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Biomedical subjects

J Lewtas

Publications and source records attributed to J Lewtas.

At least 19 recordsLinked to original sources
PubMed2001

Increased DNA alterations in atherosclerotic lesions of individuals lacking the GSTM1 genotype.

Reduced glutathione (GSH) plays a critical role as an intracellular defense system providing detoxification of a broad spectrum of reactive species and their excretion as water-soluble conjugates. Conjugation of GSH with electrophiles is catalyzed by GSH S-transferases (GST), which constitute a broad family of phase II isoenzymes. Two of the GST encoding genes, GSTM1 (mu) and GSTT1 (theta), have a null genotype due to their homozygous deletion that results in lack of active protein. Polymorphisms within GSTT1 and especially GSTM1 have often been associated with cancer in various organs as well as with elevated levels of DNA adducts in various cell types. We recently demonstrated that DNA adducts are consistently detectable in smooth muscle cells (SMC) of human abdominal aorta affected by atherosclerotic lesions. Here we provide evidence that levels of adducts to SMC DNA from atherosclerotic lesions are consistently increased in individuals having the null GSTM1 genotype, whereas no association was established with the GSTT1 polymorphism. The influence of GSTM1 deletion was better expressed in never-smokers and ex-smokers than in current smokers. These findings bear relevance to the epidemiology of atherosclerosis and suggest that metabolic polymorphisms may contribute to the interindividual variability in susceptibility not only to carcinogens, but also to DNA binding atherogens.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2000

Mutagenicity in lung of big Blue((R)) mice and induction of tandem-base substitutions in Salmonella by the air pollutant peroxyacetyl nitrate (PAN): predicted formation of intrastrand cross-links.

Peroxyacetyl nitrate (PAN) is a ubiquitous air pollutant formed from NO(2) reacting with acetoxy radicals generated from ambient aldehydes in the presence of sunlight and ozone. It contributes to eye irritation associated with photochemical smog and is present in most urban air. PAN was generated in a chamber containing open petri dishes of Salmonella TA100 (gas-phase exposure). After subtraction of the background mutation spectrum, the spectrum of PAN-induced mutants selected at 3.1-fold above the background mutant yield was 59% GC-->TA, 29% GC-->AT, 2% GC-->CG, and 10% multiple mutations - primarily GG-->TT tandem-base substitutions. Using computational molecular modeling methods, a mechanism was developed for producing this unusual tandem-base substitution. The mechanism depends on the protonation of PAN near the polyanionic DNA to release NO(2)(+) resulting in intrastrand dimer formation. Insertion of AA opposite the dimerized GG would account for the tandem GG-->TT transversions. Nose-only exposure of Big Blue((R)) mice to PAN at 78ppm (near the MTD) was mutagenic at the lacI gene in the lung (mutant frequency +/-S.E. of 6.16+/-0.58/10(5) for controls versus 8.24+/-0.30/10(5) for PAN, P=0.016). No tandem-base mutations were detected among the 40 lacI mutants sequenced. Dosimetry with 3H-PAN showed that 24h after exposure, 3.9% of the radiolabel was in the nasal tissue, and only 0.3% was in the lung. However, based on the molecular modeling considerations, the labeled portion of the molecule would not have been expected to have been bound covalently to DNA. Our results indicate that PAN is weakly mutagenic in the lungs of mice and in Salmonella and that PAN produces a unique signature mutation (a tandem GG-->TT transversion) in Salmonella that is likely due to a GG intrastrand cross-link. Thus, PAN may pose a mutagenic and possible carcinogenic risk to humans, especially at the high concentrations at which it is present in some urban environments.

Air Pollutants↗
PubMed1997

Air pollution exposure-DNA adduct dosimetry in humans and rodents: evidence for non-linearity at high doses.

