[Show abstract][Hide abstract] 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. DOI:10.1016/j.mrrev.2010.04.004 · 3.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Only few studies have examined early hematological effects in human populations exposed to low benzene levels and their findings are controversial. We evaluated hematological outcomes (WBC, neutrophils, lymphocytes, monocytes, eosinophils, basophils, RBC, Hb, HCT MCV, platelets and MPV) in a population of 153 Bulgarian petrochemical workers exposed to benzene (range 0.01-23.9 ppm) and 50 unexposed subjects.
Written informed consent was obtained and a self-administered questionnaire used to collect information on current smoking habits, lifestyle, and occupational activities. Exposure assessment was based on personal monitoring sampling the day before phlebotomy. Urinary trans-trans-muconic acid (t,t-MA) was determined at the beginning and end of the work shift. Based on individual airborne benzene measurements, study subjects were categorized in three exposure categories (referents, <1 and > or =1 ppm). Mean values of each hematologic outcomes in each exposure category were compared with the referent group using a multiple linear regression model adjusted for age, gender, current smoking habits and environmental toluene level. The influence of the CYP2E1 (RsaI and DraI) and NQO1 609C>T genetic polymorphisms on differential hematological parameters was also investigated.
No dose-response effect was observed for most of the examined hematological outcomes (WBC, lymphocytes, neutrophils, monocytes, RBC, Hb, HCT, MCV, platelets and MPV). The eosinophil count was inversely related to benzene exposure only among smokers. Conversely, basophils increased with increasing exposure. No effect on benzene hematotoxicity was found for any of the investigated polymorphisms.
In our study we did not find a decline in WBC and lymphocytes related to benzene exposure. A myeloproliferative effect of benzene is highly unlikely to explain the observed reduction in eosinophils and increase in basophils as it would lead to a concordant depression in all granulocyte subpopulations. Whether benzene effects at low doses are present in Caucasian populations remains uncertain, thus warranting further investigations.
La Medicina del lavoro 03/2009; 100(2):83-90. · 0.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: DNA adducts are markers of carcinogen exposure and of their biological effect; they have been shown to be related to mutagenesis, and therefore they could be a predictive biomarker of human cancer. The objective of this study was to assess if there is a relationship between vitamins A, C, and E, which are known to play a significant role as free radical scavengers and antioxidant agents, and biomarkers of genotoxicity and oxidative stress. Three hundred and fifty-six subjects from Czech Republic, Slovak Republic and Bulgaria, who completed a questionnaire on dietary information and had a measurement of plasma A, C, E vitamins, DNA adduct levels (benzo[a]pyrene (B[a]P) and bulky (DNA-Tot) DNA adducts) and oxidative damage (cyclic pyrimidopurinone N-1,N2 malondialdehyde-2 deoxyguanosine (M1dG) and 8-oxo-7,8-dihydro-2_deoxyguanosine (8-oxodG)) were analyzed. A significant inverse correlation was observed between plasma vitamin levels and both benzo[a]pyrene (B[a]P) and bulky DNA adducts. Vitamin A was also significantly inversely correlated with M1dG, a marker of oxidative damage. The associations were stronger in non-smokers than in smokers. Dietary intake of certain antioxidants such as vitamins is associated with reduced levels of markers of DNA damage (B[a]P and DNA-Tot) and oxidation (M1dG and 8-oxodG) measured in peripheral white blood cells. This could contribute to the protective role of such a dietary pattern on cancer risk. The protective effect of dietary vitamins is less evident in smokers.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 12/2008; 672(2):129-34. DOI:10.1016/j.mrgentox.2008.11.005 · 3.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human metabolism of benzene involves pathways coded for by polymorphic genes. To determine whether the genotype at these loci might influence susceptibility to the adverse effects of benzene exposure, 208 Bulgarian petrochemical workers and controls, whose exposure to benzene was determined by active personal sampling, were studied. The frequency of DNA single-strand breaks (DNA-SSB) was determined by alkaline elution, and genotype analysis was performed for five metabolic loci. Individuals carrying the NAD(P)H:quinone oxidoreductase 1 (NQO1) variant had significantly twofold increased DNA-SSB levels compared to wild-type individuals. The same result was observed for subjects with microsomal epoxide hydrolase (EPHX) genotypes that predict the fast catalytic phenotype. Deletion of the glutathione S-transferase T1 (GSTT1) gene also showed a consistent quantitative 35-40% rise in DNA-SSB levels. Neither glutathione S-transferase M1 (GSTM1) nor myeloperoxidase (MPO) genetic variants exerted any effect on DNA-SSB levels. Combinations of two genetic polymorphisms showed the same effects on DNA-SSB as expected from the data on single genotypes. The three locus genotype predicted to produce the highest level of toxicity, based on metabolic pathways, produced a significant 5.5-fold higher level of DNA-SSB than did the genotype predicted to yield the least genotoxicity.
