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Background Airborne particulate matter (PM) may induce epigenetic changes that potentially lead to chronic diseases. Histone modifications regulate gene expression by influencing chromatin structure that can change gene expression status. We evaluated whether traffic-derived PM exposure is associated with four types of environmentally inducible global histone H3 modifications. Methods The Beijing Truck Driver Air Pollution Study included 60 truck drivers and 60 office workers examined twice, 1–2 weeks apart, for ambient PM10 (both day-of and 14-day average exposures), personal PM2.5, black carbon (BC), and elemental components (potassium, sulfur, iron, silicon, aluminum, zinc, calcium, and titanium). For both PM10 measures, we obtained hourly ambient PM10 data for the study period from the Beijing Municipal Environmental Bureau's 27 representatively distributed monitoring stations. We then calculated a 24 h average for each examination day and a moving average of ambient PM10 measured in the 14 days prior to each examination. Examinations measured global levels of H3 lysine 9 acetylation (H3K9ac), H3 lysine 9 tri-methylation (H3K9me3), H3 lysine 27 tri-methylation (H3K27me3), and H3 lysine 36 tri-methylation (H3K36me3) in blood leukocytes collected after work. We used adjusted linear mixed-effect models to examine percent changes in histone modifications per each μg/m3 increase in PM exposure. Results In all participants each μg/m3 increase in 14-day average ambient PM10 exposure was associated with lower H3K27me3 (β=−1.1%, 95% CI: −1.6, −0.6) and H3K36me3 levels (β=−0.8%, 95% CI: −1.4, −0.1). Occupation-stratified analyses showed associations between BC and both H3K9ac and H3K36me3 that were stronger in office workers (β=4.6%, 95% CI: 0.9, 8.4; and β=4.1%, 95% CI: 1.3; 7.0 respectively) than in truck drivers (β=0.1%, 95% CI: −1.3, 1.5; and β=0.9%, 95% CI: −0.9, 2.7, respectively; both pinteraction Conclusions Our results suggest a possible role of global histone H3 modifications in effects of traffic-derived PM exposures, particularly BC exposure. Future studies should assess the roles of these modifications in human diseases and as potential mediators of air pollution-induced disease, in particular BC exposure.

The aims of this study were (1) to explore the behavioral and sociodemographic factors influencing urinary cotinine (COT-U) levels in active smokers and in environmental tobacco smoke (ETS)-exposed individuals, (2) to assess the specificity and sensitivity of the questionnaire for identifying active smokers and nonsmokers, and (3) to derive the upper reference value of COT-U in non-ETS exposed individuals. The COT-U levels of 495 adults (age range 18-69 years) who classified themselves as active smokers (29%) or as nonsmokers with (17%) or without (83%) ETS exposure were quantified by LC-MS-MS (quantification limit: 0.1µg/L, range of linearity: 0.1-4000µg/L). Median COT-U levels in these groups were 883, 1.38, and 0.39µg/L, respectively. Significant determinants of COT-U levels in active smokers were the number of cigarettes per day, type of smoking product, smoking environment, as well as time between the last cigarette and urine collection. Among ETS-exposed nonsmokers, significant determinants were living with smokers, being exposed to smoke at home, ETS exposure duration, as well as time between the last exposure and urine collection. When a 30-µg/L COT-U cut-off value was used to identify active daily smoking, the sensitivity and specificity of the questionnaire were 94% and 98%, respectively. For ETS exposure, the COT-U value of 1.78 (0.90 confidence interval 1.75-1.78) µg/L, corresponding to the 95th percentiles of the COT-U distribution in non-ETS-exposed participants, is proposed as upper reference value to identify environmental exposure.

Background MicroRNAs (miRNAs) are post-transcriptional gene suppressors and potential mediators of environmental effects. In addition to human miRNAs, viral miRNAs expressed from latent viral sequences are detectable in human cells. Objective In a highly exposed population in Beijing, China, we evaluated the associations of particulate air pollution exposure on blood miRNA profiles. Methods The Beijing Truck Driver Air Pollution Study (BTDAS) included 60 truck drivers and 60 office workers. We investigated associations of short-term air pollution exposure, using measures of personal PM2.5 (particulate matter ≤ 2.5 μm) and elemental carbon (EC), and ambient PM10 (≤ 10 μm), with blood NanoString nCounter miRNA profiles at two exams separated by 1–2 weeks. Results No miRNA was significantly associated with personal PM2.5 at a false discovery rate (FDR) of 20%. Short-term ambient PM10 was associated with the expression of 12 miRNAs in office workers only (FDR < 20%). Short-term EC was associated with differential expression of 46 human and 7 viral miRNAs, the latter including 3 and 4 viral miRNAs in office workers and truck drivers, respectively. EC-associated miRNAs differed between office workers and truck drivers with significant effect modification by occupational group. Functional interaction network analysis suggested enriched cellular proliferation/differentiation pathways in truck drivers and proinflammation pathways in office workers. Conclusions Short-term EC exposure was associated with the expression of human and viral miRNAs that may influence immune responses and other biological pathways. Associations between EC exposure and viral miRNA expression suggest that latent viral miRNAs are potential mediators of air pollution–associated health effects. PM2.5/PM10 exposures showed no consistent relationships with miRNA expression. Citation Hou L, Barupal J, Zhang W, Zheng Y, Liu L, Zhang X, Dou C, McCracken JP, Díaz A, Motta V, Sanchez-Guerra M, Wolf KR, Bertazzi PA, Schwartz JD, Wang S, Baccarelli AA. 2016. Particulate air pollution exposure and expression of viral and human microRNAs in blood: the Beijing Truck Driver Air Pollution Study. Environ Health Perspect 124:344–350; http://dx.doi.org/10.1289/ehp.1408519

Supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03-0365, and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02-67 and FICYT IB09-133, and the University Institute of Oncology (IUOPA) of the University of Oviedo and the Ciber de Epidemiologia y Salud Pública., Ji, X., Bossé, Y., Landi, M.T., Gui, J., Xiao, X., Qian, D., Joubert, P., Lamontagne, M., Li, Y., Gorlov, I., de Biasi, M., Han, Y., Gorlova, O., Hung, R.J., Wu, X., McKay, J., Zong, X., Carreras-Torres, R., Christiani, D.C., Caporaso, N., Johansson, M., Liu, G., Bojesen, S.E., Le Marchand, L., Albanes, D., Bickeböller, H., Aldrich, M.C., Bush, W.S., Tardon, A., Rennert, G., Chen, C., Teare, M.D., Field, J.K., Kiemeney, L.A., Lazarus, P., Haugen, A., Lam, S., Schabath, M.B.,,rew, A.S., Shen, H., Hong, Y.-C., Yuan, J.-M., Bertazzi, P.A., Pesatori, A.C., Ye, Y., Diao, N., Su, L., Zhang, R., Brhane, Y., Leighl, N., Johansen, J.S., Mellemgaard, A., Saliba, W., Haiman, C., Wilkens, L., Fernandez-Somoano, A., Fernandez-Tardon, G., van der Heijden, E.H.F.M., Kim, J.H., Dai, J., Hu, Z., Davies, M.P.A., Marcus, M.W., Brunnström, H., Manjer, J., Melander, O., Muller, D.C., Overvad, K., Trichopoulou, A., Tumino, R., Doherty, J., Goodman, G.E., Cox, A., Taylor, F., Woll, P., Brüske, I., Manz, J., Muley, T., Risch, A., Rosenberger, A., Grankvist, K., Johansson, M., Shepherd, F., Tsao, M.-S., Arnold, S.M., Haura, E.B., Bolca, C., Holcatova, I., Janout, V., Kontic, M., Lissowska, J., Mukeria, A., Ognjanovic, S., Orlowski, T.M., Scelo, G., Swiatkowska, B., Zaridze, D., Bakke, P., Skaug, V., Zienolddiny, S., Duell, E.J., Butler, L.M., Koh, W.-P., Gao, Y.-T., Houlston, R., McLaughlin, J., Stevens, V., Nickle, D.C., Obeidat, M., Timens, W., Zhu, B., Song, L., Artigas, M.S., Tobin, M.D., Wain, L.V., Gu, F., Byun, J., Kamal, A., Zhu, D., Tyndale, R.F., Wei, W.-Q., Chanock, S., Brennan, P., Amos, C.I.

