Ivan Kalina

Publications (30)74.89 Total impact

• Source

  Available from: Alena Gábelová

  Dataset: Farmer et al 2003

  Peter B Farmer, Rajinder Singh, Balvinder Kaur, Radim J Sram, Blanka Binkova, Ivan Kalina, Todor A Popov, Seymour Garte, Emanuela Taioli, Alena Gabelova, Antonina Cebulska-Wasilewska
• Article: Pooled analysis of studies on DNA adducts and dietary vitamins.

  Camille Ragin, Aerie Minor, Antonio Agudo, Peter Farmer, Seymour Garte, Carlos Gonzales, Ivan Kalina, Giuseppe Matullo, Todor Popov, Domenico Palli, Marco Peluso, Fulvio Ricceri, Radim Sram, Paolo Vineis, Emanuela Taioli
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  ABSTRACT: There is some evidence that dietary components that are rich in antioxidant and vitamins are inversely associated with DNA adduct levels induced by environmental carcinogens such as polycyclic aromatic hydrocarbons, although the epidemiologic data are inconsistent. This study addresses the association between vitamins, DNA adducts and smoking. A combined analysis of individual data on the association between bulky DNA adducts and dietary vitamins was conducted. A Medline search was performed to identify studies on healthy subjects in which smoking and vitamins intake information were available, and bulky DNA adducts were measured in peripheral blood with 32P-postlabelling. Eight published studies met the eligibility criteria, and individual data from 7 data sets including 2758 subjects were obtained. GSTM1 and GSTT1 were also available on all the subjects. Vitamin E was inversely significantly associated with DNA adducts after adjustment for possible confounding factors. Vitamins A and C were not independent predictors of DNA adducts. A stratified analysis showed that vitamin A had a significant inverse association with DNA adducts in ever smokers only. This result is relevant to planning any future chemo-preventive interventions directed to high risk subgroups of the population, for cancer prevention.
  Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 10/2010; 705(2):77-82. · 2.85 Impact Factor
• Article: Exposure to environmental polycyclic aromatic hydrocarbons: influences on cellular susceptibility to DNA damage (sampling Kosice and Sofia).

  Antonina Cebulska-Wasilewska, Igor Pawłyk, Agnieszka Panek, Anna Wiecheć, Ivan Kalina, Todor Popov, Tzveta Georgieva, Peter B Farmer
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  ABSTRACT: The aim of this study was to investigate a possible influence of occupational exposure to carcinogenic environmental polycyclic aromatic hydrocarbons (c-PAHs) on cellular susceptibility to the induction of the DNA damage. Monitoring was performed and blood samples were collected from two groups of male subjects: occupationally exposed and matched controls. The group exposed to c-PAHs (average age of 35.1 years) consisted of 52 policemen from Kosice and 26 policemen and 25 bus drivers (51 altogether) from Sofia. The control group (average age of 36.4 years) consisted of 54 unexposed subjects from Kosice and 24 from Sofia. In the investigated groups 52.5% of exposed subjects and 45.3% of control were current smokers. A challenging dose of X-rays (3Gy) and an alkaline version of the single cell gel electrophoresis (SCGE) assay, known as Comet assay, were used to evaluate levels of induced DNA damage and repair kinetics in isolated human blood lymphocytes. DNA damage detected in lymphocytes prior to or after irradiation did not differ significantly between exposed and unexposed subjects. A significant decrease in repair efficiency due to exposure to PAHs was observed in the exposed individuals from Kosice and Sofia, when analysed separately or together. A negative influence of tobacco smoking on the efficiency of DNA repair was observed. Statistically significant differences were found between subgroups stratified according to education level in Sofia: the half times for DNA repair declined with the increasing level of education. These results confirm that environmental exposure to c-PAHs can alter the ability of blood lymphocytes to repair DNA damage and, as a result could potentially lead to effects that are hazardous to human health.
  Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 08/2007; 620(1-2):145-54. · 2.85 Impact Factor
• Article: Repair competence assay in studies of the influence of environmental exposure to c-PAHs on individual susceptibility to induction of DNA damage.

