Dioxin suppresses the checkpoint protein, MAD2, by an aryl hydrocarbon receptor-independent pathway.
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The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown recently to be carcinogenic, but little is currently known about the molecular mechanism of TCDD affecting cell proliferation and carcinogenesis. In this report, we demonstrate that TCDD suppresses the expression of the checkpoint protein, Mad2. Suppression of Mad2 was also observed in aryl hydrocarbon receptor-deficient mouse embryonic fibroblasts, suggesting that TCDD suppresses Mad2 by a novel TCDD receptor signaling mechanism. In addition, HeLa cells treated with TCDD failed to arrest in mitosis after nocodazole treatment. The Mad2 protein plays a significant role in accurate chromosome segregation in mitotic cells. Our data suggest that TCDD may increase chromosomal instability through the suppression of Mad2 expression. (+info)
Biomarkers of genotoxicity of air pollution (the AULIS project): bulky DNA adducts in subjects with moderate to low exposures to airborne polycyclic aromatic hydrocarbons and their relationship to environmental tobacco smoke and other parameters.
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The levels of bulky DNA adducts were measured by (32)P-post-labelling in lymphocytes of 194 non-smoking students living in the city of Athens and the region of Halkida, Greece, once in the winter and again in the following summer. Personal exposures to particulate-bound polycyclic aromatic hydrocarbons (PAH) were significantly higher in Athens subjects during both seasons. There was hardly any diagonal radioactive zone in the pattern of DNA adducts observed. Highest adduct levels were observed in a sub-group of subjects living in or near the Halkida Institute campus, which was located in rural surroundings with a minimal burden of urban air pollution. The remaining Halkida subjects had intermediate levels, while Athens subjects showed the lowest levels. This trend, which was observed over both monitoring seasons, consistently paralleled the variation in three markers of exposure to environmental tobacco smoke (ETS), namely (i) declared times of exposure to ETS during the 24 h prior to blood donation, (ii) plasma cotinine levels and (iii) chrysene/benzo[g,h,i]perylene ratios in the profile of personal PAH exposure. Furthermore, among the Halkida campus area subjects (but not the remaining subjects) positive correlations were observed between DNA adducts and (i) measured personal exposures to chrysene or benzo[a]pyrene, (ii) time of declared ETS exposure and (iii) chrysene/benzo[g,h,i] perylene ratios. These correlations suggest that, for a group suffering minimal exposure to urban air pollution, exposure to ETS was a significant determinant of the observed DNA damage. Gender had a consistent and significant effect on adduct levels (males having higher levels), which remained significant even after multiple regression analysis. Habitual consumption of roasted meat was significantly associated with an enhancement of adduct levels and the effect was strengthened when only individuals unexposed to ETS were taken into consideration. No significant effects were observed for other dietary parameters or factors reflecting exposure to air pollution. (+info)
Update on the genotoxicity and carcinogenicity of cobalt compounds.
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OBJECTIVE: To integrate recent understandings of the mechanisms of genotoxicity and carcinogenicity of the different cobalt compounds. METHOD: A narrative review of the studies published since the last IARC assessment in 1991 (genotoxicity, experimental carcinogenesis, and epidemiology). RESULTS: Two different mechanisms of genotoxicity, DNA breakage induced by cobalt metal and especially hard metal particles, and inhibition of DNA repair by cobalt (II) ions contribute to the carcinogenic potential of cobalt compounds. There is evidence that soluble cobalt (II) cations exert a genotoxic and carcinogenic activity in vitro and in vivo in experimental systems but evidence in humans is lacking. Experimental data indicate some evidence of a genotoxic potential for cobalt metal in vitro in human lymphocytes but there is no evidence available of a carcinogenic potential. There is evidence that hard metal particles exert a genotoxic and carcinogenic activity in vitro and in human studies, respectively. There is insufficient information for cobalt oxides and other compounds. CONCLUSION: Although many areas of uncertainty remain, an assessment of the carcinogenicity of cobalt and its compounds requires a clear distinction between the different compounds of the element and needs to take into account the different mechanisms involved. (+info)
Cytogenetic analysis of Greek farmers using the micronucleus assay in peripheral lymphocytes and buccal cells.
