Myeloperoxidase--463A variant reduces benzo[a]pyrene diol epoxide DNA adducts in skin of coal tar treated patients.
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The skin of atopic dermatitis patients provides an excellent model to study the role of inflammation in benzo[a]pyrene (BaP) activation, since these individuals are often topically treated with ointments containing high concentrations of BaP. In this study we have determined, by HPLC with fluorescence detection, the BaP diol epoxide (BPDE)-DNA adduct levels in human skin after topical treatment with coal tar and their modulation by the -463G-->A myeloperoxidase (MPO) polymorphism, which reduces MPO mRNA expression. BPDE-DNA adduct levels were 2.2 and 14.2 adducts/10(8) nt for MPO-463AA/AG and -463GG, respectively. The predominant BaP tetrol observed was tetrol I-1, which is derived after hydrolysis of the anti-BPDE-DNA adduct. The tetrol I-1/II-2 ratio, corresponding to the anti/syn ratio, was 6.7. The (32)P-post-labeling assay was also performed and thin layer chromatograms showed a major spot with a chromatographic location corresponding to BPDE-DNA. The mean values of the BPDE-DNA adduct spots were 3.8 +/- 2.4 per 10(8) nt for MPO-463AA/AG (n = 3) and 18.4 +/- 11.0 per 10(8) nt for MPO-463GG (n = 7), respectively (P = 0.03). One individual with the homozygous mutant genotype (-463AA) even had a 13-fold lower adduct level (1.4 per 10(8) nt) as compared to MPO-463GG subjects. In conclusion, these data show for the first time: (i) the in vivo formation of BPDE-DNA adducts in human skin treated with coal tar; (ii) that the MPO-463AA/AG genotype reduced BPDE-DNA adduct levels in human skin. (+info)
Effect of a complex environmental mixture from coal tar containing polycyclic aromatic hydrocarbons (PAH) on the tumor initiation, PAH-DNA binding and metabolic activation of carcinogenic PAH in mouse epidermis.
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Human exposure to polycyclic aromatic hydrocarbons (PAH) occurs through complex mixtures such as coal tar. The effect of complex PAH mixtures on the activation of carcinogenic PAH to DNA-binding derivatives and carcinogenesis were investigated in mice treated topically with NIST (National Institute of Standards and Technology) Standard Reference Material 1597 (SRM), a complex mixture of PAH extracted from coal tar, and either additional benzo[a]pyrene (B[a]P) or dibenzo[a,l]pyrene (DB[a,l]P). In an initiation-promotion study using 12-O-tetradecanoylphorbol-13-acetate as the promoter for 25 weeks, the SRM and B[a]P co-treated mice had a similar incidence of papillomas per mouse compared with the group exposed to B[a]P alone as the initiator. PAH-DNA adduct analysis of epidermal DNA by 33P-post-labeling and reversed-phase high-performance liquid chromatography found the SRM co-treatment led to a significant decrease in the total level of DNA adducts and B[a]P-DNA adducts to less than that observed in mice treated with B[a]P alone at 6, 12 and 72 h exposure. After 24 and 48 h exposure, there was no significant difference in the levels of adducts between these groups. In the DB[a,l]P initiation-promotion study, the co-treated group had significantly fewer papillomas per mouse than mice treated with DB[a,l]P alone as initiator. Averaging over the times of exposure gave strong evidence that mice co-treated with SRM and DB[a,l]P had a significantly lower level of PAH-DNA adducts than mice treated with DB[a,l]P alone. Western immunoblots showed that both cytochrome P450 (CYP) 1A1 and 1B1 were induced by the SRM. These results are consistent with the hypothesis that two major factors determining the carcinogenic activity of PAH within a complex mixture are (i) the persistence of certain PAH-DNA adducts as well as total adduct levels, and (ii) the ability of the components present in the mixture to inhibit the activation of carcinogenic PAH by the induced CYP enzymes. (+info)
A polycyclic aromatic hydrocarbon-degrading bacterium isolated from coal tar-contaminated soil in Denmark was characterized by a polyphasic approach. Phylogenetically and chemotaxonomically, it was related to members of the genus Mycobacterium. The isolate contains chemotaxonomic markers that are diagnostic for the genus Mycobacterium; i.e. the meso isomer of 2,6-diaminopimelic acid, arabinose and galactose as diagnostic whole-cell sugars, MK-9(H2) as the principal isoprenoid quinone, a mycolic acid pattern of alpha-mycolates, ketomycolates and wax-ester mycolates, unbranched saturated and unsaturated fatty acids plus a small amount of tuberculostearic acid and a significant amount of a C18:0 secondary alcohol. Based on the unique combination of chemical markers among mycobacteria, it is proposed that the isolate should be assigned to a new species, Mycobacterium frederiksbergense sp. nov. This novel species is phylogenetically closely related to Mycobacterium diernhoferi, Mycobacterium neoaurum and Mycobacterium hodleri. The type strain of M. frederiksbergense is strain FAn9T (= DSM 44346T = NRRL B-24126T). (+info)
Occurrence of H-ras codon 61 CAA to AAA mutation during mouse liver tumor progression.
