Recombinant human chorionic gonadotropin and gonadotropin-releasing hormone agonist differently affect the profile of extracellular vesicle microRNAs in human follicular fluid.

PURPOSE: To compare the expression profile of extracellular vesicle microRNAs (EV-miRNAs) derived from follicular fluid after a trigger with recombinant human chorionic gonadotropin (r-hCG) or with a gonadotropin-releasing hormone GnRH agonist (GnRH-a) for final oocyte maturation. METHODS: A retrospective analysis of a prospective cohort. Women undergoing in vitro fertilization at a tertiary university-affiliated hospital were recruited between 2014 and 2016. EV-miRNAs were extracted from the follicular fluid of a single follicle, and their expression was assessed using TaqMan Open Array®. Genes regulated by EV-miRNAs were analyzed using miRWalk2.0 Targetscan database, DAVID Bioinformatics Resources, Kyoto-Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO). RESULTS: Eighty-two women were included in the r-hCG trigger group and 9 in the GnRH-a group. Of 754 EV-miRNAs screened, 135 were detected in at least 50% of the samples and expressed in both groups and were further analyzed. After adjusting for multiple testing, 41 EV-miRNAs whose expression levels significantly differed between the two trigger groups were identified. Bioinformatics analysis of the genes regulated by these EV-miRNAs showed distinct pathways between the two triggers, including TGF-beta signaling, cell cycle, and Wnt signaling pathways. Most of these pathways regulate cascades associated with apoptosis, embryo development, implantation, decidualization, and placental development. CONCLUSIONS: Trigger with GnRH-a or r-hCG leads to distinct EV-miRNAs expression profiles and to downstream biological effects in ovarian follicles. These findings may provide an insight for the increased apoptosis and the lower implantation rates following GnRH-a trigger vs. r-hCG in cases lacking intensive luteal phase support.

ß-2 adrenergic receptor gene methylation is associated with decreased asthma severity in inner-city schoolchildren: asthma and rhinitis.

BACKGROUND: Genetic variation in the ß-2 adrenergic receptor gene (ADRB2) has been implicated in asthma severity and control with conflicting results. Epigenetic variation in the ADRB2 may play an important role in asthma phenotype. OBJECTIVE: We aimed to evaluate whether DNA methylation of ADRB2 is associated with asthma phenotypes in inner-city school-aged children. METHODS: Multiple CpG sites in the promoter region of ADRB2 gene were analysed in 177 children enrolled in the School Inner-City Asthma Study. Blood- or saliva-derived DNA was measured by bisulphite-polymerase chain reaction pyrosequencing assay. Average percentage DNA methylation across the sites was evaluated for association with asthma severity (report of dyspnoea, night-time symptoms, rescue medication use, and baseline spirometry) and morbidity (school absences and unscheduled healthcare visits). Three clades composed of highly correlated methylation sites within the methylated segment of ADRB2 were further analysed. RESULTS: Methylation of individual sites generally ranged from 0% to 6% with average percentage methylation across sites of 2.4%. Univariate analyses strongly favoured the association of higher percentage methylation with lower asthma severity measured by report of dyspnoea. Furthermore, there was a non-significant trend towards less rescue medication use, night-time symptoms, school absences, activity limitation due to asthma, and improved lung function measurements with increased methylation. Multivariate analysis demonstrated methylation of ADRB2 gene significantly associated with less dyspnoea (odds ratio (OR) 0.2, 95% confidence interval (CI), 0.1-0.6, P = 0.002). Each of the three clades of methylation sites showed a strong, but not statistically significant, effect on decreased dyspnoea. CONCLUSIONS AND CLINICAL RELEVANCE: DNA methylation in the ADRB2 gene is associated with decreased asthma symptom severity, suggesting a role for methylation in asthma phenotypes.