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The potential cytogenetic damage associated with pesticide use in Greek agricultural workers was evaluated using micronuclei (MN) as biomarkers in lymphocytes of peripheral blood and exfoliated cells of the buccal mucosa. In addition, the effects of pesticide exposure and other variables on the cytokinesis block proliferation index (CBPI) in lymphocytes were also evaluated. Both the exposed and control individuals were selected from Nea Makri, a village near Athens (Greece). This location was selected for its high greenhouse density. Micronuclei were analysed in 50 agricultural workers exposed to pesticides (30 men and 20 women) and in 66 non-exposed individuals that constituted the control group (41 men and 25 women). The comparison between workers and controls did not reveal any statistical significant difference in the MN frequency for either lymphocytes or buccal cells. Nevertheless, the multiple regression analysis revealed that the age and the interaction between gender and the number of X-ray examinations during the last 3 years preceding the sampling increased the number of MN in lymphocytes. Moreover, the results of the negative binomial regression analysis suggested that the level of MN in buccal cells could be reduced by the intake of fish, whilst being increased by olive oil consumption. Regarding CBPI, the value found in the exposed group was lower than in controls, the difference being statistically significant. On the other hand, CBPI was inversely associated with both age and X-ray exposure. (+info)
Occupational exposure to carcinogens in Estonia, Latvia, Lithuania and the Czech Republic in 1997.
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OBJECTIVES: The aim of the study was to estimate the numbers of workers exposed to carcinogens in Estonia, Latvia, Lithuania, and the Czech Republic. METHODS: CAREX is an international information system on occupational exposure to 139 known and suspected carcinogens. It provides exposure data and estimates of the numbers of exposed workers by country, carcinogen, and industry. The CAREX method, which has been previously applied in the member states of the European Union, was applied in the present study to the exposure situation in Estonia, Latvia, Lithuania, and the Czech Republic in 1997. The preliminary estimates generated by CAREX were reviewed and revised by national experts mainly for asbestos, benzene, and lead, which were of special interest for this project. RESULTS: The numbers of workers exposed to carcinogens covered by CAREX in 1997 were about 180,000 (29% of employed persons) in Estonia, 260,000 (28% of employed persons) in Latvia, 470,000 (28% of employed persons) in Lithuania, and 1,400,000 (28% of employed persons) in the Czech Republic. The most common exposures were solar radiation (7-13% exposed at least 75% of the worktime), environmental tobacco smoke (4-5% exposed at least 75% of the worktime), wood dust (3-5% exposed), crystalline silica (2-3% exposed), diesel exhaust (2-3% exposed), radon and its decay products (2% exposed), benzene (0.9-1.7% exposed), and lead and inorganic lead compounds (0.8-1.4% exposed). Exposure to asbestos was slightly less prevalent (0.3-1.1% exposed). CONCLUSIONS: These preliminary results indicate that a substantial proportion of the workers in the studied countries were exposed to carcinogens. (+info)
Current smoking, occupation, N-acetyltransferase-2 and bladder cancer: a pooled analysis of genotype-based studies.
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The aim of this study was to investigate the association of NAT2 gene polymorphism with bladder cancer using the data derived from the International Project on Genetic Susceptibility to Environmental Carcinogens. Four case control studies conducted in four European countries, plus two case series, one from England and one from Germany, for a total of 1530 cases and 731 controls (all Caucasian) were included. The interaction between NAT2 and bladder cancer considering smoking habits and occupational exposure was studied. There was a significant association between NAT2 and bladder cancer (odds ratio: 1.42, 95% confidence interval: 1.14-1.77), with a slightly significant heterogeneity among studies. However, heterogeneity disappeared when smokers were divided into current and ex-smokers. The risk of cancer was elevated in smokers and occupationally exposed subjects, with the highest risk among slow acetylators. The increase in risk was limited, in fact, to current smokers (odds ratio = 1.74, 95% confidence interval: 0.96-3.15). This analysis confirms that the NAT2 genotype is a risk factor for bladder cancer by interacting with smoking or occupational exposures. Our observation suggests that NAT2 is not a risk factors per se but modulates the effect of carcinogens contained in tobacco smoke (probably arylamines) or associated with occupational exposures. (+info)
Combined effects of well-done red meat, smoking, and rapid N-acetyltransferase 2 and CYP1A2 phenotypes in increasing colorectal cancer risk.