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

Background The opportunity to assess short term impact of air pollution relies on the causal interpretation of the exposure-response association. However, up to now few studies explicitly faced this issue within a causal inference framework. In this paper, we reformulated the problem of assessing the short term impact of air pollution on health using the potential outcome approach to causal inference. We considered the impact of high daily levels of particulate matter ≤10 μm in diameter (PM10) on mortality within two days from the exposure in the metropolitan area of Milan (Italy), during the period 2003–2006. Our research focus was the causal impact of a hypothetical intervention setting daily air pollution levels under a pre-fixed threshold. Methods We applied a matching procedure based on propensity score to estimate the total number of attributable deaths (AD) during the study period. After defining the number of attributable deaths in terms of difference between potential outcomes, we used the estimated propensity score to match each high exposure day, namely each day with a level of exposure higher than 40 μg/m3, with a day with similar background characteristics but a level of exposure lower than 40 μg/m3. Then, we estimated the impact by comparing mortality between matched days. Results During the study period daily exposures larger than 40 μg/m3 were responsible for 1079 deaths (90% CI: 116; 2042). The impact was more evident among the elderly than in the younger age classes. Exposures ≥ 40 μg/m3 were responsible, among the elderly, for 1102 deaths (90% CI: 388, 1816), of which 797 from cardiovascular causes and 243 from respiratory causes. Clear evidence of an impact on respiratory mortality was found also in the age class 65–74, with 87 AD (90% CI: 11, 163). Conclusions The propensity score matching turned out to be an appealing method to assess historical impacts in this field, which guarantees that the estimated total number of AD can be derived directly as sum of either age-specific or cause-specific AD, unlike the standard model-based procedure. For this reason, it is a promising approach to perform surveillance focusing on very specific causes of death or diseases, or on susceptible subpopulations. Finally, the propensity score matching is free from issues concerning the exposure-confounders-mortality modeling and does not involve extrapolation. On the one hand this enhances the internal validity of our results; on the other, it makes the approach scarcely appropriate for estimating future impacts.

The aim of the present study was to evaluate the potential association between dietary nutrients and alterations in DNA methylation in a set of five candidate genes, including CD14, Et-1, iNOS, HERV-w and TNFα, in a population of overweight/obese subjects. We evaluated possible associations between gene methylation and clinical blood parameters, including total cholesterol (TC), low- and high-density lipoprotein cholesterol (LDL-C and HDL-C), triglyceride and homocysteine levels. We employed validated methods to assess anthropometric, clinical and dietary data, as well as pyrosequencing to evaluate DNA methylation of the five candidate genes in 165 overweight/obese subjects. There was no association between body mass index and DNA methylation of the five candidate genes in this group of subjects. Positive associations were observed between TNFα methylation and blood levels of LDL-C (β = 0.447, p = 0.002), TC/HDL-C (β = 0.467, p = 0.001) and LDL-C/HDL-C (β = 0.445, p = 0.002), as well as between HERV-w methylation and dietary intakes of β-carotene (β = 0.088, p = 0.051) and carotenoids (β = 0.083, p = 0.029). TNFα methylation showed negative associations with dietary intakes of cholesterol (β = −0.278, p = 0.048), folic acid (β = −0.339, p = 0.012), β-carotene (β = −0.332, p = 0.045), carotenoids (β = −0.331, p = 0.015) and retinol (β = −0.360, p = 0.008). These results suggest a complex relationship among nutrient intake, oxidative stress and DNA methylation.

A new solid phase microextraction-gas chromatography-mass spectrometry method (SPME-GC-MS) to detect urinary unmetabolized 3-, 6-ring polycyclic aromatic hydrocarbons (PAHs) was applied to coke oven workers and general population subjects with the aim to assess exposure to carcinogenic PAHs, to evaluate the role of occupational and environmental variables on PAHs levels, and to compare present results with those previously obtained with a less sensitive method.A total of 104 coke oven workers (CW) from Poland [recruited in 2000 (CW-2000; n=55) and 2006 (CW-2006; n=49)], and 45 control subjects from the same area, provided urine spot samples for measurement of 10 PAHs (from phenanthrene to benzo[g,h,i]perylene). The comparison between the two methods was performed only on CW-2000 subjects. Information regarding personal characteristics and job variables was collected by a questionnaire.The new method enables the quantification of 5-, 6-ring PAHs; precision and accuracy were in the 7.3-20.8% and 89.4-110% range, respectively; in CW-2000 samples results obtained with the new and the old method were highly correlated (Lin's concordance correlation coefficients: from 0.790 to 0.965); the mean difference between measured PAHS increased with the molecular weight of the analytes (from +5 to +27%). Urinary PAHs were above or equal to the quantification limit, depending on the compound, in 67-100% (min-max), 26-100% and 6-100% of samples from CW-2000, CW-2006 and controls, respectively. Chrysene and benz[a]anthracene were the most abundant carcinogenic PAHs with median levels of 43.4, 13.4, and 2.3 ng/L and 45.9, 14.9, and 0.7 ng/L in CW-2000, CW-2006, and controls, respectively, while benzo[a]pyrene levels were 6.5, 0.7 and0.5 ng/L. The multiple linear regression model showed that the determinants of exposure were the use of wood and/or coke for house heating for controls, and job title or the plant for CW-2006.Urinary benzo[a]pyrene and other carcinogenic PAHs were, for the first time, quantified in urine samples from both occupationally and environmentally exposed subjects. These results show that urinary PAHs can discriminate exposure at different levels. Moreover, the simultaneous determination of several PAHs allows for the development of excretion profiles to assess exposure to specific compounds.

Background and goals: As part of the authorization process for the solid waste incinerator (SWI) in Modena, Italy, a human biomonitoring cross-sectional pilot study was conducted to investigate the degree to which people living and working in the proximity of the plant were exposed to SWI emissions. Methods: Between May and June 2010, 65 subjects living and working within 4 km of the incinerator (exposed) and 103 subjects living and working outside this area (unexposed) were enrolled in the study. Blood, serum and urinary metals (Pb, Cd, Cu, Zn, Hg, Mn, Ni), urinary benzene, toluene, xylene (BTEX), S-phenylmercapturic acid (SPMA), and urinary polycyclic aromatic hydrocarbons (PAHs) were analysed. Information about lifestyle, anthropometric characteristics, residence, and health status was collected by a self-administered questionnaire. Exposure to particulate matter (PM) emitted from the SWI was estimated using fall-out maps from a quasi-Gaussian dispersion model. A multiple linear regression analysis investigated the relationship between biomarkers and the distance of a subject's place of residence from the SWI plant or the exposure to PM. Results: Urinary BTEX and SPMA and blood, serum and urinary metals showed no differences between exposed and unexposed subjects. PAHs were higher in exposed than in unexposed subjects for phenanthrene, anthracene, and pyrene (median levels: 9.5 vs. 7.2 ng/L, 0.8 vs.

Worldwide lung cancer incidence is decreasing or leveling off among men, but rising among women. Sex differences in associations of tobacco carcinogens with lung cancer risk have been hypothesized, but the epidemiologic evidence is conflicting. We tested sex-smoking interaction in association with lung cancer risk within a population-based case-control study, the Environment and Genetics in Lung Cancer Etiology (EAGLE) Study (Lombardy, Italy, 2002-2005). Detailed lifetime smoking histories were collected by personal interview in 2,100 cases with incident lung cancer and 2,120 controls. Odds ratios and 95% confidence intervals for pack-years of cigarette smoking were estimated by logistic regression, adjusted for age, residence area, and time since quitting smoking. To assess sex-smoking interaction, we compared the slopes of odds ratios for logarithm of pack-years in a model for men and women combined. Overall, the slope for pack-years was steeper in men (odds ratio for female-smoking interaction = 0.39, 95% confidence interval: 0.24, 0.62; P < 0.0001); after restriction to ever smokers, the difference in slopes was much smaller (odds ratio for interaction = 0.63, 95% confidence interval: 0.29, 1.37; P = 0.24). Similar results were found by histological type. Results were unchanged when additional confounders were evaluated (e.g., tobacco type, inhalation depth, Fagerstrom-assessed nicotine dependence). These findings do not support a higher female susceptibility to tobacco-related lung cancer.

The aim of this study is to evaluate inflammatory markers and pro-inflammatory CD14 and Toll-like Receptor 4 (TLR4) polymorphisms in workers exposed to flour dust.Polymorphisms in TLR4 and CD14 were identified in our study population of 167 workers that included 63 healthy subjects (HS), 45 atopic subjects (A), and 59 subjects diagnosed clinically with occupational asthma/rhinitis (OAR). Endpoint measures in this study included fractional exhaled nitric oxide and serum concentrations of interleukin IL-6, IL-8, and tumor necrosis factor-alpha (TNF-α).We identified a polymorphism in CD14 (rs2569190) that may be differentially expressed (P = 0.06). IL-6 concentrations in the serum were significantly higher in the A and OAR groups (P 0.01) than in subjects in the HS group, while IL-8 concentrations were significantly elevated only in the OAR group (P 0.01). Interestingly, TNF-α concentrations in the OAR group were significantly reduced when compared with subjects in the HS group (P 0.01).Cytokines are likely a defensive response in atopic and healthy workers. A protective genotype is hypothesized for occupational asthma.