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The initiating mutations of a tumor are present in each of the cancerous cells comprising the tumor. Identification and measurement of the subsequent mutations that occur during tumor progression, however, requires mutation detection in a smaller subset of the tumor cells. In this study, allele-specific competitive blocker PCR (ACB-PCR), a genotypic selection method with the sensitivity to detect a specific point mutation in the presence of a 10(5)-fold excess of wild-type DNA sequence, was used to measure H-ras codon 61 CAA to AAA mutation in mouse liver tumors that did not have this mutation as an initiating event. Twenty-one spontaneous or chemically induced mouse liver tumors, negative for the H-ras codon 61 CAA to AAA mutation by DNA sequencing or denaturing gradient gel electrophoresis, were analyzed for this mutation by ACB-PCR. The mutation was detected at some level in 71% of these tumors. The mutation was detected in adenomas and carcinomas more frequently (13 of 14 tumors) and at significantly higher mutant fractions than it was detected in histiocytic sarcomas (1 of 5 tumors). These data indicate that the same oncogenic point mutation that can be identified as a tumor-initiating event based on its clonal amplification in a tumor can also be present in only a small sub-population of tumor cells where the mutation must have been fixed at a later stage in tumor development. The occurrence of a mutation as a primary or secondary event probably reflects the stochastic nature of mutation and is likely to be affected by the mutation rate for each target site. (+info)
Cancer mortality among man-made graphite electrode manufacturing workers: results of a 38 year follow up.
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BACKGROUND AND AIMS: To examine the risk for cancer mortality among workers exposed to coal tar and coal tar pitch volatiles in a man-made graphite electrode factory. The risk for cancer mortality in this type of factory is still inconclusive, although coal tar and coal tar pitch are recognised as human carcinogens. METHODS: The study cohort consisted of 332 male employees who served more than five years in the period 1951-74. The cohort was traced until 1988. Analyses used standardised mortality ratios (SMRs) to compare cause specific mortality with that in the general and local population. Effect of smoking was estimated based on the information collected from the subgroup of the cohort. SMRs for leading causes of death were compared among different job titles, duration of employment, time since first employment, and observation subperiods. Exposure level for tar and benzo[a]pyrene (BaP) in the factory was also discussed, based on measurements done by other researchers in the past. RESULTS: During the study period, 52 deaths were identified (SMR 0.68), including 22 cancer deaths (SMR 1.01). The SMR for lung cancer was significantly increased in comparison with the general population (SMR 2.62). It was slightly decreased in comparison with the local population, but remained significant (SMR 2.35). Excess deaths were also observed for lymphatic and haematopoietic cancers (SMR 3.46). Smoking habits in the subgroup were similar to those in the general population; thus the increased SMR for lung cancer was unlikely to be explained by smoking. CONCLUSION: Previous environmental measurements suggested that considerable exposure to tar and BaP had existed in the factory. The results suggest a possible risk for lung cancer among the cohort, but the limitations of the study, such as the small study population and insufficient information on exposure, indicate that further study is required. (+info)
nahR, encoding a LysR-type transcriptional regulator, is highly conserved among naphthalene-degrading bacteria isolated from a coal tar waste-contaminated site and in extracted community DNA.