The impact of air pollution exposure on the level of total DNA adducts in human white blood cells (WBCs) was evaluated in two populations in the Czech Republic and compared to the exposure-DNA adduct relationship in other populations in the US and China in human lung cells and rodent lung tissue. The human populations examined were exposed to respirable particles (< 2.5 microm) (PM2.5) in urban, rural, and occupational settings where the particles originated from coal and petroleum fuel combustion, coke production, and other coal-tar aerosols (e.g., used in aluminum production). These particles contain carcinogenic polycyclic aromatic hydrocarbons (PAHs) that are known to form DNA adducts through covalent binding. Personal exposure to PM2.5 and PAHs were measured prior to collection of blood samples for DNA adduct analysis by 32P-postlabeling. Coke oven workers (n = 76), in 10 job categories on the top and side of a coke oven in Ostrava, CZ, were studied and compared to a different population exposed to environmental levels of PAHs from air pollution in Teplice, CZ. Personal exposures to airborne particles ranged from < 1 to more than 15,000 microg/m3 and carcinogenic PAHs exposure ranged from < 5 to > 200,000 ng/m3. At low to moderate environmental exposures to carcinogenic PAHs, DNA adduct levels in the WBCs were significantly correlated with exposure. However, at the higher occupational levels found on the coke oven, the exposure-DNA adduct relationship became non-linear. Under these high exposure conditions, the relative DNA adduct level per unit of exposure (DNA-binding potency) was significantly lower than measured at environmental exposures. This finding is consistent with observations in lung cells from bronchoalveolar lavage of humans exposed to a wide range of PAH. This same high exposure-dose non-linearity was also observed in lung DNA from rats exposed by inhalation to a coal-tar pitch aerosol. DNA adduct levels in all these cases show evidence of a form of non-linearity at high doses that has been described by Lutz (W.K. Lutz, Dose-response relationship and low dose extrapolation in chemical carcinogenesis, Carcinogenesis, 11 (1990) 1243-1247) as a superlinear dose response. This superlinear response may be due to saturation of metabolic activation enzymes, induction of either DNA repair processes or detoxification enzymes, or other mechanisms. Regardless of the mechanism, this decrease in the DNA-binding potency at moderate to high doses of PAH has important implications for dose-response extrapolation in risk assessment.

Air Pollutants↗
PubMed1997

Development of a standard reference material for diesel mutagenicity in the Salmonella plate incorporation assay.

The present study documents the mutagenicity of a new National Institute of Standards and Technology (NIST) standard reference material (SRM) in the Salmonella plate incorporation assay. This study is in response to a previous recommendation by the World Health Organization to develop large batches of new SRMs for biological and chemical research. SRM 1975 is a dichloromethane (DCM) extract of 5.6 kg of filter-collected combustion particulate matter (SRM 2975) from operating forklifts with diesel engines. The mutagenicity and a summary of the related chemical analysis of mutagens in SRM 1975 is presented in this paper, and are available from the NIST. Mutagenicity test conditions were: Salmonella typhimurium TA98, TA100 (standard strains); TA98NR, TA100NR (nitroreductase (NR) gene deficient); and YG1021 and YG1026 (NR gene addition); 10 dose levels in the linear portion of the dose-response curve; duplicate plates per dose; and S9 at 6.4% or 1.1 mg of protein/plate. Four rounds of testing were conducted. Rounds were conducted at least 1 week apart. Slopes (revertants/microg) were calculated by the linear regression rejection model of Bernstein and by the Stead and Krewski models which analyze non-linear data. The GeneTox Manager software package developed at the EPA was used to record the data and calculate the slopes. Results demonstrated: (1) the ranking of slopes without S9 was: YG1021 > TA98 > TA98NR > YG1026 > TA100 > TA100NR in all three statistical models; (2) the mutagenic activity of SRM 1975 was significantly increased by the presence of the NR gene; (3) the slope values for the TA100 series were significantly less than for the TA98 series; (4) in general, the addition of the S9 significantly reduced mutagenic activity; (5) the mutagenic activity of the SRM 1975 was stable over time and variability was low (generally less than 20% in slope values over the 4 rounds); and (6) agreement of the slope values among the three models was excellent due to the linear nature of the data. These data will be useful in ranking other diesel and air samples for mutagenic activity, for quality assurance of data generated in different laboratories, for quality control within a laboratory, and as positive control values for future air and automotive emission studies.