Objectives In Italy, asbestos has been extensively used from 1945 to 1992. We evaluated the impact of exposure to asbestos on occurrence of malignant mesothelioma (MM) in the Lombardy Region, Northwest Italy, the most populated and industrialised Italian region. Methods From the Lombardy Mesothelioma Registry, we selected all incident cases of MM diagnosed between 2000 and 2012. We described sources of exposure to asbestos and examined time trends of MM rates. Using Poisson age-cohort models, we derived projections of burden of MM in the Lombardy population for the period 2013–2029. Results In 2000–2012, we recorded 4442 cases of MM (2850 men, 1592 women). Occupational exposure to asbestos was more frequent in men (73.6%) than in women (38.2%). Non-occupational exposure was found for 13.6% of women and 3.6% of men. The average number of cases of MM per year was still increasing (+3.6% in men, +3.3% in women). Incidence rates were still increasing in individuals aged 65+ years and declining in younger people. A maximum of 417 cases of MM (267 men, 150 women) are expected in 2019. We forecast there will be 6832 more cases (4397 in men, 2435 in women) in the period 2013–2029, for a total of 11 274 cases of MM (7247 in men, 4027 in women) in 30 years. Conclusions This study documented a high burden of MM in both genders in the Lombardy Region, reflecting extensive occupational (mainly in men) and non-occupational (mainly in women) exposure to asbestos in the past. Incidence rates are still increasing; a downturn in occurrence of MM is expected to occur after 2019.

Background: Adverse biological effects from airborne pollutants are a primary environmental concern in highly industrialized areas. Recent studies linked air pollution exposures with altered blood Deoxyribo-nucleic acid (DNA) methylation, but effects from industrial sources and underlying biological mechanisms are still largely unexplored. Methods: The Ma Ta Phut industrial estate (MIE) in Rayong, Thailand hosts one of the largest steel, oil refinery and petrochemical complexes in south-eastern Asia. We measured a panel of blood DNA methylation markers previously associated with air pollution exposures, including repeated elements [long interspersed nuclear element-1 (LINE-1) and Alu] and genes [p53, hypermethylated-in-cancer-1 (HIC1), p16 and interleukin-6 (IL-6)], in 67 MIE workers, 65 Ma Ta Phut residents and 45 rural controls. To evaluate the role of DNA damage and oxidation, we correlated DNA methylation measures with bulky DNA and 3-(2-deoxy-ß-D-erythro-pentafuranosyl)pyrimido[1,2-a]purin-10(3H)-one deoxyguanosine (M1dG) adducts. Results: In covariate-adjusted models, MIE workers, compared with rural residents, showed lower LINE-1 (74.8% vs 78.0%; P < 0.001), p53 (8.0% vs 15.7%; P < 0.001) and IL-6 methylation (39.2% vs 45.0%; P = 0.027) and higher HIC1 methylation (22.2% vs 15.3%, P < 0.001). For all four markers, Ma Ta Phut residents exhibited methylation levels intermediate between MIE workers and rural controls (LINE-1, 75.7%, P < 0.001; p53, 9.0%, P < 0.001; IL-6, 39.8%, P = 0.041; HIC1, 17.8%, P = 0.05; all P-values vs rural controls). Bulky DNA adducts showed negative correlation with p53 methylation (P = 0.01). M1dG showed negative correlations with LINE-1 (P = 0.003) and IL-6 methylation (P = 0.05). Conclusions: Our findings indicate that industrial exposures may induce alterations of DNA methylation patterns detectable in blood leucocyte DNA. Correlation of DNA adducts with DNA hypomethylation suggests potential mediation by DNA damage. © The Author 2012; all rights reserved.

Terbuthylazine (TBA) is an herbicide widely used in corn cultivation. Herein we evaluate the measurement of hair TBA as biomarkers of exposure. Five Sprague Dawley rats were gavaged with TBA for 3 days, and then the back hair was shaved and analyzed for TBA. In addition, head hair samples from 10 corn farmers, 9 rural residents, and 6 urban residents were collected at the end of the application season. Hair TBA was detected by liquid chromatography triple quadrupole mass spectrometry after solvent extraction. TBA was quantifiable in all rat samples with a mean concentration of 0.92 (±0.26)ng/mg, which corresponds to a 0.12% incorporation rate. TBA was quantifiable in all farmer samples (median: 0.67ng/mg), in 75% of rural resident samples (0.01ng/mg) and in none of the urban resident samples (0.01ng/mg), with a statistical difference among groups (P0.01). Our results suggest that TBA is incorporated in hair and prompt further investigation on the use of hair TBA as a potential biomarker of cumulative exposure.

Background: We monitored urinary benzene excretion to examine factors affecting benzene uptake in a sample of the general population living near a petrochemical plant. Methods: Our study population included 143 subjects: 33 petrochemical plant workers (W) with low level occupational benzene exposure; 30 residents in a small town 2 km from the plant (2kmR); 26 residents in a second small town located 2 to 4 km from the plant (4kmR); and 54 urban residents 25 km from the plant (25kmR). Exposure to benzene was evaluated by personal air sampling during one work-shift for the W group, and from 8.00 to 20:00 for general population subgroups, and by urinary benzene (BEN-U). Results: Median airborne benzene exposure was 25, 9, 7 and 6 μg/m3 benzene among the W, 2kmR, 4kmR, and 25kmR subgroups, respectively; the highest level was found among the workers, while there was no significant difference among the other groups. Median BEN-U was 2 to 14-fold higher in smokers compared to non-smokers; among non-smokers BEN-U was the highest in W (median 236 ng/L), and lower in the 2kmR (48 ng/L) and 4kmR (63 ng/L) subgroups than in the 25kmR (120 ng/L) subgroup. A multiple linear regression analysis, explaining up to 73% of BEN-U variability, confirmed that active smoking and airborne benzene most strongly affected BEN-U. Among the non-smoking, non-occupationally exposed study subjects, a positive association was found between BEN-U and the distance of residence from the plant. This association was explained by increased exposure to urban traffic emissions in the study group residing at a greater distance from the plant. Environmental tobacco smoke had a marginally positive role. Conclusion: Among factors affecting benzene uptake in non-occupationally exposed individuals, urban residence contributes to benzene exposure more than residing in close proximity to a petrochemical plant. Keywords: Benzene exposure, Biomonitoring, General population, Urinary benzene

Background Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system, characterized by recurrent relapses of inflammation that cause mild to severe disability. Exposure to airborne particulate matter (PM) has been associated with acute increases in systemic inflammatory responses and neuroinflammation. In the present study, we hypothesize that exposure to PM 10 ) might increase the occurrence of MS-related hospitalizations. Methods We obtained daily concentrations of PM 10 from 53 monitoring sites covering the study area and we identified 8287 MS-related hospitalization through hospital admission-discharge records of the Lombardy region, Italy, between 2001 and 2009. We used a Poisson regression analysis to investigate the association between exposure to PM 10 and risk of hospitalization. Results A higher RR of hospital admission for MS relapse was associated with exposure to PM 10 at different time intervals. The maximum effect of PM 10 on MS hospitalization was found for exposure between days 0 and 7: Hospital admission for MS increased 42% (95%CI 1.39–1.45) on the days preceded by one week with PM 10 levels in the highest quartile. The p- value for trend across quartiles was Conclusions These data support the hypothesis that air pollution may have a role in determining MS occurrence and relapses. Our findings could open new avenues for determining the pathogenic mechanisms of MS and potentially be applied to other autoimmune diseases.

Background: Benzene is an established leukemogen at high exposure levels. Although low-level benzene exposure is widespread and may induce oxidative damage, no mechanistic biomarkers are available to detect biological dysfunction at low doses. Objectives: Our goals were to determine in a large multicenter cross-sectional study whether low-level benzene is associated with increased blood mitochondrial DNA copy number (mtDNAcn, a biological oxidative response to mitochondrial DNA damage and dysfunction) and to explore potential links between mtDNAcn and leukemia-related epigenetic markers. Methods: We measured blood relative mtDNAcn by real-time polymerase chain reaction in 341 individuals selected from various occupational groups with low-level benzene exposures (> 100 times lower than the Occupational Safety and Health Administration/European Union standards) and 178 referents from three Italian cities (Genoa, Milan, Cagliari). Results: In each city, benzene-exposed participants showed higher mtDNAcn than referents: mtDNAcn was 0.90 relative units in Genoa bus drivers and 0.75 in referents (p = 0.019); 0.90 in Milan gas station attendants, 1.10 in police officers, and 0.75 in referents (p-trend = 0.008); 1.63 in Cagliari petrochemical plant workers, 1.25 in referents close to the plant, and 0.90 in referents farther from the plant (p-trend = 0.046). Using covariate-adjusted regression models, we estimated that an interquartile range increase in personal airborne benzene was associated with percent increases in mtDNAcn equal to 10.5% in Genoa (p = 0.014), 8.2% (p = 0.008) in Milan, 7.5% in Cagliari (p = 0.22), and 10.3% in all cities combined (p < 0.001). Using methylation data available for the Milan participants, we found that mtDNAcn was associated with LINE-1 hypomethylation (–2.41%; p = 0.007) and p15 hypermethylation (+15.95%, p = 0.008). Conclusions: Blood MtDNAcn was increased in persons exposed to low benzene levels, potentially reflecting mitochondrial DNA damage and dysfunction.