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Heterocyclic amines (HAAs) are suspected carcinogens that are formed in meat when it is cooked at high temperature for long durations. These compounds require metabolic activation by CYP1A2 and N-acetyltransferase (NAT) 2 or NAT1 before they can bind to DNA. It has been hypothesized that well-done meat increases the risk of colorectal cancer (CRC), especially in individuals with the rapid phenotype for CYP1A2 and NAT2. This association may be particularly strong in smokers because smoking is known to induce CYP1A2. We conducted a population-based case-control study on Oahu, Hawaii to specifically test this hypothesis. An in-person interview assessed the diet and preference for well-done red meat of 349 patients with CRC and 467 population controls. A urine collection after caffeine challenge and a blood collection were used to assess phenotype for CYP1A2 and NAT2 and genotype for NAT2 and NAT1, respectively. No statistically significant main effect association with CRC was found for red meat intake, preference for well-done red meat, the NAT2 rapid genotype, the CYP1A2 rapid phenotype or the NAT1*10 allele. However, in ever-smokers, preference for well-done red meat was associated with an 8.8-fold increased risk of CRC (95% confidence interval, 1.7-44.9) among subjects with the NAT2 and CYP1A2 rapid phenotypes, compared with smokers with low NAT2 and CYP1A2 activities who preferred their red meat rare or medium. No similar association was found in never-smokers, and there was no increased risk for well-done meat among smokers with a rapid phenotype for only one of these enzymes or for smokers with both rapid phenotypes who did not prefer their red meat well-done. These data provide additional support to the hypothesis that exposure to carcinogens (presumably HAAs) through consumption of well-done meat increases the risk of CRC, particularly in individuals who are genetically susceptible (as determined by a rapid phenotype for both NAT2 and CYP1A2) and suggest that smoking, by inducing CYP1A2, facilitates this effect. (+info)
Photocarcinogenesis in human adult skin grafts.
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It has been demonstrated previously that the exposure to 7,12-dimethyl[a]benzanthracene (DMBA) and UVB radiation leads to the development of epidermal cysts, squamous cell carcinomas (SCC), melanocytic hyperplasia and melanoma in human foreskins from newborns grafted to immunodeficient mice. Improved techniques in grafting full-thickness skin from adults have enabled us to study photocarcinogenesis in human skin from different body sites and from older donors. One hundred and fifty-five normal white skin specimens from the trunk and face of 53 adult individuals were grafted onto severe combined immunodeficient (SCID) and recombinase activating gene-1 (Rag-1) knockout mice and irradiated two to three times weekly with 40 mJ/cm(2) UVB or solar-simulated UV (SSUV) over a period of up to 10 months with or without one prior topical application of DMBA. Over an observation period of 2-22 months, histopathological and immunohistochemical analyses of 134 specimens revealed actinic keratoses in 30% of the DMBA- + UV-treated grafts, in 18% of the grafts exposed to SSUV only, and in 10% of the grafts exposed to UVB only. Actinic keratoses were absent in grafts treated with DMBA only. One SCC was found in an abdominal skin graft 3 months after exposure to DMBA followed by UVB. Point mutations in codon 61 of the human Ha-ras gene were detected in the SCC, five of six analyzed actinic keratoses and in non-lesional epidermis of DMBA- and UVB-treated grafts, indicating that DMBA as well as UVB alone can induce these mutations in human skin. In contrast to the previous experience with neonatal foreskin grafts, melanocytic lesions were not found except for mild hyperplasia in few cases. The data suggest that melanocytes from young individuals are more susceptible to the transforming effects of genotoxic agents than melanocytes from adults. (+info)