Mutagenicity Tests↗
PubMed1997

Metabolic activation of 2- and 3-nitrodibenzopyranone isomers and related compounds by rat liver S9 and the effect of S9 on the mutational specificity of nitrodibenzopyranones.

The effect of rat liver S9 on the mutagenicity of 10 nitrated polycyclic aromatic hydrocarbons (nitro-PAHs) was evaluated with Salmonella typhimurium TA98NR using S9 from phenobarbital-, 3-methylcholanthrene (MC)-, beta-naphthoflavone- and polychlorobiphenyl-treated and untreated rats. 2-Nitrofluorene (2-NFI), 2-nitrofluoren-9-one (2-NFlone), 2-nitrocarbazole (2-NCz), 3-NCz, 2-nitrodibenzothiophene (2-NDBT), 2-nitro-6H-dibenzo[b,d]pyran-6-one (2-NDBP) and 3-NDBP were metabolically activated by one or more of the S9 fractions, and the highest enhancement of the mutagenic potency of nitro-PAHs was observed with 3-MC-induced S9. Only in the case of 3-NFlone was the mutagenicity in strain TA98NR decreased by the addition of S9, regardless of S9 induction. 2-NDBP was most efficiently activated among nitro-PAHs tested by all S9 fractions used. The cytosolic fraction of S9 accounted for more of the activation of 2-NDBP than the microsomal fraction. NADH and NADPH were the most effective electron donors on the activation of 2-NDBP by S9, 2-NDBP was also metabolically activated by NADH plus commercial preparations of xanthine oxidase. These activations of 2-NDBP were inhibited by allopurinol, indicating that cytosolic xanthine oxidase in rat liver S9 participates in the activation of 2-NDBP. The potency of 2- and 3-NDBP isomers as base-substitution mutagens was also enhanced by S9. In the presence of S9, both compounds showed the highest mutagenicity in strain TA7005 (C.G-->A.T) followed by strains TA7004 (G.C-->A.T), TA7006 (C.G-->G.C) and TA7002 (T.A-->A.T), and this mutation specificity was similar to that without S9, indicating that the mechanism of mutagenesis caused by NDBP isomers with S9 is similar to that without S9.

Animals↗
PubMed1997

Molecular epidemiology of atherosclerosis.

It has been hypothesized that mutational events may be involved in the atherogenetic process and that at least a portion of atherosclerotic plaques may develop according to an initiation-promotion process of arterial smooth muscle cells, akin to benign tumors. We conducted a study to evaluate the occurrence of oxidative DNA damage and formation of DNA adducts in human atherosclerotic lesions and to assess the relationships of these promutagenic alterations with exposure to atherogenic risk factors. Pure DNA was extracted from the tunica media (composed mainly of smooth muscle cells) of abdominal aorta fragments taken at surgery from 85 patients suffering from severe atherosclerotic lesions. DNA adducts were detected by synchronous fluorescence spectrophotometry and 32P postlabeling after enrichment of adducts with either butanol or nuclease P1. 8-Hydroxy-2'-deoxyguanosine (8-OH-dG), a typical indicator of oxidative DNA damage, was measured by HPLC/electrochemical detection. A complete questionnaire reporting general, clinical, and laboratory characteristics was available for each patient. All 84 samples tested by 32P postlabeling were positive by displaying the presence of diagonal radioactive zones and up to 9 individual DNA adducts. Of 52 samples tested, 32 (61.5%) yielded typical positive signals at synchronous fluorescence spectrophotometry. All but one of 39 samples tested had very high levels of 8-OH-dG, thus showing a remarkable oxidative DNA damage. Statistically significant correlations were found between the levels of molecular biomarkers and atherogenic risk factors including age, number of currently smoked cigarettes, ratio of total-to-high density lipoprotein blood cholesterol, blood triglycerides, and blood pressure. The DNA alterations detected in our study may be only one component of the genetic basis of atherogenesis. Moreover, no causal role in the atherogenetic process can be inferred from our results. However, DNA alterations, including oxidative damage and adduction of reactive molecules of either endogenous or exogenous source, were systematically present in the smooth muscle cells of human atherosclerotic lesions and their intensity was significantly correlated with the occurrence of atherogenic risk factors in the patients studied.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1996