Affordable early screening in subjects with high risk of lung cancer has great potential to improve survival from this deadly disease. We measured gene expression from lung tissue and peripheral whole blood (PWB) from adenocarcinoma cases and controls to identify dysregulated lung cancer genes that could be tested in blood to improve identification of at-risk patients in the future. Genome-wide mRNA expression analysis was conducted in 153 subjects (73 adenocarcinoma cases, 80 controls) from the Environment And Genetics in Lung cancer Etiology study using PWB and paired snap-frozen tumor and noninvolved lung tissue samples. Analyses were conducted using unpaired t tests, linear mixed effects, and ANOVA models. The area under the receiver operating characteristic curve (AUC) was computed to assess the predictive accuracy of the identified biomarkers. We identified 50 dysregulated genes in stage I adenocarcinoma versus control PWB samples (false discovery rate ≤0.1, fold change ≥1.5 or ≤0.66). Among them, eight (TGFBR3, RUNX3, TRGC2, TRGV9, TARP, ACP1, VCAN, and TSTA3) differentiated paired tumor versus noninvolved lung tissue samples in stage I cases, suggesting a similar pattern of lung cancer–related changes in PWB and lung tissue. These results were confirmed in two independent gene expression analyses in a blood-based case–control study (n = 212) and a tumor–nontumor paired tissue study (n = 54). The eight genes discriminated patients with lung cancer from healthy controls with high accuracy (AUC = 0.81, 95% CI = 0.74–0.87). Our finding suggests the use of gene expression from PWB for the identification of early detection markers of lung cancer in the future. Cancer Prev Res; 4(10); 1599–608. ©2011 AACR.

Background Shortened leukocyte telomere length (LTL) is a marker of cardiovascular risk that has been recently associated with long-term exposure to ambient particulate matter (PM). However, LTL is increased during acute inflammation and allows for rapid proliferation of inflammatory cells. Whether short-term exposure to proinflammatory exposures such as PM increases LTL has never been evaluated. Objectives We investigated the effects of acute exposure to metal-rich PM on blood LTL, as well as molecular mechanisms contributing to LTL regulation in a group of steel workers with high PM exposure. Methods We measured LTL, as well as mRNA expression and promoter DNA methylation of the telomerase catalytic enzyme gene [human telomerase reverse transcriptase (hTERT)] in blood samples obtained from 63 steel workers on the first day of a workweek (baseline) and after 3 days of work (postexposure). Results LTL was significantly increased in postexposure (mean ± SD, 1.43 ± 0.51) compared with baseline samples (1.23 ± 0.28, p-value < 0.001). Postexposure LTL was positively associated with PM10 (β = 0.30, p-value = 0.002 for 90th vs. 10th percentile exposure) and PM1 (β = 0.29, p-value = 0.042) exposure levels in regression models adjusting for multiple covariates. hTERT expression was lower in postexposure samples (1.31 ± 0.75) than at baseline (1.68 ± 0.86, p-value < 0.001), but the decrease in hTERT expression did not show a dose–response relationship with PM. We found no exposure-related differences in the methylation of any of the CpG sites investigated in the hTERT promoter. Conclusions Short-term exposure to PM caused a rapid increase in blood LTL. The LTL increase did not appear to be mediated by PM-related changes in hTERT expression and methylation.

Benzene is a ubiquitous pollutant; smoking habit, genetic polymorphisms, and analytical difficulties impact the identification of the best biomarker.To apply a systematic quantitative approach to evaluate urinary benzene (BEN-U) and S-phenylmercapturic acid (SPMA) as biomarkers of low benzene exposures.Seventy-one blue collar refinery workers, 97 white collar refinery workers and 108 general population subjects were included. Intrinsic characteristics, sampling and analytical issues were compared.BEN-U and SPMA were detected in 99% and 78% of samples, which correlated with benzene exposure (r = 0.456 and r = 0.636, respectively) and with urinary cotinine (r = 0.630 and r = 0.570, respectively). Intrinsic characteristics were similar for the two biomarkers: specificity (0.64 and 0.69 for BEN-U and SPMA), sensitivity (0.74 and 0.83), as well as intra- and inter-individual variability (150% and14 for both).BEN-U and SPMA show similar intrinsic characteristics; analytical issues in detecting SPMA suggest that BEN-U is more convenient for investigating low exposure levels.

Methyl tert-butyl ether (MTBE) and benzene are added to gasoline to improve the combustion process and are found in the urban environment as a consequence of vehicular traffic. Herein we evaluate urinary MTBE (MTBE-U) and benzene (BEN-U) as biomarkers of exposure to urban traffic. Milan urban policemen (130 total) were investigated in May, July, October, and December for a total of 171 work shifts. Personal exposure to airborne benzene and carbon monoxide (CO), and atmospheric data, were measured during the work shift, while personal characteristics were collected by a questionnaire. A time/activity diary was completed by each subject during the work shift. Spot urine samples were obtained for the determination of MTBE-U and BEN-U. Median personal exposure to CO and airborne benzene were 3.3 mg/m3 and 9.6 μg/m3, respectively; median urinary levels in end-of-shift (ES) samples were 147 ng/L (MTBE-U) and 207 ng/L (BEN-U). The time spent on traffic duty at crossing was about 40% of work time. Multiple linear regression models, taking into account within-subject correlations, were applied to investigate the role of urban pollution, atmospheric conditions, job variables and personal characteristics on the level of biomarkers. MTBE-U was influenced by the month of sampling and positively correlated to the time spent in traffic guarding, CO exposure and atmospheric pressure, while negatively correlated to wind speed (R2 for total model 0.63, P

Global DNA hypomethylation affecting repeat sequences has been reported in different cancer types. Herein, we investigated the methylation levels of repetitive DNA elements in chronic lymphocytic leukemia (CLL), their correlation with the major cytogenetic and molecular features, and clinical relevance in predicting therapy-free survival (TFS). A quantitative bisulfite-PCR Pyrosequencing method was used to evaluate methylation of Alu, long interspersed nuclear elements-1 (LINE-1) and satellite-α (SAT-α) sequences in 77 untreated early-stage (Binet A) CLL patients. Peripheral B-cells from 7 healthy donors were used as controls. Methylation levels (median %5mC) were lower in B-CLLs compared with controls (21.4 vs. 25.9; 66.8 vs. 85.7; 84.0, vs. 88.2 for Alu, LINE-1 and SAT-α, respectively) (p < 0.001). Among CLL patients, a significant association was observed with 17p13.1 deletion (16.8 vs. 22.4; 51.2 vs. 68.5; 52.6 vs. 85.0, for Alu, LINE-1 and SAT-α) but not with other major genetic lesions, IgVH mutation status, CD38 or ZAP-70 expression. Follow-up analyses showed that lower SAT-α methylation levels appeared to be an independent prognostic marker significantly associated with shorter TFS. Our study extended previous limited evidences in methylation of repetitive sequences in CLL suggesting an important biological and clinical relevance in the disease.

See also Mannucci PM. Fine particulate: it matters. This issue, pp 659–61; Dales RE, Cakmak S, Vidal CB. Air pollution and hospitalization for venous thromboembolic disease in Chile. This issue, pp 669–74. Summary. Background: Particulate matter (PM) exposure has been linked to increased risk of cardiovascular disease, possibly resulting from hypercoagulability and thrombosis. Lung and systemic inflammation resulting from PM inhalation may activate blood coagulation, but mechanisms for PM-related hypercoagulability are still largely unknown. Objectives: To identify coagulation mechanisms activated by PM in a population with well-characterized exposure. Methods: We measured prothrombin time (PT), activated partial thromboplastin time, endogenous thrombin potentials (ETPs) with/without exogenous triggers and with/without soluble thrombomodulin, tissue-type plasminogen activator (t-PA) antigen, D-dimer and C-reactive protein (CRP) in 37 workers in a steel production plant with well-characterized exposure to PM with aerodynamic diameter of

The authors investigated the relation between alcohol consumption and lung cancer risk in the Environment and Genetics in Lung Cancer Etiology (EAGLE) Study, a population-based case-control study. Between 2002 and 2005, 2,100 patients with primary lung cancer were recruited from 13 hospitals within the Lombardy region of Italy and were frequency-matched on sex, area of residence, and age to 2,120 randomly selected controls. Alcohol consumption during adulthood was assessed in 1,855 cases and 2,065 controls. Data on lifetime tobacco smoking, diet, education, and anthropometric measures were collected. Adjusted odds ratios and 95% confidence intervals for categories of mean daily ethanol intake were calculated using unconditional logistic regression. Overall, both nondrinkers (odds ratio = 1.42, 95% confidence interval: 1.03, 2.01) and very heavy drinkers (>/=60 g/day; odds ratio = 1.44, 95% confidence interval: 1.01, 2.07) were at significantly greater risk than very light drinkers (0.1-4.9 g/day). The alcohol effect was modified by smoking behavior, with no excess risk being observed in never smokers. In summary, heavy alcohol consumption was a risk factor for lung cancer among smokers in this study. Although residual confounding by tobacco smoking cannot be ruled out, this finding may reflect interplay between alcohol and smoking, emphasizing the need for preventive measures.

