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As part of a large human biomonitoring study, we conducted occupational monitoring in a glass fibre factory inSlovakia. Shopfloor workers (n = 80), with a matched group of administrators in the same factory (n = 36), weremonitored for exposure to glass fibres and to polycyclic aromatic hydrocarbons (PAHs). The impact of occupationalexposure on chromosomal aberrations, DNA damage and DNA repair, immunomodulatory markers, andthe role of nutritional and lifestyle factors, as well as the effect of polymorphisms in metabolic and DNA repairgenes on genetic stability, were investigated. The (enzyme-modified) comet assay was employed to measure DNA strand breaks (SBs) and apurinic sites,oxidised and alkylated bases. Antioxidant status was estimated by resistance to H2O2-induced DNA damage. Baseexcision repair capacity was measured with an in vitro assay (based on the comet assay). Exposure of workers to fibres was low, but still was associated with higher levels of SBs, and SBs plus oxidisedbases, and higher sensitivity to H2O2. Multivariate analysis showed that exposure increased the risk of high levelsof SBs by 20%. DNA damage was influenced by antioxidant enzymes catalase and glutathione S-transferase(measured in blood). DNA repair capacity was inversely correlated with DNA damage and positively withantioxidant status. An inverse correlation was found between DNA base oxidation and the percentage ofeosinophils (involved in the inflammatory response) in peripheral blood of both exposed and reference groups.Genotypes of XRCC1 variants rs3213245 and rs25487 significantly decreased the risk of high levels of baseoxidation, to 0.50 (p = 0.001) and 0.59 (p = 0.001), respectively. Increases in DNA damage owing to glass fibre exposure were significant but modest, and no increases wereseen in chromosome aberrations or micronuclei. However, it is of concern that even low levels of exposure tothese fibres can cause significant genetic damage.

Electrophilic diol epoxide metabolites are involved in the carcinogenicity of benzo[a]pyrene, one of the widely studied polycyclic aromatic hydrocarbons (PAHs). The exposure of humans to this PAH can be assessed by measuring stable blood protein adducts, such as to histidine and lysine in serum albumin, from their reactive metabolites. In this respect, measurement of the adducts originating from the genotoxic (+)-anti-benzo[a]pyrene diol epoxide is of interest. However, these are difficult to measure at such low levels as are expected in humans generally exposed to benzo[a]pyrene from air pollution and the diet. The analytical methods detecting PAH-biomarkers still suffer from low selectivity and/or detectability to enable generation of data for calculation of in vivo doses of specific stereoisomers, for evaluation of risk factors and assessing risk from exposures to PAH. Here, we suggest an analytical methodology based on high-pressure liquid chromatography (HPLC) coupled to high-resolution tandem mass spectrometry (MS) to lower the detection limits as well as to increase the selectivity with improvements in both chromatographic separation and mass determination. Method development was performed using serum albumin alkylated in vitro by benzo[a]pyrene diol epoxide isomers. The (+)-anti-benzo[a]pyrene diol epoxide adducts could be chromatographically resolved by using an HPLC column with a pentafluorophenyl stationary phase. Interferences were further diminished by the high mass accuracy and resolving power of Orbitrap MS. The achieved method detection limit for the (+)-anti-benzo[a]pyrene diol epoxide adduct to histidine was approximately 4 amol/mg serum albumin. This adduct as well as the adducts to histidine from (−)-anti- and (+/−)-syn-benzo[a]pyrene diol epoxide were quantified in the samples from benzo[a]pyrene-exposed mice. Corresponding adducts to lysine were also quantified. In human serum albumin, the anti-benzo[a]pyrene diol epoxide adducts to histidine were detected in only two out of twelve samples and at a level of approximately 0.1 fmol/mg.