Biomarker studies in northern Bohemia.

Studies were conducted in northern Bohemia to simultaneously evaluate personal exposures to air pollution in the form of respirable particles containing polycyclic aromatic hydrocarbons (PAHs) and biomarkers of exposure, biological effective dose, genetic effects, and metabolic susceptibility. The series of biomarkers included PAH metabolites in urine, urine mutagenicity, PAH-DNA adducts in white blood cells determined by 32P-postlabeling, PAH-albumin adducts determined by enzyme-linked immunosorbent assay (ELISA), DNA damage in lymphocytes detected by comet assay, chromosomal aberrations, sister chromatid exchanges, and glutathione S-transferase M1 (GSTM1) genotypes. For these studies, a group of women who work outdoors about 30% of their daily time was selected. In a pilot study, a group of women from a polluted area of the Teplice district (northern Bohemia) was compared with a group of women from a control district of southern Bohemia (Prachatice). In a follow-up repeated-measures study, a group of nonsmoking women from Teplice was sampled repeatedly during the winter season of 1993 to 1994. Personal exposure monitoring for respirable particles (< 2.5 microns) was conducted for the 24-hr period before collection of blood and urine. Particle extracts were analyzed for carcinogenic PAHs. In the pilot study and in the follow-up study, a highly significant correlation between individual personal exposures to PAHs and DNA adducts was found (r = 0.54, p = 0.016; r = 0.710, p < 0.001, respectively). The comet parameter (percentage DNA in tail; %T) correlated with exposures to respirable particles (r = 0.304, p = 0.015). The GSTM1 genotype had a significant effect on urinary PAH metabolites, urine mutagenicity, and comet parameters (% T and tail moment) when the GSTM1 genotype was considered as a single factor affecting these biomarkers. Multifactor analysis o variance considering exposure and adjusting the data for GSTM1, age, and diet showed that the effect of personal exposures to PAHs on the variability of biomarkers (DNA adducts, comet parameters, urine mutagenicity) might be higher than the effect of the GSTM1 genotype. These results show the importance of considering all potential factors that may affect the biomarkers being analyzed.

Adolescent↗
PubMed1996

Teplice program--the impact of air pollution on human health.

The aim of the Teplice Program is to investigate and assess the impact of air pollution on the health of the population in the district of Teplice, Czech Republic. Characterization of the air pollutants demonstrated unusually high concentrations during winter inversions of fine particles dominated by acidic sulfates, genotoxic organic compounds, and toxic trace elements. The major source of airborne fine particles is the burning of coal for heating and power. Human exposure and biomarker studies demonstrated large seasonal variations in air pollution within the Teplice District and higher seasonal average pollution levels than the comparative district, Prachatice. Personal exposures to fine particles and organic carcinogens [e.g., polycyclic aromatic hydrocarbons (PAH)] were correlated with excretion of PAH metabolites in urine, several trace metals in blood, and DNA adducts in white blood cells. Respiratory and neurobehavioral studies of school children were conducted using questionnaires and clinical measures. A significantly higher prevalence of adverse respiratory symptoms and decreased lung function were found in the Teplice district than in Prachatice. The neurobehavioral studies indicated significantly higher teacher referrals for clinical assessment in Teplice, but the majority of objective performance measures did not differ. Reproductive studies were conducted in both males and females. A study of the effects of exposure on pregnancy and birth found an excess prevalence of low birth weight and premature births in Teplice; these adverse effects were more common in infants conceived in the winter and whose mothers were smokers. Based on questionnaires and medical examination, the reproductive development of young men was not different between districts and seasons, however, measures of semen quality suggest that exposure to high levels of air pollution are associated with transient decrements in semen quality.