Objectives To assess dermal exposure to 16 polycyclic aromatic hydrocarbons (PAHs) in asphalt workers by applying polypropylene pads to six body sites (neck, shoulder, upper arm, wrist, groin, ankle), to identify the compounds and exposure sites most representative, and to integrate dermal exposure results with environmental and biological data. Methods Twenty-four asphalt workers were recruited. Dermal exposure was assessed during a single work shift. Sixteen PAHs (from naphthalene to indeno[1,2,3-cd]pyrene) were quantified via gas chromatography-mass spectrometry. Airborne exposure, urinary PAHs and monohydroxy metabolites were also investigated. Results Phenanthrene (PHE), present in all samples, was the most abundant compound (median 0.805–1.825 ng/cm 2 ). Benzo[a]pyrene (BaP) was present in 75% of the samples (0.046–0.101 ng/cm 2 ). Wrist had the highest contamination, with median PHE, pyrene (PYR), and BaP concentrations of 1.825, 0.527, and 0.063 ng/cm 2 . PHE and PYR on wrist correlated with almost all 3- to 4-ring PAHs (0.405≤r≤0.856), but not with BaP; BaP correlated with almost all 4- to 6- ring PAHs (0.584≤r≤0.633). Significant correlations were observed between PHE level, airborne exposure, and the corresponding urinary PHE and monohydroxy metabolites. For PYR, significant correlations existed only between urinary PYR and monohydroxy metabolites. Multiple linear regression analysis revealed that 42% of the end-of-shift monohydroxy metabolites were the result of airborne exposure, dermal exposure, and baseline levels of biomarkers. Conclusions Dermal exposure to PAHs was in the low ng/cm 2 range. PHE or PYR and BaP were the most representative compounds and the wrist was the best location to perform dermal exposure assessments. Both dermal and airborne exposure contributed to the total body burden of PAHs, though the relative contribution was analyte-dependent.

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]pyrene diolepoxide (anti-B[a]PDE)-DNA adduct levels, a critical genetic damage from B[a]P. We also evaluated whether PAH-induced DNA methylation states were in turn associated with micronuclei in PBLs, an indicator of chromosomal instability.

Multiple myeloma (MM) is characterized by a wide spectrum of genetic changes. Global hypomethylation of repetitive genomic sequences such as long interspersed nuclear element 1 (LINE-1), Alu and satellite alpha (SAT-alpha) sequences has been associated with chromosomal instability in cancer. Methylation status of repetitive elements in MM has never been investigated. In the present study, we used a quantitative bisulfite-polymerase chain reaction pyrosequencing method to evaluate the methylation patterns of LINE-1, Alu and SAT-alpha in 23 human myeloma cell lines (HMCLs) and purified bone marrow plasma cells from 53 newly diagnosed MM patients representative of different molecular subtypes, 7 plasma cell leukemias (PCLs) and 11 healthy controls. MMs showed a decrease of Alu [median: 21.1 %5-methylated cytosine (%5mC)], LINE-1 (70.0%5mC) and SAT-alpha (77.9%5mC) methylation levels compared with controls (25.2, 79.5and 89.5%5mC, respectively). Methylation levels were lower in PCLs and HMCLs compared with MMs (16.7 and 14.8%5mC for Alu, 45.5 and 42.4%5mC for LINE-1 and 33.3 and 43.3%5mC for SAT-alpha, respectively). Notably, LINE-1 and SAT-alpha methylation was significantly lower in the non-hyperdiploid versus hyperdiploid MMs (P = 0.01 and 0.02, respectively), whereas Alu and SAT-alpha methylation was significantly lower in MMs with t(4;14) (P = 0.02 and 0.004, respectively). Finally, we correlated methylation patterns with DNA methyltransferases (DNMTs) messenger RNA levels showing in particular a progressive and significant increase of DNMT1 expression from controls to MMs, PCLs and HMCLs (P < 0.001). Our results indicate that global hypomethylation of repetitive elements is significantly associated with tumor progression in MM and may contribute toward a more extensive stratification of the disease.

Background Altered patterns of gene expression mediate the effects of particulate matter (PM) on human health, but mechanisms through which PM modifies gene expression are largely undetermined. Objectives We aimed at identifying short- and long-term effects of PM exposure on DNA methylation, a major genomic mechanism of gene expression control, in workers in an electric furnace steel plant with well-characterized exposure to PM with aerodynamic diameters < 10 μm (PM10). Methods We measured global genomic DNA methylation content estimated in Alu and long interspersed nuclear element-1 (LINE-1) repeated elements, and promoter DNA methylation of iNOS (inducible nitric oxide synthase), a gene suppressed by DNA methylation and induced by PM exposure in blood leukocytes. Quantitative DNA methylation analysis was performed through bisulfite PCR pyrosequencing on blood DNA obtained from 63 workers on the first day of a work week (baseline, after 2 days off work) and after 3 days of work (postexposure). Individual PM10 exposure was between 73.4 and 1,220 μg/m3. Results Global methylation content estimated in Alu and LINE-1 repeated elements did not show changes in postexposure measures compared with baseline. PM10 exposure levels were negatively associated with methylation in both Alu [β = −0.19 %5-methylcytosine (%5mC); p = 0.04] and LINE-1 [β = −0.34 %5mC; p = 0.04], likely reflecting long-term PM10 effects. iNOS promoter DNA methylation was significantly lower in postexposure blood samples compared with baseline (difference = −0.61 %5mC; p = 0.02). Conclusions We observed changes in global and gene specific methylation that should be further characterized in future investigations on the effects of PM.

ObjectiveThe pathogenesis of sporadic pituitary tumors is unknown. Loss-of-function mutations of aryl hydrocarbon receptor-interacting protein (AIP) have been identified in patients with familial pituitary tumors. AIP is a chaperone protein with multifunction properties, including modulation of the transcriptional activity of the aryl hydrocarbon receptor, which mediates toxicological and carcinogenic dioxin effects.DesignWe investigated the incidence of pituitary tumors in the Seveso population exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin following an industrial accident in 1976.MethodsThrough the hospital discharge registration system of Lombardy Region, we identified incident cases of pituitary adenomas between 1976 and 1996 in the Seveso population, subdivided in zone A (n=804), B (n=5.941), and R (n=38.624) according to high, intermediate, and low exposure to dioxin respectively, and in the surrounding non-contaminated area, as reference (n=232 745).ResultsWe identified 42 pituitary adenomas in the reference area, 1 prolactinoma in zone A (rate ratio (RR) 6.2; 95% CI 0.9–45.5, P=0.07), 2 nonfuctioning pituitary tumors (NFPAs) in zone B (RR 1.9; 95% CI 0.5–7.7, P=0.39), and 3 prolactinomas and 2 NFPAs in zone R (RR 0.7; 95% CI 0.3–1.8, P=0.48).ConclusionsThe study is unique with regard to the availability of epidemiological and clinical data in an area of relatively pure dioxin exposure. The study indicates no statistically significant increase of incident pituitary tumors in this area, although the tendency toward a higher risk (three cases in zones A and B) of pituitary tumors in subjects exposed to high–intermediate dioxin concentrations in comparison with nonexposed population suggests the need for extended follow-up.