Journal of Toxicology and Environmental Health Part A 02/2008; 71(22):1482-9. DOI:10.1080/15287390802349974 · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Principal aims of this study were at first, to find a relevant human derived cell line to investigate the genotoxic potential of PAH-containing complex mixtures and second, to use this cell system for the analysis of DNA adduct forming activity of organic compounds bound onto PM10 particles. Particles were collected by high volume air samplers during summer and winter periods in three European cities (Prague, Kosice, and Sofia), representing different levels of air pollution. The genotoxic potential of extractable organic matter (EOM) was compared with the genotoxic potential of individual carcinogenic polycyclic aromatic hydrocarbons (c-PAHs) as well as their artificial mixtures. Metabolically competent human hepatoma HepG2 cells, confluent cultures of human diploid lung fibroblasts (HEL), and the human monocytic leukemia cell line THP-1 were used as models. DNA adducts were analyzed by (32)P-postlabeling. The total DNA adduct levels induced in HepG2 cells after exposure to EOMs were higher than in HEL cells treated under the same conditions (15-190 versus 2-15adducts/10(8) nucleotides, in HepG2 and HEL cells, respectively). THP-1 cells exhibited the lowest DNA adduct forming activity induced by EOMs (1.5-3.7adducts/10(8) nucleotides). A direct correlation between total DNA adduct levels and c-PAH content in EOM was found for all EOMs in HepG2 cells incubated with 50microg EOM/ml (R=0.88; p=0.0192). This correlation was even slightly stronger when B[a]P content in EOMs and B[a]P-like adduct spots were analyzed (R=0.90; p=0.016). As THP-1 cells possess a limited metabolic capacity for most c-PAHs to form DNA reactive intermediates and are also more susceptible to toxic effects of PAHs and various EOM components, this cell line seemed to be an inappropriate system for genotoxicity studies of PAH-containing complex mixtures. The seasonal variability of genotoxic potential of extracts was stronger than variability among the three localities studied. In HepG2 cells, the highest DNA adduct levels were induced by EOM collected in Prague in the winter period, followed by Sofia and Kosice. However, in the summer sampling period, the order was quite opposite: Kosice>Sofia>Prague. When the EOM content per m(3) of air was taken into consideration in order to compare real exposures of humans to genotoxic compounds in all three localities, extracts from respirable dust particles collected in Sofia exhibited the highest genotoxicity regardless of the sampling period. The results indicate that most of DNA adducts detected in cells incubated with EOMs have their origin in low concentrations of c-PAHs representing 0.03-0.17% of EOM total mass. Finally, our results suggest that HepG2 cells have a metabolic capacity for PAHs similar to human hepatocytes and represent therefore the best in vitro model for investigating the genotoxic potential of complex mixtures containing PAHs among the three cell lines tested in this study.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 08/2007; 620(1-2):123-34. DOI:10.1016/j.mrfmmm.2007.03.002 · 3.68 Impact Factor
[Show abstract][Hide abstract] 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. DOI:10.1016/j.mrfmmm.2007.02.024 · 3.68 Impact Factor
[Show abstract][Hide abstract] 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. DOI:10.1016/j.mrfmmm.2007.02.025 · 3.68 Impact Factor
[Show abstract][Hide abstract] 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. DOI:10.1016/j.mrfmmm.2007.03.004 · 3.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acellular assay of calf thymus DNA+/-rat liver microsomal S9 fraction coupled with (32)P-postlabelling was used to study the genotoxic potential of organic compounds bound onto PM10 particles collected in three European cities-Prague (CZ), Kosice (SK) and Sofia (BG) during summer and winter periods. B[a]P alone induced DNA adduct levels ranging from 4.8 to 768 adducts/10(8) nucleotides in the concentration dependent manner. However, a mixture of 8 c-PAHs with equimolar doses of B[a]P induced 3.7-757 adducts/10(8) nucleotides, thus suggesting the inhibition of DNA adduct forming activity by interaction among various PAHs. Comparison of DNA adduct levels induced by various EOMs indicates higher variability among seasons than among localities. DNA adduct levels for Prague collection site varied from 19 to 166 adducts/10(8) nucleotides, for Kosice from 22 to 85 and for Sofia from 6 to 144 adducts/10(8) nucleotides. Bioactivation with S9 microsomal fraction caused 2- to 7-fold increase in DNA adduct levels compared to -S9 samples, suggesting a crucial role of indirectly acting genotoxic EOM components, such as PAHs. We have demonstrated for the first time a significant positive correlation between B[a]P content in EOMs and total DNA adduct levels detected in the EOM treated samples (R=0.83; p=0.04). These results suggest that B[a]P content in EOM is an important factor for the total genotoxic potential of EOM and/or B[a]P is a good indicator of the presence of other genotoxic compounds causing DNA adducts. Even stronger correlation between the content of genotoxic compounds in EOMs and total DNA adduct levels detected (R=0.94; p=0.005) was found when eight c-PAHs were taken into the consideration. Our findings support a hypothesis that a relatively limited number of EOM components is responsible for a major part of its genotoxicity detectable as DNA adducts by (32)P-postlabelling.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 08/2007; 620(1-2):114-22. DOI:10.1016/j.mrfmmm.2007.03.001 · 3.68 Impact Factor
[Show abstract][Hide abstract] 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. DOI:10.1016/j.mrfmmm.2007.02.016 · 3.68 Impact Factor
[Show abstract][Hide abstract] 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. DOI:10.1016/j.mrfmmm.2007.02.023 · 3.68 Impact Factor
[Show abstract][Hide abstract] 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. DOI:10.1016/j.mrfmmm.2007.02.021 · 3.68 Impact Factor
[Show abstract][Hide abstract] 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. DOI:10.1016/j.mrfmmm.2007.02.026 · 3.68 Impact Factor
[Show abstract][Hide abstract] 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. DOI:10.1016/j.mrfmmm.2007.02.017 · 3.68 Impact Factor
[Show abstract][Hide abstract] 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. DOI:10.1016/j.mrfmmm.2007.02.018 · 3.68 Impact Factor
[Show abstract][Hide abstract] 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 06/2007; 120(11):2499-503. DOI:10.1002/ijc.22477 · 5.09 Impact Factor