Extracellular histones mediate the effects of metal-rich air particles on blood coagulation.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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 diameters <1 µm (PM1) or <10 µm (PM10) and PM10 metal components were estimated for each participant. RESULTS: The coagulation marker ETP, measured in the presence of soluble thrombomodulin (ETP TM+), showed significant positive associations with PM1 (ß=107.84, p=0.03), PM10 (ß=83.06, p=0.02), and zinc (ß=75.14, p=0.03); and a marginal association with iron (ß=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 (ß=0.20, p=0.02; ß=0.16, p=0.05, respectively). H3K4me3, but not H3K9ac, was associated with zinc (ß=0.13, p=0.03) and iron (ß=0.32, p=0.01) contained in PM. ETP TM+ was increased in association with higher plasma H3K4me3 (ß=0.50, p=0.05) and H3K9ac (ß=0.54, p=0.05). CONCLUSIONS: This observational study suggests potential roles of extracellular histones in PM-induced hypercoagulability. Experimental studies are warranted to further characterize these findings.

Early-life risk factors, accelerated biological aging and the late-life risk of mortality and morbidity.

BACKGROUND: Early-life exposure increases health risks throughout an individual's lifetime. Biological aging is influenced by early-life risks as a key process of disease development, but whether early-life risks could accelerate biological aging and elevate late-life mortality and morbidity risks remains unknown. Knowledge is also limited on the potential moderating role of healthy lifestyle. METHODS: We investigate associations of three early-life risks around birth, breastfeeding, maternal smoking and birth weight, with biological aging of 202 580 UK Biobank participants (54.9 ± 8.1 years old). Biological aging was quantified as KDM-BA, PhenoAge and frailty. Moderate alcohol intake, no current smoking, healthy diet, BMI <30 kg/m2 and regular physical activity were considered as healthy lifestyles. Mortality and morbidity data were retrieved from health records. RESULTS: Individual early-life risk factors were robustly associated with accelerated biological aging. A one-unit increase in the 'early-life risk score' integrating the three factors was associated with 0.060 (SE=0.0019) and 0.036-unit (SE = 0.0027) increase in z-scored KDM-BA acceleration and PhenoAge acceleration, respectively, and with 22.3% higher odds (95% CI: 1.185-1.262) of frailty. Increased chronological age and healthy lifestyles could mitigate the accelerations of KDM-BA and PhenoAge, respectively. Associations of early-life risk score with late-life mortality and morbidity were mediated by biological aging (proportions: 5.66-43.12%). KDM-BA and PhenoAge accelerations could significantly mediate the impact on most outcomes except anxiety, and frailty could not mediate the impact on T2D. CONCLUSION: Biological aging could capture and mediate the late-life health risks stemming from the early-life risks, and could be potentially targeted for healthy longevity promotion.

Blood leukocyte Alu and LINE-1 methylation and gastric cancer risk in the Shanghai Women's Health Study.

BACKGROUND: Recent data suggest a link between blood leukocyte DNA methylation, and cancer risk. However, reports on DNA methylation from a prospective study are unavailable for gastric cancer. METHODS: We explored the association between methylation in pre-diagnostic blood leukocyte DNA and gastric cancer risk in a case-control study nested in the prospective Shanghai Women's Health Study cohort. Incident gastric cancer cases (n=192) and matched controls (n=384) were included in the study. Methylation of Alu and long interspersed nucleotide elements (LINE)-1 were evaluated using bisulphite pyrosequencing. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated from logistic regression adjusting for potential confounders. RESULTS: Alu methylation was inversely associated with gastric cancer risk, mainly among cases diagnosed one or more years after blood collection. After excluding cases diagnosed during the first year of follow-up, the ORs for the third, second, and first quartiles of Alu methylation compared with the highest quartile were 2.43 (1.43-4.13), 1.47(0.85-2.57), and 2.22 (1.28-3.84), respectively. This association appeared to be modified by dietary intake, particularly isoflavone. In contrast, LINE-1 methylation levels were not associated with gastric cancer risk. CONCLUSION: Evidence from this prospective study is consistent with the hypothesis that DNA hypomethylation in blood leukocytes may be related to cancer risk, including risk of gastric cancer.