  Antonina Cebulska-Wasilewska, Blanka Binkova, Radim J Sram, Ivan Kalina, Teodor Popov, Peter B Farmer
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  ABSTRACT: Previous results from studies performed in three European cities suggested a decrease in DNA repair efficiency observed in lymphocytes of subjects occupationally exposed to environmental carcinogenic polycyclic aromatic hydrocarbons (c-PAHs). The aim of this study was to investigate whether a relationship between exposure to environmental c-PAHs and cellular vulnerability to the induction of DNA damage and its repair is confirmed in a pooled group of subjects from Prague, Kosice and Sofia. The investigated pool consisted of 144 subjects occupationally exposed to environmental c-PAHs, who were municipal policemen or bus drivers. A control group of 115 matched individuals consisted of males unexposed at work to c-PAHs. The repair efficacy was evaluated by a comparison of the DNA damage detected by the single cell gel electrophoresis (SCGE) immediately after challenging the cells with X-ray irradiation, with residual damage (RD) being measured after an incubation period of 60min. A stochastic concept for a mechanism of the interaction between DNA and various genotoxic exposures, was applied to analyze a relationship between exposure and biological effect in the studied sample. The outcome of the study confirms that the exposure to environmental c-PAHs or smoking cigarettes, significantly decreases DNA repair efficiency (repair efficiency in the pooled group of exposed individuals was 61.8+/-11.8% versus 67.9+/-9.9 in control, p<0.001, and repair efficiency in group of smoking individuals was 63.0+/-11.5% versus 65.9+/-11.1 in nonsmokers, p<0.005). The repair efficiency can be affected by a genetic polymorphism, such as subjects with a homozygous mutation in polymorphic CYP1A1((Val/Val)) enzyme, or slow NAT2 acetylators, who showed a considerably lower DNA repair efficiency (i.e. average repair efficiency in subgroups of fast acetylators was for the control subgroup 68.1% versus 66.5% in exposed subjects, while in the case of subgroups of slow acetylators, for the control group was 68.0% versus significantly less in the exposed subjects, 60.6%, p<0.05). Smoking habits, or the diet's vitamin content, significantly affected the process. The results obtained confirm a potential value of the method as a biomarker of susceptibility in molecular epidemiology or preclinical studies, aimed at predicting susceptibility to various genotoxic exposures (environmental, occupational, therapeutic). To conclude, the research proved the influence of environmental c-PAHs, genotypes, and life styles on DNA damage and on its repair efficiency. Even low exposure to environmental c-PAHs altered DNA repair abilities of the subjects, which may result in an increased cancer risk. The findings confirm that c-PAHs should become pollutants that are subject to regulation.
  Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 08/2007; 620(1-2):155-64. · 2.85 Impact Factor
• Article: Effects of environmental air pollution on endogenous oxidative DNA damage in humans.

  Rajinder Singh, Balvinder Kaur, Ivan Kalina, Todor A Popov, Tzveta Georgieva, Seymour Garte, Blanka Binkova, Radim J Sram, Emanuela Taioli, Peter B Farmer
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  ABSTRACT: Epidemiological studies conducted in metropolitan areas have demonstrated that exposure to environmental air pollution is associated with increases in mortality. Carcinogenic polycyclic aromatic hydrocarbons (c-PAHs) are the major source of genotoxic activities of organic mixtures associated with respirable particulate matter, which is a constituent of environmental air pollution. In this study,we wanted to evaluate the relationship between exposure to these genotoxic compounds present in the air and endogenous oxidative DNA damage in three different human populations exposed to varying levels of environmental air pollution. As measures of oxidative DNA damage we have determined 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and cyclic pyrimidopurinone N-1,N(2) malondialdehyde-2'-deoxyguanosine (M(1)dG) by the immunoslot blot assay from lymphocyte DNA of participating individuals. The level of endogenous oxidative DNA damage was significantly increased in individuals exposed to environmental air pollution compared to unexposed individuals from Kosice (8-oxodG adducts) and Sofia (M(1)dG adducts). However, there was no significant difference in the level of endogenous oxidative DNA and exposure to environmental air pollution in individuals from Prague (8-oxodG and M(1)dG adducts) and Kosice (M(1)dG adducts). The average level of M(1)dG adducts was significantly lower in unexposed and exposed individuals from Kosice compared to those from Prague and Sofia. The average level of 8-oxodG adducts was significantly higher in unexposed and exposed individuals from Kosice compared to those from Prague. A significant increasing trend according to the interaction of c-PAHs exposure and smoking status was observed in levels of 8-oxodG adducts in individuals from Kosice. However, no other relationship was observed for M(1)dG and 8-oxodG adduct levels with regard to the smoking status and c-PAH exposure status of the individuals. The conclusion that can be made from this study is that environmental air pollution may alter the endogenous oxidative DNA damage levels in humans but the effect appears to be related to the country where the individuals reside. Genetic polymorphisms of the genes involved in metabolism and detoxification and also differences in the DNA repair capacity and antioxidant status of the individuals could be possible explanations for the variation observed in the level of endogenous oxidative DNA damage for the different populations.
  Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 08/2007; 620(1-2):71-82. · 2.85 Impact Factor
• Article: Effects of polycyclic aromatic hydrocarbons (PAHs) in environmental pollution on exogenous and oxidative DNA damage (EXPAH project): description of the population under study.

  Emanuela Taioli, Radim J Sram, Seymour Garte, Ivan Kalina, Todor A Popov, Peter B Farmer
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  ABSTRACT: The EXPAH project was a molecular epidemiology study whose aims were to evaluate the hypothesis that polycyclic aromatic hydrocarbons (PAHs) are a major source of genotoxic activities of organic mixtures associated with air pollution. Biomarkers of exposure, effects and susceptibility, and oxidative DNA damage were measured in three PAH-exposed populations from Prague (Czech Republic), Kosice (Slovakia) and Sofia (Bulgaria). Control populations were included from each city. In total 356 individuals were enrolled. A questionnaire was used to determine life style/dietary factors. Ambient air exposure was measured by stationary monitoring, and personal exposure monitoring was also carried out. The characteristics of the population are described in this paper together with their personal exposure to carcinogenic PAHs (c-PAHs). The dose of c-PAH exposure was found to vary between the occupationally exposed (e.g. policemen and bus drivers) and the control populations in each country, and also varied from country to country.
  Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 08/2007; 620(1-2):1-6. · 2.85 Impact Factor
• Source

  Available from: le.ac.uk

  Article: The relationship between biomarkers of oxidative DNA damage, polycyclic aromatic hydrocarbon DNA adducts, antioxidant status and genetic susceptibility following exposure to environmental air pollution in humans.