Background: Particulate air pollution is a risk factor for cardiovascular diseases and thrombosis. Long-term exposure to particulate matter with a diameter

Background: Population-based estimates of absolute risk of lung cancer recurrence, and of mortality rates after recurrence, can inform clinical management. Methods: We evaluated prognostic factors for recurrences and survival in 2098 lung cancer case patients from the general population of Lombardy, Italy, from 2002 to 2005. We conducted survival analyses and estimated absolute risks separately for stage IA to IIIA surgically treated and stage IIIB to IV non–surgically treated patients. Results: Absolute risk of metastases exceeded that of local recurrence in every stage and cell type, highlighting the systemic threat of lung cancer. In stage I, the probability of dying within the first year after diagnosis was 2.7%, but it was 48.3% within first year after recurrence; in stage IV, the probabilities were 57.3% and 80.6%, respectively. Over half the patients died within one year of first metastasis. Although in stages IA to IB about one-third of patients had a recurrence, stage IIA patients had a recurrence risk (61.2%) similar to stage IIB (57.9%) and IIIA (62.8%) patients. Risk of brain metastases in stage IA to IIIA surgically treated non–small cell lung cancer patients increased with increasing tumor grade. Absolute risk of recurrence was virtually identical in adenocarcinoma and squamous cell carcinoma patients. Conclusions: This population-based study provides clinically useful estimates of risks of lung cancer recurrence and mortality that are applicable to the general population. These data highlight the need for more effective adjuvant treatments overall and within specific subgroups. The estimated risks of various endpoints are useful for designing clinical trials, whose power depends on absolute numbers of events. Lung cancer is the leading cause of cancer deaths worldwide (

Several epidemiologic investigations have demonstrated that ambient air pollution is associated with increased risk of cardiovascular disease (Brook et al. 2004). In particular, acute increases in ambient particulate matter (PM) levels have been associated with myocardial infarction, stroke, and other adverse effects on cardiovascular function (Biggeri et al. 2004; Forastiere et al. 2005; Katsouyanni et al. 2001; O’Neill et al. 2005; Samet et al. 2000b; Schwartz et al. 2005; Wellenius et al. 2005; Zanobetti and Schwartz 2005; Zanobetti et al. 2004). The mechanisms linking inhalation of air pollutants to an increased cardiovascular risk are not fully understood (Bhatnagar 2006; Brook et al. 2002; Donaldson et al. 2001; Nel 2005; Peters et al. 1997, 2001). Epidemiologic investigations have demonstrated that high plasma levels of total homocysteine (tHcy) are an independent risk factor for vascular disease, including coronary artery, cerebrovascular, and peripheral occlusive disease (Davey Smith and Ebrahim 2005; Welch and Loscalzo 1998). In addition to fasting tHcy measurements, tHcy determination after oral methionine load is used to identify individuals with mild impairment of Hcy metabolism, in whom fasting tHcy may be normal but postmethionine-load (PML) tHcy concentration is increased (Refsum et al. 2004). Alveolar and systemic inflammation has been proposed as a central component in the series of events linking the exposure to inhaled pollutants to the observed increases in cardiovascular morbidity and mortality (Brook et al. 2004; Seaton et al. 1995). Inflammation is a known determinant of hyperhomocysteinemia (Gori et al. 2005; von Eckardstein et al. 1994), and both air pollution and plasma tHcy have been associated with increased levels of C-reactive protein, fibrinogen, and interleukin-6 (Evans et al. 1997; Ghio et al. 2003; Gori et al. 2005; Pekkanen et al. 2000; Peters et al. 2001; Schwartz 2001; Seaton et al. 1999; von Eckardstein et al. 1994). However, whether air pollution exposure is correlated with increased tHcy levels has never been determined. Gori et al. (2005) suggested previously that short-term changes in inflammatory markers are associated with hyperhomocysteinemia when coupled with a mild persistent inflammatory state. In healthy subjects, tobacco smoking is a common cause of persistent low-level inflammation, and smoking has been also shown to induce elevated tHcy levels (Bazzano et al. 2003; De Bree et al. 2002; Guttormsen et al. 1996). In the present study, we investigate the effects of air pollution levels on fasting and PML tHcy in 1,213 normal subjects from Lombardia, Italy. In addition, we examined potential effect modification by cigarette smoking of the relation between air pollution and tHcy.

Benzene is a human carcinogen and an ubiquitous environmental pollutant. Identification of specific and sensitive biological markers is critical for the definition of exposure to low benzene level and the evaluation of the health risk posed by this exposure. This investigation compared urinary trans,trans-muconic acid (t,t-MA), S-phenylmercapturic acid, and benzene (U-benzene) as biomarkers to assess benzene exposure and evaluated the influence of smoking and the genetic polymorphisms CYP2E1 (RsaI and DraI) and NADPH quinone oxidoreductase-1 on these indices. Gas station attendants, urban policemen, bus drivers, and two groups of controls were studied (415 subjects). Median benzene exposure was 61, 22, 21, 9 and 6 μg/m3, respectively, with higher levels in workers than in controls. U-benzene, but not t,t-MA and S-phenylmercapturic acid, showed an exposure-related increase. All the biomarkers were strongly influenced by cigarette smoking, with values up to 8-fold higher in smokers compared with nonsmokers. Significant correlations of the biomarkers with each other and with urinary cotinine were found. A possible influence of genetic polymorphism of CYP2E1 (RsaI and/or DraI) on t,t-MA and U-benzene in subjects with a variant allele was found. Multiple linear regression analysis correlated the urinary markers with exposure, smoking status, and CYP2E1 (RsaI; R2 up to 0.55 for U-benzene). In conclusion, in the range of investigated benzene levels (

Summary Background The Seveso, Italy accident of 1976 exposed a large population to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or simply dioxin). The accident resulted, mostly among children, in one of the largest ever-reported outbreaks of chloracne, the typical skin disorder due to halogenated-hydrocarbon compounds. Objectives Approximately 20 years after the accident, we conducted an epidemiological study in Seveso to investigate (a) the health status of chloracne cases; (b) TCDD-chloracne exposure–response relationship; and (c) factors modifying TCDD toxicity. Methods From 1993 to 1998, we recruited 101 chloracne cases and 211 controls. Trained interviewers administered a structured questionnaire assessing, among other epidemiological variables, information on an extensive list of diseases. During the interview, individual pigmentary characteristics were determined. We measured plasma TCDD levels using high-resolution gas chromatography/mass spectrometry. Results Plasma TCDD was still elevated (> 10 ppt) in 78 (26·6%) of the 293 subjects with adequate plasma samples, particularly in females, in subjects who had eaten home-grown animals, and in individuals with older age, higher body mass index and residence near the accident site. After 20 years, health conditions of chloracne cases were similar to those of controls from the Seveso area. Elevated plasma TCDD was associated with chloracne [odds ratio (OR) = 3·7, 95% confidence interval (CI) 1·6–8·8, adjusted for age, sex and residence]. Chloracne risk was higher in subjects younger than 8 years at the accident (OR = 7·4, 95% CI 1·8–30·3) and, contrary to previous hypotheses, did not increase at puberty onset or in teenage years. Subjects with elevated TCDD levels and light hair colour had higher relative odds of chloracne (OR = 9·2, 95% CI 2·6–32·5). Conclusions Dioxin toxicity in chloracne cases was confined to the acute dermatotoxic effects. Chloracne occurrence appeared related to younger age and light hair colour. Age-related dioxin elimination or dilution must be taken into account in interpreting these results.

Approximately 20 years after the Seveso, Italy accident, we conducted a population-based study to evaluate the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure upon immune and mechanistically based biomarkers of dioxin response in humans. TCDD toxic effects are known to be mediated by the aryl-hydrocarbon receptor (AhR). We randomly selected 62 study subjects from the highest exposed zones and 59 from the surrounding non-contaminated area. Current lipid-adjusted plasma TCDD concentrations in these subjects ranged from 3.5 to 90 ng/kg (or ppt) and were negatively associated with plasma IgG concentrations (r=-0.35; P = 0.0002). The expression of genes in the AhR-dependent pathway, including AhR, aryl-hydrocarbon receptor nuclear translocator (ARNT), CYP1A1, and CYP1B1 transcripts, and the CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) activity was measured in lymphocytes. AhR mRNA levels in uncultured lymphocytes were negatively associated with plasma TCDD (P=0.03). When mitogen-induced lymphocytes were cultured with 10nM TCDD, all AhR-dependent genes were induced 1.2- to 13-fold. In these cells, plasma TCDD was associated with decreased EROD activity. Markers within the AhR pathway were correlated with one another. Our findings suggest the presence of long-term effects in the subjects exposed to TCDD after the Seveso accident.

Background Blood pressure (BP) is a complex, multifactorial clinical outcome driven by genetic susceptibility, behavioral choices, and environmental factors. Many molecular mechanisms have been proposed for the pathophysiology of high BP even as its prevalence continues to grow worldwide, increasing morbidity and marking it as a major public health concern. To address this, we evaluated miRNA profiling in blood leukocytes as potential biomarkers of BP and BP-related risk factors. Methods The Beijing Truck Driver Air Pollution Study included 60 truck drivers and 60 office workers examined in 2008. On two days separated by 1–2 weeks, we examined three BP measures: systolic, diastolic, and mean arterial pressure measured at both pre- and post-work exams for blood NanoString nCounter miRNA profiles. We used covariate-adjusted linear mixed-effect models to examine associations between BP and increased miRNA expression in both pooled and risk factor-stratified analyses. Results Overall 43 miRNAs were associated with pre-work BP (FDR

