found in numerous plant species, against cisplatin-induced genotoxicity and apoptosis in vivo were evaluated by use of standard techniques in somatic and germinal cells of mice. Pre-treatment of mice with resveratrol significantly reduced cisplatin-induced genotoxicity and apoptosis and effectively suppressed the apoptotic signalling triggered by cisplatin. The protective effect of resveratrol was found to be stronger at the higher dose, indicating the dose-dependent effect of resveratrol. Cisplatin induced marked biochemical alterations characteristic of oxidative DNA stress. Prior administration of resveratrol before the cisplatin challenge ameliorated these biochemical markers. In conclusion, this study provides evidence for the first time that resveratrol has a protective role in the abatement of cisplatin-induced genotoxicity and apoptosis in somatic and germinal cells of mice. This activity resides, at least in part, in its radical scavenger activity. Therefore, resveratrol can be a promising chemoprotective agent to avert secondary malignancies and abnormal reproductive outcomes in cured cancer patients exposed to cisplatin, without diminishing its anti-neoplastic activity.
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TL;DR: It is provided for the first time that proanthocyanidins have a protective role in the abatement of doxorubicin-induced mutagenesis and cell proliferation changes in germinal cells of mice that reside, at least in part, in their radical scavengeractivity.
Abstract: This study has been initiated to determine whether proanthocyanidins can protect against doxorubicin-induced mutagenicity in mice and to elucidate the potential mechanism of this protection. Pretreatment of mice with proanthocyanidins (100 mg/kg/day, orally) for 7 days and simultaneously with doxorubicin (12 mg/kg, i.p.) for another day, significantly reduced the frequency of bone marrow DNA strand breaks and micronucleated polychromatic erythrocytes compared to doxorubicin-treated mice alone. Furthermore, proanthocyanidins caused a reduction in bone marrow suppression induced by doxorubicin treatment. In male germline, orally administration of proanthocyanidins (100 mg/kg/day, orally) for 7 consecutive days before and 7 consecutive days after treatment with doxorubicin (12 mg/kg, i.p.), significantly elevated the levels of sperm count and motility reduced by doxorubicin treatment. Furthermore, proanthocyanidins significantly decreased the elevated levels of spermatogonial and spermatocyte chromosomal aberrations and sperm head abnormality induced by doxorubicin. Prior administration of proanthocyanidins ahead of doxorubicin reduced the doxorubicin induced testicular lipid peroxidation and prevented the reduction in testicular non-protein sulfhydryl significantly. Conclusively, this study provides for the first time that proanthocyanidins have a protective role in the abatement of doxorubicin-induced mutagenesis and cell proliferation changes in germinal cells of mice that reside, at least in part, in their radical scavenger activity. Therefore, proanthocyanidins can be a promising chemopreventive agent to avert secondary malignancy and abnormal reproductive outcomes risks in cancer patients receiving doxorubicin-involved treatment.
47 citations
TL;DR: A slight difference in mutagenicity using the BMCyt assay was found between the two different sampling times (pesticide application and leaf harvest), with higher micronucleus frequencies during pesticide application and higher cotinine levels during leaf harvest.
Abstract: Tobacco is a major Brazilian cash crop. Tobacco farmers apply large amounts of pesticides to control insect growth. Workers come into contact with green tobacco leaves during the tobacco harvest and absorb nicotine through the skin. In the present study, micronucleus frequency, cell death, and the frequency of basal cells were measured in tobacco farmers using the buccal micronucleus cytome assay (BMCyt), in parallel with measurement of blood butyrylcholinesterase (BChE) and nicotine levels. Polymorphisms in PONIGln192Arg and CYP2A6*9(−48T>G) were evaluated to verify the relationship between genetic susceptibility and the measured biomarkers. Peripheral blood and buccal cell samples were collected from 106 agricultural workers, at two different crop times (during pesticide application and leaf harvest), as well as 53 unexposed controls. BMCyt showed statistically significant increases in micronuclei, nuclear buds, and binucleated cells among exposed subjects in differentiated cells, and in micronuclei in basal cells. In addition, the exposed group showed higher values for condensed chromatin, karyorrhectic, pyknotic, and karyolitic cells, indicative of cell death, and an increase in the frequency of basal cells compared to the unexposed control group. A slight difference in mutagenicity using the BMCyt assay was found between the two different sampling times (pesticide application and leaf harvest), with higher micronucleus frequencies during pesticide application. Elevated cotinine levels were observed during the leaf harvest compared to the unexposed controls, while BChE level was similar among the farmers and controls. PONIGln192Arg and CYP2A6*9(−48T>G) polymorphisms were associated with DNA damage induced by pesticides and cell death. Environ. Mol. Mutagen., 2012. © 2012 Wiley Periodicals, Inc.
32 citations
References
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TL;DR: Current knowledge about the metabolism and disposition kinetics of nicotine, some other naturally occurring tobacco alkaloids, and nicotine analogs that are under development as potential therapeutic agents are reviewed.