[Epigenetic effects as mediators of procoagulant action of thin dust with high metal content. Study on occupational epidemiology]. / Effetti epigenetici come mediatori dell'azione pro-coagulante delle polveri sottili ad alto contenuto metallico. Uno studio di epidemiologia occupazionale.

Blood hypo-methylation mediates the effects of metal-rich airborne particles on blood coagulation: An occupational epidemiological study. Particulate matter (PM) exposure is associated with increased coagulation and thrombosis, but the biological mechanism has not yet been clarified. DNA methylation represents a potential mechanism because it can be modified by environmental factors. Foundry workers are exposed to PM components and showed increased cardiovascular risk. In a group of 63 steel workers we found that PM and zinc airborne levels were negatively associated with leukocyte DNA methylation in genes NOS3 and ET-1 (b = -1.1; p = 0.002 and b = -1.5; p = 0.003, for zinc exposure respectively in multivariate regression models; b = -0.9 with p = 0.01 for PM10 exposure and NOS3) and in turn, DNA hypo-methylation resulted associated with increased Endogenous Thrombin Potential (for NOS3 b = -45.0, p = 0.001; and for ET-1 b = -16.4, p = 0.03). Our study based on healthy subject exposed in occupational setting, suggests that gene specific hypomethylation contributes to environmentally-induced hypercoagulability.

Global DNA methylation and low-level exposure to benzene.

INTRODUCTION: Global genomic hypomethylation is a common event in cancer tissues that is frequently observed in hematopoietic malignancies, including leukemia. Benzene, an established leukemogen at high doses, has been suggested to induce hypomethylation based on investigations of DNA methylation in LINE-1 and Alu repetitive elements. Whether global genomic DNA methylation content is reduced in response to benzene exposure is still undetermined. METHODS: We measured global DNA methylation in 78 gasoline station attendants and 58 controls in peripheral blood cells using high-resolution gas chromatography-mass spectrometry. PCR-Pyrosequencing measures of DNA methylation at Alu and LINE-1 repetitive elements, representing a large proportion of methylation in non-coding regions, were also available. Exposure markers included personal airborne benzene, and urinary benzene, t,t-muconic acid (t,t-MA) and S-phelylmercapturic acid. RESULTS: Mean global DNA methylation was 5.474 (+/- 0.083) %5mC in controls and 5.409 (+/- 0.142) %5mC in exposed participants (p = 0.01). All methylation markers were negatively correlated with airborne benzene. Alu and LINE-1 methylation, but not global DNA methylation, were negatively associated with t,t-MA; no association with the other urinary biomarkers was found. Multiple linear regression analysis adjusted for gender and age confirmed the results of correlation analysis and showed a 1.6% decrease in global DNA methylation associated with being gasoline station attendants. Alu and LINE-1 methylation levels were not associated with global DNA methylation. CONCLUSION: Our results show that benzene exposure is associated with alterations in both global DNA and repetitive element methylation. Global and repetitive element methylation levels are not correlated in blood DNA, likely representing independent responses to benzene exposure.

Risk of renal cell carcinoma in relation to blood telomere length in a population-based case-control study.

BACKGROUND: There are few known risk factors for renal cell carcinoma (RCC). Two small hospital-based case-control studies suggested an association between short blood telomere length (TL) and increased RCC risk. METHODS: We conducted a large population-based case-control study in two metropolitan regions of the United States comparing relative TL in DNA derived from peripheral blood samples from 891 RCC cases and 894 controls. Odds ratios and 95% confidence intervals were estimated using unconditional logistic regression in both unadjusted and adjusted models. RESULTS: Median TL was 0.85 for both cases and controls (P=0.40), and no differences in RCC risk by quartiles of TL were observed. Results of analyses stratified by age, sex, race, tumour stage, and time from RCC diagnosis to blood collection were similarly null. In multivariate analyses among controls, increasing age and history of hypertension were associated with shorter TL (P<0.001 and P=0.07, respectively), and African Americans had longer TL than Caucasians (P<0.001). CONCLUSION: These data do not support the hypothesis that blood TL is associated with RCC. This population-based case-control study is, to our knowledge, the largest investigation to date of TL and RCC.