  Rajinder Singh, Radim J Sram, Blanka Binkova, Ivan Kalina, Todor A Popov, Tzveta Georgieva, Seymour Garte, Emanuela Taioli, Peter B Farmer
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  ABSTRACT: Polycyclic aromatic hydrocarbons (PAHs) appear to be significant contributors to the genotoxicity and carcinogenicity of air pollution present in the urban environment for humans. Populations exposed to environmental air pollution show increased levels of PAH DNA adducts and it has been postulated that another contributing cause of carcinogenicity by environmental air pollution may be the production of reactive oxygen species following oxidative stress leading to oxidative DNA damage. The antioxidant status as well as the genetic profile of an individual should in theory govern the amount of protection afforded against the deleterious effects associated with exposure to environmental air pollution. In this study we investigated the formation of total PAH (bulky) and B[a]P DNA adducts following exposure of individuals to environmental air pollution in three metropolitan cities and the effect on endogenously derived oxidative DNA damage. Furthermore, the influence of antioxidant status (vitamin levels) and genetic susceptibility of individuals with regard to DNA damage was also investigated. There was no significant correlation for individuals between the levels of vitamin A, vitamin E, vitamin C and folate with M(1)dG and 8-oxodG adducts as well as M(1)dG adducts with total PAH (bulky) or B[a]P DNA adducts. The interesting finding from this study was the significant negative correlation between the level of 8-oxodG adducts and the level of total PAH (bulky) and B[a]P DNA adducts implying that the repair of oxidative DNA damage may be enhanced. This correlation was most significant for those individuals that were non smokers or those unexposed to environmental air pollution. Furthermore the significant inverse correlation between 8-oxodG and B[a]P DNA adducts was confined to individuals carrying the wild type genotype for both the GSTM1 and the GSTT1 gene (separately and interacting). This effect was not observed for individuals carrying the null variant.
  Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 08/2007; 620(1-2):83-92. · 2.85 Impact Factor
• Article: Role of GSTT1 deletion in DNA oxidative damage by exposure to polycyclic aromatic hydrocarbons in humans.

  Seymour Garte, Emanuela Taioli, Todor Popov, Ivan Kalina, Radim Sram, Peter Farmer
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  ABSTRACT: A useful approach for studies on the mechanisms of genetic variation in cancer susceptibility is to use intermediary biochemical endpoints with mechanistic relevance to the genes under study. We examined the effects of individual genotype at seven metabolic gene loci on a marker of oxidative DNA damage, 8-oxo-7,8-dihydro-2-deoxyguanosine, in people exposed to polycyclic aromatic hydrocarbons (PAH) from three Central European cities. The GSTT1 homozygous deletion variant was associated with a significant protective effect for exposure to total PAHs and to eight specific PAHs, although the magnitude and significance of the effect varied among these compounds. Categorical sensitivity analysis was used to determine that the frequency of the GSTT1 deletion was significantly higher in people who proved to be more resistant to the DNA damaging effects of PAH exposure than in people who were the most sensitive. There is a growing literature on the protective effect of GSTT1 deletion in both disease and intermediary endpoints related to environmental carcinogenesis. The mechanism for this effect might be related to specific PAH substrate specificities, or could be related to other functions of GSTT1 gene in oxidative stress induced damage pathways.
  International Journal of Cancer 07/2007; 120(11):2499-503. · 5.44 Impact Factor
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  Available from: Ivo Solansky

  Article: Chromosomal aberrations by fluorescence in situ hybridization (FISH)--Biomarker of exposure to carcinogenic PAHs.

  Olena Beskid, Blanka Binkova, Zdik Dusek, Pavel Rössner, Ivo Solansky, Ivan Kalina, Jozef Zidzik, Todor A Popov, Peter B Farmer, Radim J Sram
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  ABSTRACT: The fluorescence in situ hybridization (FISH) technique with whole chromosome painting for chromosomes #1 and #4 was used to study the impact of air pollution containing higher concentrations of carcinogenic polycyclic aromatic hydrocarbons (c-PAHs) in three European cities, Prague (Czech Republic), Kosice (Slovakia) and Sofia (Bulgaria). In each site were followed an exposed group, who were police officers or bus drivers who work usually through busy streets for at least 8h, and a reference group, who spent more than 90% of their daily time indoors. In Prague, a significant increase was observed in percentage of aberrant cells (% AB.C.) in the police officers compared to the reference group (0.33+/-0.25 versus 0.24+/-0.18, p<0.05). In Kosice, the exposed group differed from reference in the endpoints F(G)/100 1.52+/-1.18 versus 1.12+/-1.30, p<0.05; % AB.C. 0.30+/-0.19 versus 0.21+/-0.20, p<0.05; t/1000 3.91+/-3.18 versus 2.84+/-3.10, p<0.05. In Sofia were followed two exposed groups: police officers and bus drivers. All FISH endpoints were significantly higher in police officers compared to reference group (F(G)/100 1.60+/-0.99 versus 0.82+/-0.79, p<0.01; % AB.C. 0.25+/-0.14 versus 0.13+/-0.13, p<0.01; t/1000 4.19+/-2.65 versus 2.13+/-2.05, p<0.05; rcp 1.46+/-1.07 versus 0.70+/-0.76, p<0.05). In bus drivers compared to reference there was an increase in % AB.C. (0.25+/-0.18 versus 0.13+/-0.13, p<0.05). This is the first study when FISH method was used to analyze the impact of environmental air pollution. According to the original hypothesis it is expected that the most important group of chemicals responsible for the biological activity of air pollution represent c-PAHs.
  Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 07/2007; 620(1-2):62-70. · 2.85 Impact Factor
• Article: Effects of diet on biomarkers of exposure and effects, and on oxidative damage.