Background B-cell chronic lymphocytic leukemia (CLL) is a common type of adult leukemia. It often follows an indolent course and is preceded by monoclonal B-cell lymphocytosis, an asymptomatic condition, however it is not known what causes subjects with this condition to progress to CLL. Hence the discovery of prediagnostic markers has the potential to improve the identification of subjects likely to develop CLL and may also provide insights into the pathogenesis of the disease of potential clinical relevance. Results We employed peripheral blood buffy coats of 347 apparently healthy subjects, of whom 28 were diagnosed with CLL 2.0–15.7 years after enrollment, to derive for the first time genome-wide DNA methylation, as well as gene and miRNA expression, profiles associated with the risk of future disease. After adjustment for white blood cell composition, we identified 722 differentially methylated CpG sites and 15 differentially expressed genes (Bonferroni-corrected p

The ontological tree based on DM genes. Figure S2. Methylation of HOX and IRX gene clusters in the short- and long-TtD subgroups. Figure S3. B-cell distribution in controls and CLL cases. (PDF 1281 kb)

The utility of blood-based omic profiles for linking environmental exposures to their potential health effects was evaluated in 649 individuals, drawn from the general population, in relation to tobacco smoking, an exposure with well-characterised health effects. Using disease connectivity analysis, we found that the combination of smoking-modified, genome-wide gene (including miRNA) expression and DNA methylation profiles predicts with remarkable reliability most diseases and conditions independently known to be causally associated with smoking (indicative estimates of sensitivity and positive predictive value 94% and 84%, respectively). Bioinformatics analysis reveals the importance of a small number of smoking-modified, master-regulatory genes and suggest a central role for altered ubiquitination. The smoking-induced gene expression profiles overlap significantly with profiles present in blood cells of patients with lung cancer or coronary heart disease, diseases strongly associated with tobacco smoking. These results provide proof-of-principle support to the suggestion that omic profiling in peripheral blood has the potential of identifying early, disease-related perturbations caused by toxic exposures and may be a useful tool in hazard and risk assessment.

Journal URL: http://www.springer.com/11756

Methyl-DNA adducts are induced by a number of lifestyle, environmental and occupational carcinogens, however knowledge about their kinetics is scarce. Here, N7-methylguanine (N7-MeGua) and O6-methylguanine (O6-MeGua) levels were determined in the DNA of white blood cells from eight cancer patients treated iv with the antitumour drug dacarbazine (DTIC). Five of the patients were treated with the drug as a single agent (a single dose of 800 mg m-2) and three on three successive days with dacarbazine (225 mg m-2 day-1) in combination with other drugs. The data indicate that maximum adduct levels are reached at 4-8 h after treatment and that the amount of N7-MeGua is at least 20-fold higher than that of O6-MeGua. The half-life of N7-MeGua is 40-96 h and that of O6-MeGua 25-27 h. Following treatment on three consecutive days, an accumulation of N7-MeGua was observed but not of O6-MeGua. The data show substantial interindividual differences in adduct levels but not in the ratio of N7/O6-MeGua. This may reflect differences in the metabolism of dacarbazine or in repair capacities. © 1996 Taylor & Francis Ltd.

Journal URL: http://www.informaworld.com/smpp/title~content=t713693137

with additional results can be found in the Additional file documents; RKelly_Additional_files.docx. (DOCX 72 kb)

This file contains the supplementary tables and figures for this paper, including Tables S1-S6, and Figures S1-S4. (DOCX 1257Â kb)

Journal URL: http://monographs.iarc.fr/ENG/Publications/index.php

Journal URL: http://www.sciencedirect.com/science/journal/00275107

Journal URL: http://cancerres.aacrjournals.org/

This file contains the supplementary tables and figures for this paper, including Tables S1-S6, and Figures S1-S4. (DOCX 1257Â kb)

with additional results can be found in the Additional file documents; RKelly_Additional_files.docx. (DOCX 72 kb)

Text. Results on WBC composition in case and control subjects, omic profiles in different subgroups of subjects and assessment of the profile robustness across the cohorts. (PDF 614 kb)

Journal URL: http://www.sciencedirect.com/science/journal/0361090X