Abstract: Nicotine is of importance as the addictive chemical in tobacco, pharmacotherapy for smoking cessation, a potential medication for several diseases, and a useful probe drug for phenotyping cytochrome P450 2A6 (CYP2A6). We review current knowledge about the metabolism and disposition kinetics of nicotine, some other naturally occurring tobacco alkaloids, and nicotine analogs that are under development as potential therapeutic agents. The focus is on studies in humans, but animal data are mentioned when relevant to the interpretation of human data. The pathways of nicotine metabolism are described in detail. Absorption, distribution, metabolism, and excretion of nicotine and related compounds are reviewed. Enzymes involved in nicotine metabolism including cytochrome P450 enzymes, aldehyde oxidase, flavin-containing monooxygenase 3, amine N-methyltransferase, and UDP-glucuronosyltransferases are represented, as well as factors affecting metabolism, such as genetic variations in metabolic enzymes, effects of diet, age, gender, pregnancy, liver and kidney diseases, and racial and ethnic differences. Also effects of smoking and various inhibitors and inducers, including oral contraceptives, on nicotine metabolism are discussed. Due to the significance of the CYP2A6 enzyme in nicotine clearance, special emphasis is given to the effects and population distributions of CYP2A6 alleles and the regulation of CYP2A6 enzyme.
1,416 citations
"The genotoxic and cytotoxic effects..." refers background in this paper
...Nevertheless, the metabolism of nicotine is known to produce reactive intermediates capable of binding to proteins and DNA [ 44 ]....
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TL;DR: After the workshop an effort was made to determine what single protocol would satisfy the requirements set for the micronucleus test by as many regulatory agencies as possible, including the requirements of six regulatory authorities in Canada, the European Economic Community, the Organization for Economic Co‐operation and Development, Japan, and the United States.
Abstract: The workshop was designed to present what is known about the production of micronuclei, what protocols are now accepted or proposed internationally, what new results have been obtained, and what new methods and protocols are likely to be forthcoming. This report is designed to convey the flavour of the workshop and to provide the essence of the new information. After the workshop an effort was made to determine what single protocol would satisfy the requirements set for the micronucleus test by as many regulatory agencies as possible. The result, reported here, includes the requirements of six regulatory authorities in Canada, the European Economic Community, the Organization for Economic Co-operation and Development, Japan, and the United States.
532 citations
"The genotoxic and cytotoxic effects..." refers background in this paper
...When the a-centrics form micronuclei, they result in structures that are smaller in size than the ones produced by entire chromosomes [ 2 ]....
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TL;DR: The mechanism of micronucleus formation, a generalized protocol for manual detection, enumeration ofmicronuclei, and data interpretation in light of published information thus far, are described on the regulatory aspects of this assay.
Abstract: In vivo rodent micronucleus assay has been widely used to detect genotoxicity. Evaluation of micronucleus induction is the primary in vivo test in a battery of genotoxicity tests and is recommended by the regulatory agencies around the globe to be conducted as part of product safety assessment. The assay, when performed appropriately, detects both clastogenicity and aneugenicity. Methods for performing micronucleus evaluation have evolved since its initial description in the 1970s. In recent years, the focus has been directed toward improving micronucleus detection with high efficiency by proposing data-based recommendations to the standard initial protocol design. Such improvements include, e.g., the use of appropriate harvest time(s), inclusion of one or both sexes, number of doses tested, limit dose, integrating micronucleus assessment into the routine toxicology studies, use of fluorescent staining, automation of micronucleus detection and assessment of micronuclei in multiple tissues. This protocol paper describes: the mechanism of micronucleus formation, a generalized protocol for manual detection, enumeration of micronuclei, and data interpretation in light of published information thus far, on the regulatory aspects of this assay. Certain recent protocol issues that are practical in nature are equally valid in relation to standard manual method and provide robust database, which are also included for consideration. It is expected that such improvements of the protocol will continue to drive the utility of this assay in the product safety assessment.
414 citations
"The genotoxic and cytotoxic effects..." refers methods in this paper
...The assay, when performed properly, detects clastogenicity due to chromosome breakage, and aneugenicity due to chromosome lagging resulting from dysfunctioning of the mitotic apparatus [3]....
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...[3] G....
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TL;DR: Data from abstinent smokers support the conclusion that nicotine deprivation functions to maintain smoking in nicotine-dependent persons, in part, because nicotine can reverse withdrawal-induced deficits in several areas of performance.
Abstract: The purpose of this review was to examine the effects of nicotine administration and cigarette smoking on human performance to clarify the role of such effects in controlling smoking. The results of 101 studies (129 experiments) published in scientific journals from 1970-1993 were reviewed. In nonabstinent smokers and nonsmokers, nicotine enhanced finger tapping and motor responses in tests of attention; cognitive functioning was not reliably enhanced. It is unlikely that these limited performance-enhancing effects of nicotine play an important role in the initiation of cigarette smoking. In contrast, data from abstinent smokers support the conclusion that nicotine deprivation functions to maintain smoking in nicotine-dependent persons, in part, because nicotine can reverse withdrawal-induced deficits in several areas of performance.
358 citations
"The genotoxic and cytotoxic effects..." refers background in this paper
...However, the principal source of nicotine exposure is through the use of tobacco and nicotine-replacement therapies such as transdermal nicotine patches and nicotine-containing gum [ 4 ]....
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TL;DR: Cigarette smoking among teenagers was associated with increases in disomic sperm and a diminution in specific aspects of semen quality that may affect male fertility and may increase future chances of fathering offspring with aneuploidy syndromes.
229 citations
"The genotoxic and cytotoxic effects..." refers background in this paper
...Additional data from humans showed that the proportions of diploid oocytes [35] and disomic spermatozoa [ 36 ] were higher in smokers....
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