  Sara Raimondi, Seymour Garte, Radim J Sram, Blanka Binkova, Ivan Kalina, K Lyubomirova, Emanuela Taioli, Rajinder Singh, Peter B Farmer
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  ABSTRACT: Modification of DNA is believed to be a key step in carcinogenesis, and therefore DNA adducts have been proposed as predictive biomarkers of human cancer. Smoked and grilled foods are important contributors of PAH-DNA adduct levels, while the consumption of flavonoids and other antioxidants seems to decrease the level of DNA adducts. The aim of this study was to assess the effect of each group of foods and of different dietary profiles on the DNA adducts levels and on oxidative damage to DNA. Occupationally exposed men were recruited in Czech Republic, Slovak Republic and Bulgaria. Non-occupationally exposed subjects were matched on age and gender to PAH-exposed workers. Three hundred and fifty-six subjects who completed the questionnaire for dietary information and had a measurement of DNA adduct levels and oxidative damage to DNA were included in this study. No food item seemed to be individually associated with markers of exposure or DNA damage. Total DNA adducts levels were significantly higher for subjects who had eaten, in the previous 24h, smoked or fried food. A Principal Components Analysis was performed to identify groups of subjects with similar dietary profiles: no significant differences in biomarker levels were observed among the groups defined according to dietary profiles. In conclusion, this study did not show any significant association between diet and biomarkers of DNA damage, oxidative damage to DNA and chromosomal aberrations, neither when each food was considered separately, nor when the effect of different dietary profiles was tested. The recent consumption of smoked or fried food was associated with an increase in total DNA adducts levels.
  Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 07/2007; 620(1-2):93-102. · 2.85 Impact Factor
• Article: Effects of metabolic genotypes on intermediary biomarkers in subjects exposed to PAHS: results from the EXPAH study.

  Seymour Garte, Emanuela Taioli, Sara Raimondi, Valentina Paracchini, Blanka Binkova, Radim J Sram, Ivan Kalina, Todor A Popov, Rajinder Singh, Peter B Farmer
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  ABSTRACT: Data from the EXPAH project on PAH exposure and intermediary biomarkers were analyzed with respect to individual genotypes at seven metabolic gene loci. The GSTM1 null allele was associated with significantly higher levels of two biomarkers, malondialdehyde-2'-deoxyguanosine and benzo[a]pyrene DNA adducts in the total population from three Central and Eastern European countries. The CYP1B1 Leu/Val variant demonstrated effects on both markers of oxidative DNA damage in opposite directions, producing a higher level of M(1)dG with a trend from wild type (Leu/Leu) to heterozygotes to homozygous (Val/Val) variants, whereas the effects of these variants were reversed for 8-oxodG. Cluster Analysis was used to group composite genotypes in order to determine if combined genotypes of multiple loci could explain some of the variation seen with the biomarkers, expressed per unit of exposure, referred to as a sensitivity index. This analysis revealed two closely related genotypes each involving four of the loci (GSTM1*0/*0, CYP1A1*1*1, CYP1B1*1/*2, GSTP1*1/*1 and GSTT1*0/*0, CYP1A1*1*1, CYP1B1*1/*2, GSTP1*1/*1.) that conferred significant resistance to the DNA damaging effects of benzo[a]pyrene, measured as the level of a benzo[a]pyrene-like adduct per unit of benzo[a]pyrene exposed.
  Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 07/2007; 620(1-2):7-15. · 2.85 Impact Factor
• Article: Biomarkers of exposure to carcinogenic PAHs and their relationship with environmental factors.

  Emanuela Taioli, Radim J Sram, Blanka Binkova, Ivan Kalina, Todor A Popov, Seymour Garte, Peter B Farmer
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  ABSTRACT: The EXPAH project is a multicentre European study in which biomarkers of exposure, biomarkers of effect, genetic susceptibility and environmental factors were studied in populations exposed to differing levels of carcinogenic polycyclic aromatic hydrocarbons (c-PAHs). We describe here the relationships between the levels of DNA adducts (as biomarkers of exposure), the exposure to air pollution and smoking status. Lymphocyte bulky DNA adducts were significantly correlated with exposure when subjects were classified either by job description or by personal monitor measurements, and both bulky and benzo(a)pyrene (B[a]P) DNA adducts were also correlated with smoking status. These associations varied across the countries studied (Czech Republic, Slovakia, Bulgaria). Results from a multivariate analysis show that factors mainly contributing to bulky and B[a]P DNA adducts are age, smoking habit, country of origin and environmental exposure to c-PAHs. The B[a]P DNA adducts were more strongly associated with smoking status than with the environmental exposure to c-PAHs.
  Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 07/2007; 620(1-2):16-21. · 2.85 Impact Factor
• Source

  Available from: Alena Gábelová

  Article: Sensitivity of different endpoints for in vitro measurement of genotoxicity of extractable organic matter associated with ambient airborne particles (PM10).