DNA methylation in repetitive elements and Alzheimer disease.

Epigenetics is believed to play a role in Alzheimer's disease (AD). DNA methylation, the most investigated epigenetic hallmark, is a reversible mechanism that modifies genome function and chromosomal stability through the addition of methyl groups to cytosine located in CpG dinucleotides to form 5 methylcytosine (5mC). Methylation status of repetitive elements (i.e. Alu, LINE-1 and SAT-α) is a major contributor of global DNA methylation patterns and has been investigated in relation to a variety of human diseases. However, the role of methylation of repetitive elements in blood of AD patients has never been investigated so far. In the present study, a quantitative bisulfite-PCR pyrosequencing method was used to evaluate methylation of Alu, LINE-1 and SAT-α sequences in 43 AD patients and 38 healthy donors. In multivariate analysis adjusting for age and gender, LINE-1 was increased in AD patients compared with healthy volunteers (ADs: 83.6%5mC, volunteers: 83.1%5mC, p-value: 0.05). The group with best performances in mini mental state examination (MMSE) showed higher levels of LINE-1 methylation compared to the group with worst performances (MMSE>22: 83.9%5mC; MMSE≤22: 83.2%5mC; p=0.05). Our data suggest that LINE-1 methylation may lead to a better understanding of AD pathogenesis and course, and may contribute to identify novel markers useful to assess risk stratification. Further prospective investigations are warranted to evaluate the dynamics of DNA methylation from early-stage AD to advanced phases of the disease.

Environmental epigenetics.

Epigenetics investigates heritable changes in gene expression that occur without changes in DNA sequence. Several epigenetic mechanisms, including DNA methylation and histone modifications, can change genome function under exogenous influence. We review current evidence indicating that epigenetic alterations mediate effects caused by exposure to environmental toxicants. Results obtained from animal models indicate that in utero or early-life environmental exposures produce effects that can be inherited transgenerationally and are accompanied by epigenetic alterations. The search for human equivalents of the epigenetic mechanisms identified in animal models is under way. Recent investigations have identified a number of environmental toxicants that cause altered methylation of human repetitive elements or genes. Some exposures can alter epigenetic states and the same and/or similar epigenetic alterations can be found in patients with the disease of concern. On the basis of current evidence, we propose possible models for the interplay between environmental exposures and the human epigenome. Several investigations have examined the relationship between exposure to environmental chemicals and epigenetics, and have identified toxicants that modify epigenetic states. Whether environmental exposures have transgenerational epigenetic effects in humans remains to be elucidated. In spite of the current limitations, available evidence supports the concept that epigenetics holds substantial potential for furthering our understanding of the molecular mechanisms of environmental toxicants, as well as for predicting health-related risks due to conditions of environmental exposure and individual susceptibility.

Collaboration between centres of the World Health Organization. Italy supports a Mexican university.

BACKGROUND: Mexico is the third most populous country in America. A sizeable percentage of Mexicans live under unfavorable conditions such as malnutrition, marginalization and overcrowding. Environmental injustice includes: indigenous exposed to wood smoke, families living in mining zones, children working and living in garbage dumps and brick factories. Polycyclic aromatic hydrocarbons, pesticides, electronic waste and heavy metals exposure represent a health risk. These pollutants can induce biochemical lesions as DNA damage and epigenetic changes which could modif the gene expression profile of each individual. OBJECTIVES: The aim of this work is to create an Italy-Mexico collaboration (within the context of WHO collaborating centres) between the Center of Molecular and Genetic Epidemiology, University of Milan and the University of San Luis Potosi, will allow molecular approaches to develop early indicators of susceptibility to adult disease and cancer.

