We investigated the effect of chronic exposure to polycyclic aromatic hydrocarbons (PAHs) on DNA methylation states (percentage of methylated cytosines (%mC)) in Polish male nonsmoking coke-oven workers and matched controls. Methylation states of gene-specific promoters (p53, p16, HIC1 and IL-6) and of Alu and LINE-1 repetitive elements, as surrogate measures of global methylation, were quantified by pyrosequencing in peripheral blood lymphocytes (PBLs). DNA methylation was evaluated in relation to PAH exposure, assessed by urinary 1-pyrenol and anti-benzo [a] We found that Alu and LINE-1 methylation levels and those of the inflammatory cytokine IL-6, to a lesser extent, were higher in polycyclic aromatic hydrocarbon (PAH)-exposed coke-oven workers than controls (p < 0.001 and p 5 0.094). Conversely, methylation of p53 and HIC1 tumor suppressors was lower in workers compared with controls (p < 0.001 and p < 0.05). Global and IL-6 hypermethylation and p53 hypomethylation were significantly correlated, not only to PAH-exposure (urinary 1-pyrenol) but also to the anti-B[a]PDE-DNA adduct levels (p < 0.01). Overall, linear multivariate regression analysis showed that the only significant determinant of increasing micronuclei (MN) (p < 0.01) was p53 hypomethylation and not the other LINE-1, Alu, p53, HIC1 and IL-6 methylation states.Gene-specific promoters (mainly p53) and global (Alu and LINE-1 repeats) DNA methylation changes in circulating peripheral blood lymphocytes (PBLs), related to anti-B[a]PDE-DNA adduct and MN, suggest that these events could be determined to identify subjects at high cancer risk.Understanding how environmental factors are involved in cancer etiology and development is one of the main goals of biomedical research. 1 Extensive research has been conducted to determine how known or potential environmental carcinogens modify the DNA sequence, as a component of malignant transformation. However, an investigative approach exclusively based on genetic damage, as well as on inheritance of genetic variants, has been revealed to be insufficient to account for multistage carcinogenic processes. 2 It has been proposed that DNA methylation, one of the best known epigenetic mechanisms, shares critical roles with DNA mutations in the theoretical continuum for exposure to cancer. 3,4 One potential mechanism for environmental factors is through hypermethylation or hypomethylation on somatic cells, leading to activation or silencing of key genes in critical pathways of cancer. 5,6 From some years, the disruption of DNA methylation status by exposure to genotoxic agents has been an issue in the literature, but the clear demonstration that such epigenetic alterations were caused by one or more specific agents in people has been demanding (for a review see Ref. 7 and references therein).Benzo [a]pyrene (B[a]P), the most well-studied PAH carcinogen (especially of the lung), has a well-established genotoxic mechanism, via metabolic activation to diol epoxide. 8 The stereoselective binding of anti-benzo[a]pyrene di...
Aim of the study was the assessment of exposure of coke-oven workers to polycyclic aromatic hydrocarbons (PAHs) by determination of urinary profiles of hydroxylated and unmetabolized PAHs. Fifty-five Polish coke-oven workers were investigated by measurement of 12 hydroxylated metabolites of PAHs (OHPAHs) (1-, 2-hydroxynaphthalene; 2-, 9-hydroxyfluorene; 1-, 2-, 3-, 4-, 9-hydroxyphenanthrene; 1-hydroxyypyrene, 6-hydroxychrysene and 3-hydroxybenzo[a]pyrene) and 13 unmetabolized PAHs (U-PAHs) (from naphthalene to benzo[a]pyrene), in spot urine samples collected at the end of the workshift. U-PAHs with four or less rings were detected in all samples. In particular, median levels for urinary naphthalene, phenanthrene, pyrene, chrysene and benz[a]anthracene were 0.806, 0.721, 0.020, 0.032 and 0.035 microg/L. OHPAHs up to 1-hydroxypyrene were found in all samples, while high molecular-weight OHPAHs were always below quantification limit. Median level of 1-hydroxyypyrene was 15.4 microg/L. In all subjects significant correlations between OHPAHs and U-PAHs were observed (0.27 < r < 0.70, p < 0.01). Our results suggest that both hydroxylated metabolites and unmetabolized PAHs in urine are useful biomarkers of exposure to PAHs. Moreover, the simultaneous determination of several biomarkers permits to obtain specific excretion profiles that might help in exposure characterization and in better defining the excretion patterns.
Micronuclei (MN) frequency associated to biologically effective dose of polycyclic aromatic hydrocarbons [PAH; anti-benzo[a]pyrene diolepoxide (B[a]PDE)-DNA] within the same subjects' peripheral blood lymphocytes (PBL) was evaluated. Study subjects were nonsmoking male Polish coke-oven workers (n = 49) and matched controls (n = 45) verified for PAH exposure by urinary 1-pyrenol. We found that coke-oven workers, heavily exposed to PAHs (80% workers exceeded the urinary 1-pyrenol biological exposure index value), presented significantly higher MN frequency in PBLs than controls (P < 0.01). Substantial difference was also found for adduct levels in PBLs (P < 0.01). Increase in MN levels was significantly related to anti -B[a]PDE-DNA formation, key adduct of the ultimate carcinogenic metabolite of B[a]P (n = 94; r = 0.47; P < 0.001). The dose-response relationship was improved when subjects with adduct levels above the 3rd tertile (z4.35 adducts/10 8 nucleotides) were excluded (n = 61; r = 0.69; P < 0.001). Saturation of adduct/MN formation at high levels may disturb the underlying relationship. Linear multiple regression analysis, without subjects of 3rd tertile adduct level (n = 61), revealed that adduct formation (t = 4.61; P < 0.001), but not 1-pyrenol, was the significant determinant in increasing MN. In conclusion, the increase in MN frequency is mainly related to the specific anti -B[a]PDE-DNA formation within PBLs of the same subject. Our results substantiate, with the use of an early indicator of biological effect as well, that workers are at higher cancer risk than controls. (Cancer Epidemiol Biomarkers Prev
Current analytical techniques allow specific and simultaneous measurement of several urinary determinants of PAHs in humans. The results of these measurements support the use of U-PAHs as biomarkers of exposure and suggest the spectrum of chemicals to be investigated, including carcinogenic chrysene and benzo[a]anthracene, should be widened.
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