  Alena Gábelová, Zuzana Valovicová, Gabriela Bacová, Juraj Lábaj, Blanka Binková, Jan Topinka, Oksana Sevastyanova, Radim J Srám, Ivan Kalina, Viera Habalová, Todor A Popov, Teodor Panev, Peter B Farmer
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  ABSTRACT: Sensitivity and correlations among three endpoints were evaluated to assess the genotoxic potential of organic complex mixtures in vitro. This study was focused on DNA adduct formation, DNA single strand break induction and tumour suppressor p53 protein up-regulation produced by extractable organic matter (EOM) absorbed on respirable particulate matter PM(10) (particulate matter<10microm) collected in three European cities (Prague, Sofia, Kosice) during winter and summer period. To compare the sensitivity of particular endpoints for in vitro measurement of complex mixture genotoxicity, the metabolically competent human hepatoma cell line Hep G2 was treated with equivalent EOM concentration of 50microg/ml. Cell exposure to EOMs resulted in significant DNA adduct formation and DNA strand break induction, however, a lack of protein p53 up-regulation over the steady-state level was found. While the maximum of DNA strand breaks was determined after 2h cell exposure to EOMs, 24h treatment interval was optimal for DNA adduct determination. No substantial location- and season-related differences in EOM genotoxicity were detected using DNA strand break assessment. In agreement with these results no significant variation in DNA adduct levels were found in relation to the locality and season except for the monitoring site in Prague. The Prague EOM sample collected during summer period produced nearly three-fold lower DNA adduct level in comparison to the winter EOM sample. Comparable results were obtained when the ambient air genotoxicity, based on the concentration of carcinogenic PAHs in cubic meter of air (ng c-PAHs/m(3)), was elicited using either DNA adduct or strand break determination. In general, at least six-fold higher genotoxicity of the winter air in comparison to the summer air was estimated by each particular endpoint. Moreover, the genotoxic potential of winter air revealed by DNA adduct assessment and DNA strand break measurement increased in the same order: Kosice<Prague<Sofia. Based on these data we suppose that two endpoints DNA breakage and DNA adduction are sensitive in vitro biomarkers for estimation of genotoxic activity of organic complex mixture associated with airborne particles. On the other hand, the measurement of protein p53 up-regulation manifested some limitations; therefore it cannot be used as a reliable endpoint for in vitro genotoxicity assessment.
  Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 07/2007; 620(1-2):103-13. · 2.85 Impact Factor
• Article: Influence of PAHs in ambient air on chromosomal aberrations in exposed subjects: international study - EXPAH.

  Jozef Zidzik, Ivan Kalina, Jan Salagovic, Radim J Sram, Pavel Rössner, Todor Popov, Peter B Farmer
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  ABSTRACT: The aim of this study was to determine the influence of carcinogenic polycyclic aromatic hydrocarbons (c-PAHs) in complex mixtures in ambient air on DNA damage (chromosomal aberrations) in occupationally exposed subjects measured as percent of aberrant cells (% AB.C.). There were in total 203 exposed subjects and 150 respective controls in the whole project, allocated in three different European cities - Kosice (Slovakia), Prague (Czech Republic) and Sofia (Bulgaria). The studied population from Kosice (Slovakia) consisted of 106 subjects. From these 51 were exposed policemen and 55 were controls. The Czech population comprised 52 exposed policemen and 50 controls. In Bulgaria, there were two equally numerous exposed groups: 50 policemen and 50 professional bus drivers together with 45 controls. According to personal monitoring, policemen and bus drivers in the Bulgarian capital Sofia were exposed to the highest levels of c-PAHs amongst the exposed subject groups in the cities (45.3+/-25.9ng/m(3) in policemen resp. 36.1+/-31.6ng/m(3) in bus drivers in Sofia, 26.8+/-39.8ng/m(3) for policemen in Kosice and 11.9+/-11.2ng/m(3) for policemen in Prague), compared to the respective controls (24.9+/-17.7ng/m(3) for controls in Sofia, 7.9+/-3.8ng/m(3) for controls in Kosice and 6.2+/-3.6ng/m(3) for controls in Prague). We observed the following frequency of % AB.C. scored by conventional method: 2.60+/-2.64 in exposed policemen and 2.14+/-1.61 in controls in Kosice (p=n.s.); 2.33+/-1.53 in exposed policemen and 1.94+/-1.28 in controls in Prague (p=n.s.); 3.04+/-1.64 in exposed policemen, respectively, 3.60+/-1.63 in exposed bus drivers and 1.79+/-0.77 in the control group in Sofia (p<0.05, respectively, p<0.05). According to data from multiple regression analysis, and group comparison of smokers versus nonsmokers in Sofia also cigarette smoking (p=0.055) and the age (p=0.020) seem to play an important role within the aberrant cell formation in addition to the occupational c-PAHs exposure (p=0.000). Smoking status was the modifying factor for % AB.C. in Kosice (p=0.020) after multiple regression approach was employed. In summary, we can say that subjects occupationally exposed to higher levels of c-PAHs in ambient air in Sofia are at greater genotoxic risk compared to those working indoors.
  Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 07/2007; 620(1-2):41-8. · 2.85 Impact Factor
• Article: Metabolic gene polymorphisms and lung cancer risk in non-smokers. An update of the GSEC study.