Air Pollution↗
PubMed1996

In vitro characterization of DNA adducts formed by foundry air particulate matter.

This study is part of an ongoing investigation of biomarkers in iron foundry workers exposed to polycyclic aromatic compounds. Foundry workers with the highest exposures had elevated levels of DNA adducts in their white blood cells in previous studies. The purpose of this study was to characterize the nature of DNA reactive chemicals in foundry air samples through incubating the foundry filter extract with DNA and activation enzymes. Calf thymus DNA was incubated with foundry filter extract and activated by either rat liver activation mixture (S9 mix) or xanthine oxidase. A complex pattern of adducts was observed on thin-layer chromatography (TLC) by the 32P-postlabeling assay. Two selected polycyclic aromatic hydrocarbons (PAHs)--1-NP-and anti(+/-)benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide [anti(+/-) BPDE]-DNA adducts--were used as marker compounds in characterizing the postlabeled DNA adducts by TLC combined with high-performance liquid chromatography (HPLC). After an initial separation of DNA adducts by TLC, individual spots were isolated and separated further on HPLC. HPLC analysis and spiking with anti(+/-)BPDE-DNA standard confirmed the co-migration of the anti(+/-)BPDE-DNA standard with one PAH adduct formed by the S9 mix-activated DCM extract in calf thymus DNA.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1996

Polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs and related environmental compounds: biological markers of exposure and effects.

Lung cancer caused by polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs and related environmental agents is a major problem in industrialized nations. The high case-fatality rate of the disease, even with the best supportive treatment, underscores the importance of primary lung cancer prevention. Development of biomarkers of exposure and effects to PAHs and related compounds is now underway and includes measurement of urinary metabolites of specific PAHs as well as detection of protein and DNA adducts as indicators of effective dose. Validation of these markers in terms of total environmental dose requires that concurrent measures of air levels and potential dermal exposure be made. In addition, the interrelationships between PAH biomarkers must be determined, particularly when levels of the marker in surrogate molecules (e.g., protein) or markers from surrogate tissues (e.g., lymphocyte DNA) are used to assess the risk to the target organ, the lung. Two approaches to biomarker studies will be reviewed in this article: the progress made using blood lymphocytes as surrogates for lung tissues and the progress made developing noninvasive markers of carcinogen-DNA adduct levels in lung-derived cells available in bronchial-alveolar lavage and in sputum. Data are presented from studies in which exfoliated urothelial cells were used as a surrogate tissue to assess exposure to human urinary bladder carcinogens in occupational groups.

Biomarkers↗
PubMed1996

DNA adducts and chronic degenerative disease. Pathogenetic relevance and implications in preventive medicine.