Ozone exposure, antioxidant genes, and lung function in an elderly cohort: VA normative aging study.

BACKGROUND: Ozone (O3) exposure is known to cause oxidative stress. This study investigated the acute effects of O(3) on lung function in the elderly, a suspected risk group. It then investigated whether genetic polymorphisms of antioxidant genes (heme oxygenase-1 (HMOX1) and glutathione S-transferase pi (GSTP1)) modified these associations. METHODS: 1100 elderly men from the Normative Aging Study were examined whose lung function (forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1)) was measured every 3 years from 1995 to 2005. The study genotyped the GSTP1 Ile105Val and Ala114Val polymorphisms and the (GT)n repeat polymorphism in the HMOX1 promoter, classifying repeats as short (n<25) or long (n> or =25). Ambient O(3) was measured continuously at locations in the Greater Boston area. Mixed linear models were used, adjusting for known confounders. RESULTS: A 15 ppb increase in O(3) during the previous 48 h was associated with a 1.25% decrease in FEV(1) (95% CI: -1.96% to -0.54%). This estimated effect was worsened with either the presence of a long (GT)n repeat in HMOX1 (-1.38%, 95% CI: -2.11% to -0.65%) or the presence of an allele coding for Val105 in GSTP1 (-1.69%, 95% CI: -2.63% to -0.75%). A stronger estimated effect of O(3) on FEV(1) was found in subjects carrying both the GSTP1 105Val variant and the HMOX1 long (GT)n repeat (-1.94%, 95% CI: -2.89% to -0.98%). Similar associations were also found between FVC and O(3) exposure. CONCLUSIONS: Our results suggest that O(3) has an acute effect on lung function in the elderly, and the effects may be modified by the presence of specific polymorphisms in antioxidant genes.

Effects of exposure to air pollution on blood coagulation.

BACKGROUND: Consistent evidence has indicated that air pollution increases the risk of cardiovascular diseases. The underlying mechanisms linking air pollutants to increased cardiovascular risk are unclear. OBJECTIVES: We investigated the association between the pollution levels and changes in such global coagulation tests as the prothrombin time (PT) and the activated partial thromboplastin time (APTT) in 1218 normal subjects from the Lombardia Region, Italy. Plasma fibrinogen and naturally occurring anticoagulant proteins were also evaluated. METHODS: Hourly concentrations of particulate (PM10) and gaseous pollutants (CO, NO2, SO2, and O3) were obtained from 53 monitoring sites covering the study area. Generalized additive models were applied to compute standardized regression coefficients controlled for age, gender, body mass index, smoking, alcohol, hormone use, temperature, day of the year, and long-term trends. RESULTS: The PT became shorter with higher ambient air concentrations at the time of the study of PM10 (coefficient = -0.06; P < 0.05), CO (coefficient = -0.11; P < 0.001) and NO2 (coefficient =-0.06; P < 0.05). In the 30 days before blood sampling, the PT was also negatively associated with the average PM(10) (coefficient = -0.08; P < 0.05) and NO2 (coefficient = -0.08; P < 0.05). No association was found between the APTT and air pollutant levels. In addition, no consistent relations with air pollution were found for fibrinogen, antithrombin, protein C and protein S. CONCLUSIONS: This investigation shows that air pollution is associated with changes in the global coagulation function, suggesting a tendency towards hypercoagulability after short-term exposure to air pollution. Whether these changes contribute to trigger cardiovascular events remains to be established.

Hypertensive disorders of pregnancy in women with gestational diabetes mellitus on overweight status of their children.