  Sara Raimondi, Paolo Boffetta, Sisko Anttila, Jürgen Bröckmoller, Dorota Butkiewicz, Ingolf Cascorbi, Margie L Clapper, Tommaso A Dragani, Seymour Garte, Andre Gsur, [......], Edyta Reszka, David Ryberg, Angela Risch, Marjorie Romkes, Alberto Ruano-Ravina, Bernadette Schoket, Monica Spinola, Haruhiko Sugimura, Xifeng Wu, Emanuela Taioli
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  ABSTRACT: Since genetic factors may play an important role in lung cancer development at low dose carcinogen exposure, non-smokers are a good model to study genetic susceptibility and its interaction with environmental factors. We evaluated the role of the metabolic gene polymorphisms CYP1A1MspI, CYP1A1Ile462Val, GSTM1, and GSTT1 in non-smoker lung cancer patients from the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (GSEC). Non-smokers (defined as subjects who never smoked on a regular basis) were selected from the GSEC database. We pooled the raw data from 21 case-control studies for a total of 2764 Caucasians (555 cases and 2209 controls) and 383 Asians (113 cases and 270 controls). Tests of heterogeneity and of inclusion bias were performed. A significant association between lung cancer and CYP1A1Ile462Val polymorphism was observed in Caucasians (adjusted OR=2.04, 95% CI 1.17-3.54). GSTT1 deletion seems to be a risk factor for lung cancer in Caucasian non smokers only when the analysis was restricted to studies including healthy controls (adjusted OR=1.66, 95% CI 1.12-2.46). A protective effect on lung cancer was observed with the combination of CYP1A1 wild type, GSTM1 null, and GSTT1 non-null genotypes. None of the analysed polymorphisms were associated with lung cancer in Asian non-smokers. Our analysis confirms previous findings that CYP1A1Ile462Val polymorphism may play a role in lung carcinogenesis in Caucasian non-smokers.
  Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 01/2006; 592(1-2):45-57. · 2.85 Impact Factor
• Article: The link between angiotensin-converting enzyme genotype and pulmonary artery pressure in patients with COPD.

  Ruzena Tkácová, Pavol Joppa, Branislav Stancák, Ján Salagovic, Silvia Misíková, Ivan Kalina
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  ABSTRACT: The insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with an increased risk of cardiovascular diseases. In patients with primary pulmonary hypertension, the homozygous ACE DD genotype is more prevalent than the non-DD genotype. However, the relationship of ACE gene polymorphism to secondary pulmonary hypertension remains unclear, and ethnicity may be one of the factors that can modulate the effects of ACE genotypes reported in different studies. We hypothesized that in patients with chronic obstructive pulmonary disease (COPD) the presence of the D allele in the ACE gene polymorphism is associated with increased pulmonary artery pressure (Ppa). Bodyplethysmography was used to assess lung function in 66 consecutive patients with COPD; pulmonary artery pressures were determined using echocardiography. ACE gene I/D polymorphism was identified with the polymerase chain reaction. 118 healthy persons served as the control group. All patients and controls were Caucasian. Genotype II was identified in 15 patients with COPD, genotype ID in 31 and genotype DD in 20. In the control group, genotype II was identified in 19 persons, genotype ID in 68 and genotype DD in 31. The distribution of ACE gene polymorphism did not differ between patients and the control group. In patients with COPD, no differences were seen between the three genotype groups in mean age, smoking history, hemoglobin concentrations or ventilometric or blood gas variables. Both systolic and mean Ppa differed significantly between the II, ID and DD groups (Systolic Ppa: 24.4 +/- 2.2 versus 31.3 +/- 2.5 and 36.7 +/- 3.9 mm Hg, respectively, ANOVA, p < 0.05; Mean Ppa: 13.0 +/- 1.5 versus 17.5 +/- 1.4 and 21.2 +/- 2.8 mm Hg, respectively, ANOVA, p < 0.05). In multiple linear regression analysis, the I/D ACE gene polymorphism (p < 0.05), SaO2 (p < 0.05) and the duration of COPD (p < 0.02) were independent predictors of systolic and mean Ppa. The results of the study suggest that I/D ACE gene polymorphism is linked to pulmonary artery pressure in Caucasian patients with COPD.
  Wiener klinische Wochenschrift 04/2005; 117(5-6):210-4. · 0.81 Impact Factor
• Article: The link between angiotensin-converting enzyme genotype and pulmonary artery pressure in patients with COPD