Chronic degenerative diseases are the leading causes of death in developed countries. Their control is exceedingly difficult due to their multiplicity and diversity, the interconnection with a network of multiple risk factors and protective factors, the long latency and multistep pathogenesis, and the multifocal localization. Adducts to nuclear DNA are biomarkers evaluating the biologically effective dose, reflecting an enhanced risk of developing a mutation-related disease more realistically than the external exposure dose. The localization and accumulation of these promutagenic lesions in different organs are the composite result of several factors, including (a) toxicokinetics (first-pass effect); (b) local and distant metabolism; (c) efficiency and fidelity of DNA repair; and (d) cell proliferation rate. The last factor will affect not only the dilution of DNA adducts but also the possible evolution towards either destructive processes, such as emphysema or cardiomyopathies, or proliferative processes, such as benign or malignant tumors at various sites. They also include heart tumors affecting fetal myocytes after transplacental exposure to DNA-binding agents, blood vessel tumors, and atherosclerotic plaques. In this article, particular emphasis is given to molecular alterations in the heart, which is the preferential target for the formation of DNA adducts in smokers, and in human aorta, where an extensive molecular epidemiology project is documenting the systematic presence of adducts to the nuclear DNA of smooth muscle cells from atherosclerotic lesions, and their significant correlation with known atherogenic risk factors. Exocyclic DNA adducts resulting from lipid peroxidation, and age-related indigenous adducts (I-compounds) may also originate from endogenous sources, chronic infections and infestations, and inflammatory processes. Type II I-compounds are bulky DNA lesions resulting from oxidative stress, whereas type II-compounds are presumably normal DNA modifications, which display positive correlations with median life span and are decreased in cancer and other pathological conditions. Profiles of type II-compounds strongly depend on diet and are related to the antidegenerative effects of caloric/ dietary restriction. Even broader is the possible meaning of adducts to mitochondrial DNA, which have been detected in rodents exposed to genotoxic agents and complex mixtures, as well as in untreated rodents, in larger amounts when compared to the nuclear DNA of the same cells. Mutations in mitochondrial DNA increase the number of oxidative phosphorylation-defective cells, especially in energy-requiring postmitotic tissues such as brain, heart and skeletal muscle, thereby playing an important role in aging and a variety of chronic degenerative diseases. A decreased formation of DNA adducts is an indicator of reduced risk of developing the associated disease. Therefore, these molecular dosimeters can be used as biomarkers in the prevention of chronic degenerative diseases, pursued either by avoiding exposure to adduct-forming agents or by using chemopreventive agents. Interventions addressed to the human organism by means of dietary measures or pharmacological agents have encountered a broad consensus in the area of cardiovascular diseases, and are deserving a growing interest also in cancer prevention. The efficacy of chemopreventive agents can be assessed by evaluating inhibition of nuclear DNA or mitochondrial DNA adduct formation in vitro, in animal models, and in phase II clinical trials in high-risk individuals.

Animals↗
PubMed1995

Enhanced levels of DNA adducts in the liver of woodchucks infected with hepatitis virus.

Liver DNA specimens from woodchucks kept in captivity, 10 naturally infected with hepatitis virus (WHV) and five WHV-free, were examined for the presence of carcinogen-DNA adducts by 32P-postlabeling. The number of adducts was significantly higher in WHV carriers than in uninfected animals, and the total amounts of adducts per 10(9) nucleotides were also considerably enhanced by WHV infection, when using both butanol extraction (22.2 +/- 7.1 vs. 12.6 +/- 2.8, means +/- S.D.) and nuclease P1 enrichment (8.5 +/- 5.9 vs. 2.8 +/- 1.7). Two individual adducts were also significantly higher in WHV carriers. No significant variation occurred as related to age, sex or time length of captivity. These findings are consistent with our previous studies supporting an enhanced metabolism of chemical hepatocarcinogens in both human and woodchuck hepadnavirus infections. Several significant and remarkable correlations were pointed out by relating DNA adduct data to more than 30 virological, histopathological and metabolic parameters which had been previously evaluated in the same animals. For instance, numbers and/or levels of adducts were positively related to the amounts of virus present in hepatocytes, to cell damage (gamma-glutamyltranspeptidase activity), to the severity of the liver histopathological picture, and to monooxygenase activities, while they were inversely related to cellular glutathione concentrations and to detoxification of the direct-acting mutagen 4-nitroquinoline 1-oxide. The major adduct significantly correlated with the metabolic activation of the aromatic amine 2-aminofluorene and of the heterocyclic amines 3-amino-1-methyl-5H-pyrido(4,3)indole (Trp-P-2) and 2-amino-3,4-dimethylimidazo(4,5-f)quinoline (MeIQ), whereas another adduct significantly correlated with the metabolic activation of the mycotoxin aflatoxin B1. Thus, the enhanced metabolism of chemical hepatocarcinogens and the increased formation of carcinogen-DNA adducts in the liver of WHV carriers appear to represent one of the mechanisms contributing to the association between chronic hepadnavirus infection and development of primary hepatocellular carcinoma.