Hypertensive disorders of pregnancy (HDP) as a group of medical complications in pregnancy are believed to be associated with an increased risk of poor fetal growth, but the influence on offspring's body composition is not clear. The aim of the present study was to evaluate the association between maternal HDP and overweight status in the offspring of mothers with gestational diabetes mellitus (GDM). A cross-sectional study among 1263 GDM mother-child pairs was performed in Tianjin, China. General linear models and logistic regression models were used to assess the associations of maternal hypertension in pregnancy with anthropometry and overweight status in the offspring from birth to 1-5 years old. Offspring of GDM mothers who were diagnosed with hypertensive disorders during pregnancy had higher mean values of Z-scores for birth weight for gestational age and birth weight for length, and higher mean values of Z-scores for weight for age, weight for length/height, and body mass index for age at 1-5 years old than those of GDM mothers with normal blood pressure during pregnancy. Maternal HDP were associated with increased risks of large for gestational age (OR 1.74, 95% CI 1.08-2.79) and macrosomia (OR 2.02, 95% CI 1.23-3.31) at birth and childhood overweight/obesity at 1-5 years old age (OR 1.88, 95% CI 1.16-3.04). For offspring of mothers with GDM, maternal hypertension during pregnancy was a risk factor for macrosomia at birth and childhood overweight and obesity, and controlling the maternal hypertension may be more important for preventing large-for-gestational-age babies and childhood obesity.

Association between hypertensive disorders of pregnancy and the risk of postpartum hypertension: a cohort study in women with gestational diabetes.

Previous studies in general people indicated that hypertensive disorders of pregnancy (HDP) increased the risk of subsequent hypertension after delivery. Some studies found that women with gestational diabetes mellitus (GDM) had an increased risk of HDP. However, very few studies have assessed the association between HDP and the risk of postpartum hypertension among GDM women. To evaluate the association between HDP and the risk of postpartum hypertension among GDM women, a retrospective cohort study was conducted in 1261 women with prior GDM at their postpartum 1-5 years using the baseline data from Tianjin Gestational Diabetes Mellitus Prevention Program. Cox regression models were applied to assess the single and joint associations of having a history of HDP, maternal pre-pregnancy Body mass index (BMI) (normal weight, overweight and obesity), and weight change from preconception to post-delivery with the risk of subsequent hypertension among the GDM women. We found that GDM women with a history of HDP, high pre-pregnancy BMI and weight gain >7 kg from preconception to post-delivery had an increased risk of postpartum hypertension. Joint effects analysis revealed that the positive association between a history of HDP in the index pregnancy and the risk of postpartum hypertension was consistent in GDM women with different levels of pre-pregnancy BMI or weight gain from preconception to post-delivery. In conclusion, a history of HDP, high pre-pregnancy BMI and weight gain >7 kg from preconception to post-delivery increase the risk of subsequent hypertension in postpartum 1-5 years among GDM women.

Associations of Maternal Urinary Cadmium with Trimester-Specific Blood Pressure in Pregnancy: Role of Dietary Intake of Micronutrients.

Previous studies revealed associations of urinary Cd (U-Cd), a chronic Cd exposure biomarker, with blood pressure (BP) in non-pregnant adults. However, the evidence regarding trimester-specific blood pressure in pregnancy and U-Cd and effect modification by dietary intake of micronutrients is scarce. We randomly selected 653 women from the Omega Study cohort. U-Cd was quantified by inductively coupled plasma mass spectrometry. Trimester-specific, systolic (SBP) and diastolic blood pressure (DBP) were determined employing standard protocols and mean arterial pressure (MAP) was also calculated. Associations of SBP, DBP, and MAP with U-Cd tertiles (≤0.21; 0.22-0.41; ≥0.42 µg/g Cr) were assessed using multivariable linear regression models. We also explored effect modification by pre-pregnancy BMI (≤25 or >25 kg/m2) or low/high micronutrients intake. After adjusting confounders in women with elevated (upper tertile) as compared with those with low (lowest tertile) U-Cd (≥0.42 vs. ≤0.21 µg/g Cr, respectively) had reduced third trimester MAP (-1.8; 95 % confidence interval (CI) = -3.1, -0.5 mmHg) and second trimester MAP (-1.1; 95 % CI = -2.3, -0.03 mmHg). A significant decrease in third-trimester MAP associated with increased U-Cd was observed only among normal/underweight women (BMI ≤ 25 kg/m2) and women with high dietary intake of micronutrients (calcium, magnesium, zinc, and selenium). Notably, U-Cd concentrations increased with the increased consumption of zinc and non-heme iron food sources. No significant differences in U-Cd concentrations were found in preeclamptic women compared with non-preeclamptic women. Our study provides evidence that dietary intake of micronutrients should be taken into account when assessing the health effects of Cd in pregnant women.