  Ružena Tkáčová, Pavol Joppa, Branislav Stančák, Ján Šalagovič, Silvia Mišíková, Ivan Kalina
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  ABSTRACT: OBJECTIVE: The insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with an increased risk of cardiovascular diseases. In patients with primary pulmonary hypertension, the homozygous ACE DD genotype is more prevalent than the non-DD genotype. However, the relationship of ACE gene polymorphism to secondary pulmonary hypertension remains unclear, and ethnicity may be one of the factors that can modulate the effects of ACE genotypes reported in different studies. We hypothesized that in patients with chronic obstructive pulmonary disease (COPD) the presence of the D allele in the ACE gene polymorphism is associated with increased pulmonary artery pressure (Ppa). PATIENTS AND METHODS: Bodyplethysmography was used to assess lung function in 66 consecutive patients with COPD; pulmonary artery pressures were determined using echocardiography. ACE gene I/D polymorphism was identified with the polymerase chain reaction. 118 healthy persons served as the control group. All patients and controls were Caucasian. Genotype II was identified in 15 patients with COPD, genotype ID in 31 and genotype DD in 20. In the control group, genotype II was identified in 19 persons, genotype ID in 68 and genotype DD in 31. The distribution of ACE gene polymorphism did not differ between patients and the control group. RESULTS: In patients with COPD, no differences were seen between the three genotype groups in mean age, smoking history, hemoglobin concentrations or ventilometric or blood gas variables. Both systolic and mean Ppa differed significantly between the II, ID and DD groups (systolic Ppa, 24.4 2.2 versus 31.3 2.5 and 36.7 3.9mmHg, respectively, ANOVA, p < 0.05;="" mean="">Ppa, 13.0 1.5 versus 17.5 1.4 and 21.2 2.8mmHg, respectively, ANOVA, p < 0.05).="" in="" multiple="" linear="" regression="" analysis,="" the="" i/d="" ace="" gene="" polymorphism="" (p="">< 0.05),="">2 (p < 0.05)="" and="" the="" duration="" of="" copd="" (p="">< 0.02)="" were="" independent="" predictors="" of="" systolic="" and="" mean="">Ppa. CONCLUSION: The results of the study suggest that I/D ACE gene polymorphism is linked to pulmonary artery pressure in Caucasian patients with COPD.ZIEL: Der Insertions-(I-)/Deletions-(D-)Polymorphismus des Angiotensin-converting Enzyms (ACE) scheint mit einem erhhtem Risiko fr kardiovaskulre Erkrankungen vergesellschaftet zu sein. Bei Patienten mit primrer pulmonaler Hypertonie ist der homozygote ACE-DD-Genotyp hufiger als der Non-DD-Genotyp. Bei der sekundren pulmonalen Hypertonie bleibt aber das Verhltnis zum ACE-Genpolymorphismus unklar. Die Ergebnisse verschiedener Studien lassen auch an ethnische Faktoren in diesem Zusammenhang denken. Wir haben die Hypothese aufgestellt, dass bei Patienten mit chronisch obstruktiver Lungenerkrankung (COPD) die Gegenwart des D-Allels im ACE-Genpolymorphismus mit erhhtem pulmonal arteriellen Druck (Ppa) verbunden ist. PATIENTEN UND METHODEN: Bei 66 konsekutiven Patienten mit COPD wurde die Lungenfunktion mit der Bodyplethysmographie und der pulmonal arterielle Druck durch Echokardiographie bestimmt. Der ACE-Gen-I/D-Polymorphismus wurde durch PCR erhoben. 118 Personen dienten als Kontrolle. Alle Patienten und Kontrollpersonen waren Kaukasier. ERGEBNISSE: Der II-Genotyp wurde bei 15, der ID-Genotyp bei 31 und der DD-Genotyp bei 20 Patienten mit COPD festgestellt. In der Kontrolle kam der II Genotyp 19-mal, der ID-Genotyp 68-mal, und der DD-Genotyp 31-mal vor. Die Verteilungen der ACE-Genpolymorphismen unterschieden sich nicht signifikant zwischen beiden Gruppen. In der COPD-Gruppe war auch kein signifikanter Unterschied bezglich Alter, Raucheranamnese, Hmoglobin-Konzentration und Lungenfunktionsparameter bzw. Blutgasen zwischen den drei Genotypen-Gruppen erhebbar. Sowohl der systolische als auch der mittlere Ppa waren allerdings zwischen der II-, ID- und der DD-Gruppe signifikant unterschiedlich (systolischer Ppa, 24,4 2,2 versus 31,3 2,5 bzw. 36,7 3,9mmHg, ANOVA p < 0,05;="" mittlerer="">Ppa, 13,0 1,5 versus 17,5 1,4 bzw. 21,2 2,8mmHg, ANOVA p < 0,05).="" in="" der="" multiplen="" linearen="" regressionsanalyse="" waren="" der="" i/d-ace-genpolymorphismus="" (p="">< 0,05),="" die="">2 (p < 0,05)="" und="" die="" dauer="" der="" copd="" (p="">< 0,02)="" unabhngige="" prdiktoren="" des="" systolischen="" und="" des="" mittleren="">Ppa. SCHLUSSFOLGERUNG: Unsere Studie weist darauf hin, dass der I/D-ACE-Genpolymorphismus bei kaukasischen Patienten mit COPD mit dem pulmonal arteriellen Druck verbunden ist.
  Wiener klinische Wochenschrift 01/2005; 117(5):210-214. · 0.81 Impact Factor
• Article: Association of metabolic gene polymorphisms with tobacco consumption in healthy controls.