Background Exposure to ambient particulate matter (PM) has been associated with reduced lung function. Elemental components of PM have been suggested to have critical roles in PM toxicity, but their contribution to respiratory effects remains under-investigated. We evaluated the effects of traffic-related PM2.5 and its elemental components on lung function in two highly exposed groups of healthy adults in Beijing, China. Methods The Beijing Truck Driver Air Pollution Study (BTDAS) included 60 truck drivers and 60 office workers evaluated in 2008. On two days separated by 1-2 weeks, we measured lung function at the end of the work day, personal PM2.5, and nine elemental components of PM2.5 during eight hours of work, i.e., elemental carbon (EC), potassium (K), sulfur (S), iron (Fe), silicon (Si), aluminum (Al), zinc (Zn), calcium (Ca), and titanium (Ti). We used covariate-adjusted mixed-effects models including PM2.5 as a covariate to estimate the percentage change in lung function associated with an inter-quartile range (IQR) exposure increase. Results The two groups had high and overlapping exposure distributions with mean personal PM2.5 of 94.6 μg/m3 (IQR: 48.5-126.6) in office workers and 126.8 μg/m3 (IQR: 73.9-160.5) in truck drivers. The distributions of the nine elements showed group-specific profiles and generally higher levels in truck drivers. In all subjects combined, forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) did not significantly correlate with PM2.5. However, FEV1 showed negative associations with concentrations of four elements: Si (-3.07%, 95% CI: -5.00; -1.11, IQR: 1.54), Al (-2.88%, 95% CI: -4.91; -0.81, IQR: 0.86), Ca (-1.86%, 95% CI: -2.95; -0.76, IQR: 1.33), and Ti (-2.58%, 95% CI: -4.44; -0.68, IQR: 0.03), and FVC showed negative associations with concentrations of three elements: Si (-3.23%, 95% CI: -5.61; -0.79), Al (-3.26%, 95% CI: -5.73; -0.72), and Ca (-1.86%, 95% CI: -3.23; -0.47). In stratified analysis, Si, Al, Ca, and Ti showed associations with lung function only among truck drivers, and no significant association among office workers. Conclusion Selected elemental components of PM2.5 showed effects on lung function that were not found in analyses of particle levels alone. Electronic supplementary material The online version of this article (doi:10.1186/s12989-014-0051-7) contains supplementary material, which is available to authorized users.

Several studies have proposed telomere length and telomerase activity as prognostic factors in chronic lymphocytic leukemia (CLL), whereas information addressing the role of telomere-associated genes is limited. We measured relative telomere length (RTL) and TERT expression levels in purified peripheral CD19(+) B-cells from seven healthy donors and 77 untreated CLLs in early stage disease (Binet A). Data were correlated with the major biological and cytogenetic markers, global DNA methylation (Alu and LINE-1), and clinical outcome. The expression profiles of telomere-associated genes were also investigated. RTL was decreased in CLLs as compared with controls (P 0.001); within CLL, a progressive and significant RTL shortening was observed in patients from 13q- through +12, 11q-, and 17p- alterations; short telomeres were significantly associated with unmutated IGHV configuration and global DNA hypomethylation. Decreased RTL was associated with a shorter time to first treatment. A significant upregulation of POT1, TRF1, RAP1, MRE11A, RAD50, and RPA1 transcript levels was observed in CLLs compared with controls. Our study suggests that impairment of telomere/telomerase system represents an early event in CLL pathogenesis. Moreover, the correlation between telomere shortening and global DNA hypomethylation supports the involvement of DNA hypomethylation to increase chromosome instability. © 2014 Wiley Periodicals, Inc.

Epidemiological studies have shown associations of particulate matter (PM) exposure with hypercoagulability and thrombosis. Extracellular circulating histones have recently been identified as novel mediators of inflammatory and procoagulant responses. The potential roles of extracellular histones in PM-related hypercoagulability have yet not been investigated.In 63 steel workers, we evaluated the effects of exposure to PM and PM metal components on two extracellular histone modifications (H3K4me3 and H3K9ac); and the association of H3K4me3 and H3K9ac with coagulation markers.Extracellular H3K4me3 and H3K9ac were determined in plasma through enzyme-linked immunosorbent assays. Coagulation markers included endogenous thrombin potentials (ETPs), tissue-type plasminogen activator antigen (t-PA) and D-dimer. Exposure to PM with aerodynamic diameters1 μm (PM1) or10 μm (PM10) and PM10 metal components were estimated for each participant.The coagulation marker ETP, measured in the presence of soluble thrombomodulin (ETP TM+), showed significant positive associations with PM1 (β=107.84, p=0.03), PM10 (β=83.06, p=0.02), and zinc (β=75.14, p=0.03); and a marginal association with iron (β=122.58, p=0.07). Additional PM effects were observed on t-PA, D-dimer, and ETP TM+. PM1 exposure was associated with increased plasma H3K4me3 and H3K9ac (β=0.20, p=0.02; β=0.16, p=0.05, respectively). H3K4me3, but not H3K9ac, was associated with zinc (β=0.13, p=0.03) and iron (β=0.32, p=0.01) contained in PM. ETP TM+ was increased in association with higher plasma H3K4me3 (β=0.50, p=0.05) and H3K9ac (β=0.54, p=0.05).This observational study suggests potential roles of extracellular histones in PM-induced hypercoagulability. Experimental studies are warranted to further characterize these findings.

Evidence indicates that oxidative stress generation may contribute to health effects associated with particulate matter (PM) exposure. We investigated oxidative stress markers in 113 workers exposed to metal-rich PM and 61 nonexposed comparable volunteers. The plasma levels of soluble NOX2-derived peptide (sNOX2-dp) and two oxidative stress markers, urinary 8-hydroxydeoxyguanosine (8-OHdG) and 8-iso-prostaglandinF2alpha (8-iso-PGF2α), were analyzed. The plasma levels of the antioxidant alpha-tocopherol were also evaluated. The workers' average exposure to PM with an aerodynamic diameter

Cardiovascular disease risk has been consistently linked with particulate matter (PM) exposure. Cell-derived microvesicles (MVs) are released into plasma and transfer microRNAs (miRNAs) between tissues. MVs can be produced by the respiratory system in response to proinflammatory triggers, enter the circulatory system and remotely modify gene expression in cardiovascular tissues. However, whether PM affects MV signaling has never been investigated. In this study, we evaluated expression of microRNAs contained within plasma MVs upon PM exposure both in vivo and in vitro. In the in vivo study, we isolated plasma MVs from healthy steel plant workers before and after workplace PM exposure. We measured the expression of 88 MV-associated miRNAs by real-time polymerase chain reaction. To assess a possible source of the MV miRNAs identified in vivo, we measured their miRNA expression in PM-treated A549 pulmonary cell lines in vitro. MiRNA profiling of plasma MVs showed 5.62- and 13.95-fold increased expression of miR-128 and miR-302c, respectively, after 3 days of workplace PM exposure (P

Follow-up of the population exposed to dioxin after the 1976 accident in Seveso, Italy, was extended to 1996. During the entire observation period, all-cause and all-cancer mortality did not increase. Fifteen years after the accident, mortality among men in high-exposure zones A (804 inhabitants) and B (5,941 inhabitants) increased from all cancers (rate ratio (RR) = 1.3, 95% confidence interval (CI): 1.0, 1.7), rectal cancer (RR = 2.4, 95% CI: 1.2, 4.6), and lung cancer (RR = 1.3, 95% CI: 1.0, 1.7), with no latency-related pattern for rectal or lung cancer. An excess of lymphohemopoietic neoplasms was found in both genders (RR = 1.7, 95% CI: 1.2, 2.5). Hodgkin's disease risk was elevated in the first 10-year observation period (RR = 4.9, 95% CI: 1.5, 16.4), whereas the highest increase for non-Hodgkin's lymphoma (RR = 2.8, 95% CI: 1.1, 7.0) and myeloid leukemia (RR = 3.8, 95% CI: 1.2, 12.5) occurred after 15 years. No soft tissue sarcoma cases were found in these zones (0.8 expected). An overall increase in diabetes was reported, notably among women (RR = 2.4, 95% CI: 1.2, 4.6). Chronic circulatory and respiratory diseases were moderately increased, suggesting a link with accident-related stressors and chemical exposure. Results support evaluation of dioxin as carcinogenic to humans and corroborate the hypotheses of its association with other health outcomes, including cardiovascular- and endocrine-related effects.