[DNA methylation analysis in environmental and occupational cancer research]. / Studio della metilazione del DNA nella valutazione della cancerogenicità di agenti ambientali e occupazionali.

The present paper reviews recent laboratory methods and experimental evidence concerning epigenetic biomarkers involved in carcinogenesis mechanisms. We introduce DNA methylation and its role in gene expression control. DNA methylation analysis may allow to identify early changes leading to cancer and other chronic diseases. We describe here strategies for laboratory analyses and their possible applications. We examine results from recent experimental studies suggesting that the effects of certain occupational agents are mediated by alterations in DNA methylation. Planning and conducting investigations on exposed human subjects will allow to verify whether DNA methylation changes identified in animal and in-vitro studies may be used as early-effect and susceptibility biomarkers. DNA methylation analysis has the potential for future applications in risk assessment and prevention programs conducted on subjects exposed to human carcinogens.

Occupation and lung cancer risk in Leningrad Province, Russia.

To investigate the association between occupation and lung cancer risk in Leningrad Province, Russia, we identified 540 pathologically diagnosed lung cancer cases (474 males and 66 females) and 582 controls (453 males and 129 females) from the 1993-1998 autopsy records of the 88 state hospitals of the Province. Lifetime occupational histories were obtained from personal records coded according to the standard Russian occupational classification system. Lung cancer risk was increased in workers in the manufacturing industry, particularly in the food industry and wholesale/retail trade and in the miscellaneous manufacturing industry. An increased risk was also found in subjects employed in chemical and metal production for 10 years or more. When we considered the association between specific occupations and lung cancer, waste incineration operators and loaders exhibited an excess risk that increased with employment duration. The present study, which is the first to evaluate the risk of lung cancer by occupation in Russia, suggests the presence in Leningrad Province of exposure in the workplace to lung carcinogens that require further characterization to develop targeted and effective preventive measures.

Effects of airborne fine particles (PM2.5 ) on deep vein thrombosis admissions in the northeastern United States.

BACKGROUND: Literature relating air pollution exposure to deep vein thrombosis (DVT) and pulmonary embolism (PE), despite biological plausibility, is sparse. No comprehensive study examining associations between both short- and long-term exposure to particulate matter (PM)2.5 and DVT or PE has been published. Using a novel PM2.5 prediction model, we study whether long- and short-term PM2.5 exposure is associated with DVT and PE admissions among elderly across the northeastern United States. METHODS: We estimated daily exposure of PM2.5 in each ZIP code. We investigated the long- and short-term effects of PM2.5 on DVT and PE hospital admissions. There were 453,413 DVT and 151,829 PE admissions in the study. For short-term exposure, we performed a case crossover analysis matching month and year and defined the hazard period as lag 01 (exposure of day of admission and previous day). For the long-term association, we used a Poisson regression. RESULTS: A 10-µg m(-3) increase in short-term exposure was associated with a 0.63% increase in DVT admissions (95% confidence interval [CI] = 0.03% to 1.25%) and a 6.98% (95% CI = 5.65% to 8.33%) increase in long-term exposure admissions. For PE, the associated risks were 0.38% (95% CI = -0.68% to 1.25%) and 2.67% (95% CI = 5.65% to 8.33%). These results persisted when analyses were restricted to location-periods meeting the current Environmental Protection Agency annual standard of 12 µg m(-3) . CONCLUSIONS: Our findings showed that PM2.5 exposure was associated with DVT and PE hospital admissions and that current standards are not protective of this result.