4-Nitroquinoline-1-oxide↗
PubMed1995

DNA adducts and personal air monitoring of carcinogenic polycyclic aromatic hydrocarbons in an environmentally exposed population.

The effect of personal exposure to air pollution on DNA adducts in humans was analyzed in a group (n = 30) of women working outdoors (up to 8 h/day) as postal workers or gardeners in the city of Teplice, Czech Republic (Northern Bohemia), where winter inversions may result in high levels of air pollution from coal combustion. Ten of these women were followed up during the next winter season by repeated personal exposure monitoring and analysis of the DNA adducts in their white blood cells (in four sampling periods). Personal exposure monitoring for respirable particles (< 2.5 microns) was conducted for the 24 h period prior to collection of blood and urine. Particle extracts were analyzed for carcinogenic polycyclic aromatic hydrocarbons (PAH). Urine samples were collected for cotinine analysis to control for exposure to tobacco smoke. DNA isolated from white blood cells was analyzed by 32P-postlabeling with the butanol enrichment procedure. There were 21 non-smokers and nine light smokers in the pilot study (November 1992) and only non-smokers in the follow-up study (winter season 1993/94). In both studies high personal exposure variability between the individuals sampled on the same day was observed. In the pilot study we found a significantly higher (P < 0.05) level of DNA adducts in the 14 non-smoking women sampled on November 24, when their exposure to carcinogenic PAH was also significantly higher (P < 0.05), compared with seven non-smoking women sampled on November 26. We also found a significant correlation (r = 0.541, P < 0.016) between individual exposure to carcinogenic PAH and DNA adducts for the group of non-smokers (n = 21). No significant difference in DNA adduct levels was found between non-smokers and smokers. In the follow-up study, during one sampling period the ambient and personal air monitors exhibited a significantly elevated exposure to respirable particles and carcinogenic PAH. Analyzing data from the follow-up study, a significant effect of personal exposure on DNA adduct levels and their relationship with short-term exposure to carcinogenic PAH was found. The results suggest that DNA adduct levels in white blood cells reflect a short-term environmental exposure.

Adult↗
PubMed1995

32P-postlabeling and HPLC separation of DNA adducts formed by diesel exhaust extracts in vitro and in mouse skin and lung after topical treatment.

Diesel exhaust extracts contain many carcinogenic compounds which have been shown to form polycyclic aromatic hydrocarbon (PAH)- and nitrated PAH-DNA adducts in rodent skin and lung. The aim of this study was to characterize by 32P-postlabeling, TLC and HPLC the primary postlabeled PAH-DNA adduct(s) formed in vitro and in vivo by diesel extracts. The diesel particle extracts had known concentrations of benzo[a]pyrene, benzo[b,j,k]-fluoranthenes (B[b,j,k]F) and chrysene. DNA adducts were analyzed in calf thymus DNA incubated in vitro with PAHs activated by S9 mix and in skin and lung DNA from topically treated mice. The main diesel-derived DNA adduct formed in vitro and in vivo did not co-migrate on HPLC and large TLC plates with (+/-)-r-7,t-8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti BPDE)-, B[b]F-,B[j]F-,B[k]F-or chrysene-DNA adduct standards. By co-chromatography DNA adducts formed by chrysene from both in vitro and in vivo samples were identified. Nissan diesel extract containing higher PAH concentrations than Volkswagen automobile extract formed skin DNA adducts that co-migrated with chrysene- and anti BPDE- DNA-derived adducts. We conclude that the use of a highly sensitive 32P-postlabeling method combined with HPLC improves the identification of PAH adducts formed by complex mixtures such as diesel exhaust extracts.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