  Kim M Smits, Simone Benhamou, Seymour Garte, Matty P Weijenberg, Yannis Alamanos, Christine Ambrosone, Herman Autrup, Judith L Autrup, Helena Baranova, Lisa Bathum, [......], Daniel Sinnett, Richard C Strange, Isabelle Stucker, Haruhiko Sugimura, Jordi To-Figueras, Paolo Vineis, Mimi C Yu, Wei Zheng, Paola Pedotti, Emanuela Taioli
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  ABSTRACT: Polymorphisms in genes that encode for metabolic enzymes have been associated with variations in enzyme activity between individuals. Such variations could be associated with differences in individual exposure to carcinogens that are metabolized by these genes. In this study, we examine the association between polymorphisms in several metabolic genes and the consumption of tobacco in a large sample of healthy individuals. The database of the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens was used. All the individuals who were controls from the case-control studies included in the data set with information on smoking habits and on genetic polymorphisms were selected (n = 20938). Sufficient information was available on the following genes that are involved in the metabolism of tobacco smoke constituents: CYP1A1, GSTM1, GSTT1, NAT2 and GSTP1. None of the tested genes was clearly associated with smoking behavior. Information on smoking dose, available for a subset of subjects, showed no effect of metabolic gene polymorphisms on the amount of smoking. No association between polymorphisms in the genes studied and tobacco consumption was observed; therefore, no effect of these genes on smoking behavior should be expected.
  International Journal of Cancer 07/2004; 110(2):266-70. · 5.44 Impact Factor
• Article: Glutathione S-transferase M1 gene polymorphism is related to COPD in patients with non-small-cell lung cancer.

  Ruzena Tkácová, Ján Salagovic, Marianna Ceripková, Ivan Tkác, Ján Stubna, Ivan Kalina
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  ABSTRACT: Oxidative stress contributes to the development of both lung cancer and chronic obstructive pulmonary disease (COPD). Antioxidative enzymes may protect against such damage. We hypothesized that genetic variations in glutathione S-transferase M1 and/or T1 genes (GSTM1 and GSTT1, respectively) may influence susceptibility to COPD in patients with non-small-cell lung cancer. The polymorphisms in GSTM1 and GSTT1 genes were examined in 110 patients (age: 63+/-1 years) with newly diagnosed non-small-cell lung cancer using the polymerase chain reaction. Respiratory function was assessed by bodyplethysmography. In the GSTM1 null (-/-) genotype, both FEV1 and FEV1/FVC were significantly lower than in the GSTM1 plus genotype (GSTM1 -/+ or +/+) (75.8+/-2.5 versus 86.6+/-3.6%, p<0.02; 69.1+/-1.6 versus 77.0+/-2.4, p<0.01, respectively). Among the patients with GSTM1 null genotype, 49% suffered from COPD as opposed to 21% of patients with GSTM1 plus genotype. In contrast, no differences were seen in FEV1 or FEV1/FVC when comparing patients with GSTT1 null genotype and GSTT1 plus genotype (81.4+/-4.9 versus 79.3+/-2.3, p=NS; 71.1+/-2.9 versus 72.2+/-1.6, p=NS). Multiple stepwise regression analysis identified the GSTM1 genotype (p<0.02) as a significant independent predictor of FEV1 in this group of patients. The present study suggests that in patients with non-small-cell lung cancer the presence of at least one active allele in GSTM1 has a protective effect against the development of COPD.
  Wiener klinische Wochenschrift 03/2004; 116(4):131-4. · 0.81 Impact Factor
• Article: Angiotensin-converting enzyme genotype, albuminuria and plasma fibrinogen in type 2 diabetes mellitus.

  Ivan Tkác, Ján Salagovic, Miriam Kozárová, Martin Javorský, Ruzena Tkácová, Ivan Kalina
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  ABSTRACT: Increased fibrinogen level is considered an important atherosclerosis risk factor. Patients with type 2 diabetes frequently have increased fibrinogen levels. The aim of the present study was to examine the effect of angiotensin-converting enzyme (ACE) gene polymorphism and the effects of the diabetic environment on plasma fibrinogen in type 2 diabetes. The study group included 125 patients with type 2 diabetes (40 men, 85 women). The average age of patients was 62 +/- 10 years. Fibrinogen concentration was determined with the thrombin coagulation test. ACE insertion/deletion (I/D) polymorphism was detected using polymerase chain reaction (PCR) assay. II homozygotes (n = 17) had the highest mean fibrinogen levels, ID heterozygotes (n = 75) had medium levels and DD homozygotes (n = 33) had the lowest (p = 0.054, ANOVA). II homozygotes also had significantly higher mean fibrinogen level than ID/DD carriers (4.3 +/- 1.7 vs. 3.5 +/- 1.3 g/l; p = 0.015). The indices of renal functions, i.e. albuminuria (r = 0.37; p < 0.0001) and serum creatinine (r = 0.22; p = 0.015), significantly correlated with fibrinogen levels. The correlation between albuminuria and fibrinogen was significant in the subgroups with genotypes II (r = 0.76; p = 0.001) and ID (r = 0.37, p = 0.002), whereas in the subgroup of DD homozygotes this relationship did not reach statistical significance. In the multivariate regression analysis with age, sex, BMI, creatinine, albuminuria and ACE genotype as independent variables, albuminuria was the only significant predictor of fibrinogen level (p < 0.0001). After interaction between the ACE genotype and albuminuria was included into multivariate analysis, the interaction became the only independent predictor of plasma fibrinogen level (p < 0.0001) in the model, and the model explained 25% of the plasma fibrinogen variance. ACE gene polymorphism is associated with plasma fibrinogen level in type 2 diabetes. This association is mediated by an interaction between ACE genotype and albuminuria. Diabetes patients with genotypes II or ID have increased plasma fibrinogen in the presence of albuminuria.
  Wiener klinische Wochenschrift 01/2004; 115(23):835-9. · 0.81 Impact Factor