The industrial accident that occurred in the town of Seveso, Italy, in 1976 exposed a large population to substantial amounts of relatively pure 2,3,7,8-tetrachlorodibenzo-p-dioxin. Extensive monitoring of soil levels and measurements of a limited number of human blood samples allowed classification of the exposed population into three categories, A (highest exposure), B (median exposure), and R (lowest exposure). Early health investigations including liver function, immune function, neurologic impairment, and reproductive effects yielded inconclusive results. Chloracne (nearly 200 cases with a definite exposure dependence) was the only effect established with certainty. Long-term studies were conducted using the large population living in the surrounding noncontaminated territory as reference. An excess mortality from cardiovascular and respiratory diseases was uncovered, possibly related to the psychosocial consequences of the accident in addition to the chemical contamination. An excess of diabetes cases was also found. Results of cancer incidence and mortality follow-up showed an increased occurrence of cancer of the gastrointestinal sites and of the lymphatic and hematopoietic tissue. Experimental and epidemiologic data as well as mechanistic knowledge support the hypothesis that the observed cancer excesses are associated with dioxin exposure. Results cannot be viewed as conclusive. The study is continuing in an attempt to overcome the existing limitations (few individual exposure data, short latency period, and small population size for certain cancer types) and to explore new research paths (e.g., differences in individual susceptibility). Images Figure 1

Dioxin (2,3,7,8-tetrachlorodibenzo-para-dioxin, or TCDD) is a powerful carcinogen in experimental animals, whereas the evidence in humans is limited. We examined cancer mortality from 1976 to 1991 among residents of Seveso, Italy, which was highly contaminated after an industrial accident. The area was divided into zones with decreasing exposure to dioxin (A = highest, B = lower, R = lowest). The population of a surrounding noncontaminated area was used as a reference group. Zone A was small (11,516 person-years); in that zone, we saw a moderate increase in mortality from digestive cancer among women [relative risk (RR) = 1.5; 95% confidence interval (CI) = 0.5-3.5]. In zone B, we also saw excesses at digestive sites (83,610 person-years), 10 years after the accident. Women had an increased mortality from stomach cancer (RR = 2.4; 95% CI = 0.8-5.7), and men had increased mortality from rectal cancer (RR = 6.2; 95% CI = 1.7-15.9). Hematologic neoplasms were increased. The highest risks were seen in zone B for leukemia in men (RR = 3.1; 95% CI = 1.3-6.4), multiple myeloma in women (RR = 6.6; 95% CI = 1.8-16.8), and Hodgkin's disease in both genders (RR = 3.3; 95% CI = 0.4-11.9 in men; and RR = 6.5; 95% CI = 0.7-23.5 in women). Soft tissue sarcoma was elevated only among zone R males (256,408 person-years; RR = 2.1; 95% CI = 0.6-5.4). We found no increase for all-cancer mortality or major specific sites (for example, respiratory among males, breast among females). The specific excesses that we observed were not explained by bias or confounding, and their association with dioxin exposure is plausible. The follow-up is continuing.

Exposure to particulate matter (PM) has been associated with lung cancer risk in epidemiology investigations. Elemental components of PM have been suggested to have critical roles in PM toxicity, but the molecular mechanisms underlying their association with cancer risks remain poorly understood. DNA methylation has emerged as a promising biomarker for environmental-related diseases, including lung cancer. In this study, we evaluated the effects of PM elemental components on methylation of three tandem repeats in a highly exposed population in Beijing, China. The Beijing Truck Driver Air Pollution Study was conducted shortly before the 2008 Beijing Olympic Games (June 15-July 27, 2008) and included 60 truck drivers and 60 office workers. On two days separated by 1-2 weeks, we measured blood DNA methylation of SATα, NBL2, D4Z4, and personal exposure to eight elemental components in PM2.5 , including aluminum (Al), silicon (Si), sulfur (S), potassium (K), calcium (Ca) titanium (Ti), iron (Fe), and zinc (Zn). We estimated the associations of individual elemental component with each tandem-repeat methylation in generalized estimating equations (GEE) models adjusted for PM2.5 mass and other covariates. Out of the eight examined elements, NBL2 methylation was positively associated with concentrations of Si [0.121, 95% confidence interval (CI): 0.030; 0.212, False Discovery Rate (FDR) = 0.047] and Ca (0.065, 95%CI: 0.014; 0.115, FDR = 0.047) in truck drivers. In office workers, SATα methylation was positively associated with concentrations of S (0.115, 95% CI: 0.034; 0.196, FDR = 0.042). PM-associated differences in blood tandem-repeat methylation may help detect biological effects of the exposure and identify individuals who may eventually experience higher lung cancer risk.

In Europe 23.5% of the working-age population suffers from chronic or rare diseases, including Ehlers-Danlos syndrome (EDS), an inherited disorder of the connective tissue that frequently leads to impairment also at work.We sought to evaluate the impairment of different functional areas in EDS subjects, using EDS-Disability Test (EDS-DT) (7 visual analogical scales: pain, stiffness, daily activities of life, in the home, outside the home, at work, in social relationships).We administered the EDS-DT to 50 workers with EDS (classic type n=35, hypermobile n=14, vascular n=3) and 150 healthy workers (non-EDS).EDS subjects showed higher perceived disability (median 29.31 vs 7.22, plt; 0.0001) than non-EDS. We observed a trend suggesting that the hypermobile type has a higher level of pain (54 vs 42) and work impairment (62.5 vs 42.5) (pgt;0.20), whereas the classic type has greater impairment of daily living activities (18.57 vs 11.43) and in the home (34.29 vs 25.71) (pgt;0.20). Subjects reporting moderate-to-vigorous occupational physical activities (OPA) showed a higher disability level in the work area (p=0.04).People with EDS suffer from chronic pain, impaired quality of life and employment difficulties. The hypermobile type seems more compromised in functional areas such as pain and work, while the classic type is more compromised in daily routine and home activities. The employment section was more impaired for EDS subjects who perform tasks with greater physical effort.

Background Short‐term exposures to fine (PM ) have been related with increased blood pressure ( BP ) in controlled‐human exposure and community‐based studies. However, whether coarse (2.5 to 10 μm) PM exposure increases BP is uncertain. Recent observational studies have linked PM exposures with blood DNA hypomethylation, an epigenetic alteration that activates inflammatory and vascular responses. No experimental evidence is available to confirm those observational data and demonstrate the relations between PM , hypomethylation, and BP . Methods and Results We conducted a cross‐over trial of controlled‐human exposure to concentrated ambient particles ( CAP s). Fifteen healthy adult participants were exposed for 130 minutes to fine CAP s, coarse CAP s, or HEPA ‐filtered medical air (control) in randomized order with ≥2‐week washout. Repetitive‐element ( Alu , long interspersed nuclear element‐1 [ LINE ‐1]) and candidate‐gene ( TLR4 , IL‐12 , IL‐6 , iNOS ) blood methylation, systolic and diastolic BP were measured pre‐ and postexposure. After adjustment for multiple comparisons, fine CAP s exposure lowered Alu methylation (β‐standardized=−0.74, adjusted‐ P =0.03); coarse CAP s exposure lowered TLR4 methylation (β‐standardized=−0.27, adjusted‐ P =0.04). Both fine and coarse CAP s determined significantly increased systolic BP (β=2.53 mm Hg, P =0.001; β=1.56 mm Hg, P =0.03, respectively) and nonsignificantly increased diastolic BP (β=0.98 mm Hg, P =0.12; β=0.82 mm Hg, P =0.11, respectively). Decreased Alu and TLR4 methylation was associated with higher postexposure DBP (β‐standardized=0.41, P =0.04; and β‐standardized=0.84, P =0.02; respectively). Decreased TLR4 methylation was associated with higher postexposure SBP (β‐standardized=1.45, P =0.01). Conclusions Our findings provide novel evidence of effects of coarse PM on BP and confirm effects of fine PM . Our results provide the first experimental evidence of PM ‐induced DNA hypomethylation and its correlation to BP .

The Ehlers-Danlos syndrome (EDS), inherited disorder of connective tissue, frequently leads to impairment of various functional areas, including employment. In 35 subjects with classic type EDS, 14 hypermobile, 3 vascular was administered 7 visual analogical scales (pain, stiffness, activities of daily living, instrumental activities of daily living, work, social relations). An impairment of particular significance in total score and in individual areas emerges is in the hypermobile group, followed by classic, less for the vasculature. Overall there is a significant alteration of the quality of life that deserves proper evaluation to facilitate the definition of fitness and the improvement of job insertion in patients with EDS.

Obesity is frequently associated with functional changes that may affect work capacity, so we administered to a group of 198 overweight-obese subjects with median BMI of 32.7 and median waist circumference of 101 cm, the test-TSD OC which consists of 7 sections (pain, stiffness, activities of daily life, activities of the house, instrumental activities of daily living, work, social relations) for a total of 36 visual analogical scales. After the identification of 4 workers categories (health, services, administration, commerce/industry), resulted homogeneous for age, BMI, CV, we saw that the work section was more compromised for health and services. The overall disability increases especially in relation to BMI and seems influenced by age and sex.

Numerous evidence suggests that vitamin D deficiency is implicated in the development of cardiovascular risk. It has been investigated the relationship between cardiovascular risk factors and vitamin D concentrations in 264 consecutive workers from Centro Obesità e Lavoro della Clinica del Lavoro di Milano. For these studies, glicometaboliche analysis, anthropometric measurements and impedance evalutation were performed and questionnaires to estimate nutrient levels in the diet were administered. The levels of vitamin D are found to be deficient in 166 patients (less than 20 ng/mL), insufficient in 63 patients (less than 30 ng/mL) and optimal for the remaining 35 patients. A significant negative association was observed between the concentrations of vitamin D and cardiovascular risk factors (HOMA ratio and TG/HDL) ratios and BMI. Vitamin D is a cardiovascular risk factor "corrected" for example by changing the eating habits of workers.