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In Pseudomonas putida strain G7, a LysR-type positive transcriptional activator protein encoded by nahR is necessary for activation of two operons involved in naphthalene catabolism [Schell, M. A. & Poser, E. F. (1989). J Bacteriol 171, 837-846]. The role of an nahR homologue, NCIB-nahR, in another naphthalene-metabolizing bacterium, P. putida NCIB 9816-4 was verified. Targeted disruption of NCIB-nahR by homologous recombination resulted in a growth defect in the presence of naphthalene or salicylate as sole carbon and energy source. The nahR homologues and intergenic regions between nahR-like and nahG-like genes from P. putida NCIB 9816-4 and seven bacteria native to a naphthalene-rich coal tar contaminated site were amplified by PCR using degenerate primers. The amplified nahR homologues and the intergenic regions were cloned and sequenced. Alignment of the deduced amino acid sequences from NahR homologues revealed that NahR-like proteins showed only minor variations in all investigated naphthalene-degrading isolates. The intergenic regions, together with known NahR-binding sites showed the consensus NahR-protein-binding sites (5'-ATTCACGCTN(2)TGAT-3'). Surprisingly, amplified intergenic regions from naphthalene-degrading micro-organisms native to this study site were 100% identical to that of the pDTG1 plasmid (an archetypal naphthalene-catabolic plasmid from Pseudomonas putida NCIB 9816-4), but the nahR coding regions were not. DNA representing the uncultured microbial community was extracted from six sediment samples with varying coal tar exposure histories. PCR amplification of nahR from sediment DNA was observed in contaminated samples, but in uncontaminated samples only following laboratory incubation with naphthalene. The sediment-derived PCR products were sequenced and also found to be almost identical to known nahR genes. Thus, the structure and function of nahR-nahG regulatory genes appear to be highly conserved. (+info)
A systematic review of adverse effects associated with topical treatments for psoriasis.
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Mild to moderate psoriasis is a disease that can often be treated with topical medications. The diversity of topical therapies and their disparate side effects complicates treatment planning. Our purpose is to compare the rates of adverse events associated with different topical psoriasis treatments. A review of medical literature from 1996 to March, 2002 was conducted using guidelines set by QUORUM statement criteria. In monotherapy studies, corticosteriods caused fewer adverse reactions compared to vitamin D analogues and tazarotene. In combination studies adverse event rates were higher than in monotherapy studies, except for the combination of topical steroid and calcipotriene which decreased irritation. Irritant contact dermatitis was the main side effect with vitamin D analogues, tazarotene, dithranol or coal tar, while side effects of topical corticosteriods included headache, viral infection and skin atrophy. Topical agents for psoriasis are usually well-tolerated without severe side effects. Formulating a patient's medication regimen should take into account the needs for short-term management and long-term control of psoriasis. Since clearance is not a realistic expectation, reasonable goals should be set as excessive use of topical treatments may increase the risk of both cutaneous and systemic side effects. (+info)
Horizontal transfer of phnAc dioxygenase genes within one of two phenotypically and genotypically distinctive naphthalene-degrading guilds from adjacent soil environments.
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Several distinct naphthalene dioxygenases have been characterized to date, which provides the opportunity to investigate the ecological significance, relative distribution, and transmission modes of the different analogs. In this study, we showed that a group of naphthalene-degrading isolates from a polycyclic aromatic hydrocarbon (PAH)-contaminated hillside soil were phenotypically and genotypically distinct from naphthalene-degrading organisms isolated from adjacent, more highly contaminated seep sediments. Mineralization of (14)C-labeled naphthalene by soil slurries suggested that the in situ seep community was more acclimated to PAHs than was the in situ hillside community. phnAc-like genes were present in diverse naphthalene-degrading isolates cultured from the hillside soil, while nahAc-like genes were found only among isolates cultured from the seep sediments. The presence of a highly conserved nahAc allele among gram-negative isolates from the coal tar-contaminated seep area provided evidence for in situ horizontal gene transfer and was reported previously (J. B. Herrick, K. G. Stuart-Keil, W. C. Ghiorse, and E. L. Madsen, Appl. Environ. Microbiol. 63:2330-2337, 1997). Natural horizontal transfer of the phnAc sequence was also suggested by a comparison of the phnAc and 16S ribosomal DNA sequences of the hillside isolates. Analysis of metabolites produced by cell suspensions and patterns of amplicons produced by PCR analysis suggested both genetic and metabolic diversity among the naphthalene-degrading isolates of the contaminated hillside. These results provide new insights into the distribution, diversity, and transfer of phnAc alleles and increase our understanding of the acclimation of microbial communities to pollutants. (+info)