Long-term exposure to air pollution has been associated with several adverse health effects including cardiovascular, respiratory diseases and cancers. However, underlying molecular alterations ...remain to be further investigated. The aim of this study is to investigate the effects of long-term exposure to air pollutants on (a) average DNA methylation at functional regions and, (b) individual differentially methylated CpG sites. An assumption is that omic measurements, including the methylome, are more sensitive to low doses than hard health outcomes.
This study included blood-derived DNA methylation (Illumina-HM450 methylation) for 454 Italian and 159 Dutch participants from the European Prospective Investigation into Cancer and Nutrition (EPIC). Long-term air pollution exposure levels, including NO2, NOx, PM2.5, PMcoarse, PM10, PM2.5 absorbance (soot) were estimated using models developed within the ESCAPE project, and back-extrapolated to the time of sampling when possible. We meta-analysed the associations between the air pollutants and global DNA methylation, methylation in functional regions and epigenome-wide methylation. CpG sites found differentially methylated with air pollution were further investigated for functional interpretation in an independent population (EnviroGenoMarkers project), where (N=613) participants had both methylation and gene expression data available.
Exposure to NO2 was associated with a significant global somatic hypomethylation (p-value=0.014). Hypomethylation of CpG island's shores and shelves and gene bodies was significantly associated with higher exposures to NO2 and NOx. Meta-analysing the epigenome-wide findings of the 2 cohorts did not show genome-wide significant associations at single CpG site level. However, several significant CpG were found if the analyses were separated by countries. By regressing gene expression levels against methylation levels of the exposure-related CpG sites, we identified several significant CpG-transcript pairs and highlighted 5 enriched pathways for NO2 and 9 for NOx mainly related to the immune system and its regulation.
Our findings support results on global hypomethylation associated with air pollution, and suggest that the shores and shelves of CpG islands and gene bodies are mostly affected by higher exposure to NO2 and NOx. Functional differences in the immune system were suggested by transcriptome analyses.
•We studied the effects of long-term exposure to air pollutants on DNA methylation.•A consistent global hypomethylation was observed for exposure to ambient NO2 and NOx.•This hypomethylation was observed for CpG island's shores, shelves and gene bodies.•No CpG sites were epigenome-wide significant in a combined analysis of a low and high exposed cohort.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs) and pesticides bioaccumulate through the food chain and cross the placenta. POPs are developmental toxicants in ...animals but the epidemiological evidence on pregnancy outcomes is inconsistent. Maternal gestational weight gain has been recently suggested as a key factor explaining the association between PCBs with lower birth weight.
We examined whether in utero exposure to current low levels of different POPs is associated with fetal growth and gestational age in a mother–child cohort in Crete, Greece (Rhea study), and evaluated specifically whether maternal gestational weight gain may affect this association.
We included 1117 mothers and their newborns from the Rhea study. Mothers were interviewed and blood samples collected during the first trimester of pregnancy. Information on birth outcomes was retrieved from medical records. Concentrations of several PCBs, other organochlorine compounds (dichlorodiphenyl dichloroethene DDE, dichlorodiphenyl trichloroethane DDT and hexachlorobenzene HCB) and one polybrominated diphenyl ether congener (tetra-bromodiphenyl ether BDE-47), were determined in maternal serum by triple quadrupole mass spectrometry. Multiple linear regression models were used to investigate the associations of birth weight, gestational age, and head circumference with each compound individually on the log10 scale, and with combined exposures through the development of an exposure score.
In multivariate models, birth weight was negatively associated with increasing levels of HCB (β=−161.1g; 95% CI: −296.6, −25.7) and PCBs (β=−174.1g; 95% CI: −332.4, −15.9); after further adjustment for gestational weight gain these estimates were slightly reduced (β=−154.3g; 95% CI: −300.8, −7.9 for HCB and β=−135.7g; 95% CI: −315.4, 43.9 for PCBs). Furthermore, in stratified analysis, the association between POPs and birth weight was only observed in women with inadequate or excessive gestational weight gain. Small, negative associations were observed with head circumference while no association was observed with gestational age.
The findings suggest that prenatal exposure to PCBs and HCB impairs fetal growth and adds to the growing literature that demonstrates an association between low-level environmental pollutant exposure and fetal growth. Furthermore our results suggest that the association of POPs, maternal gestational weight gain and birth weight is probably more complex than that previously hypothesized.
•Concentrations of several POPs were determined in 1st trimester maternal serum.•We examined whether in utero exposure to POPs is associated with birth outcomes.•Birth weight was lowered by PCBs and HCB.•Weight gain slightly influenced the association of POPs and birth weight.•Prenatal exposure to PCBs and HCB seems to impair fetal growth.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Several studies have recently identified strong epigenetic signals related to tobacco smoking. However, an aspect that did not receive much attention is the evolution of epigenetic changes with time ...since smoking cessation. We conducted a series of epigenome-wide association studies to capture the dynamics of smoking-induced epigenetic changes after smoking cessation, using genome-wide methylation profiles obtained from blood samples in 745 women from 2 European populations. Two distinct classes of CpG sites were identified: sites whose methylation reverts to levels typical of never smokers within decades after smoking cessation, and sites remaining differentially methylated, even more than 35 years after smoking cessation. Our results suggest that the dynamics of methylation changes following smoking cessation are driven by a differential and site-specific magnitude of the smoking-induced alterations (with persistent sites being most affected) irrespective of the intensity and duration of smoking. Analyses of the link between methylation and expression levels revealed that methylation predominantly and remotely down-regulates gene expression. Among genes whose expression was associated with our candidate CpG sites, LRRN3 appeared to be particularly interesting as it was one of the few genes whose methylation and expression were directly associated, and the only gene in which both methylation and gene expression were found associated with smoking. Our study highlights persistent epigenetic markers of smoking, which can potentially be detected decades after cessation. Such historical signatures are promising biomarkers to refine individual risk profiling of smoking-induced chronic disease such as lung cancer.
The factors underlying the increasing rates and the geographic variation of childhood cancers are largely unknown. Epidemiological studies provide limited evidence for a possible role in the etiology ...of certain types of childhood cancer of the exposure of pregnant women to environmental carcinogens (e.g., tobacco smoke and pesticides); however, such evidence is inadequate to allow definitive conclusions. Complementary evidence can be obtained from biomarker-based population studies. Such studies have demonstrated that, following exposure of pregnant mothers, most environmental carcinogens reach the fetus and, in many cases, induce therein genotoxic damage which in adults is known to be associated with increased cancer risk, implying that environmental carcinogens may contribute to the etiology of childhood cancer. During recent years, intermediate disease biomarkers, obtained via omic profiling, have provided additional insights into the impact of transplacental exposures on fetal tissues which, in some cases, are also compatible with a precarcinogenic role of certain in utero exposures. Here we review the epidemiological and biomarker evidence and discuss how further research, especially utilizing high-density profiling, may allow a better evaluation of the links between in utero environmental exposures and cancer in children.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Exposure to traffic-related air pollution (TRAP) has been associated with adverse health outcomes but underlying biological mechanisms remain poorly understood. Two randomized crossover trials were ...used here, the Oxford Street II (London) and the TAPAS II (Barcelona) studies, where volunteers were allocated to high or low air pollution exposures. The two locations represent different exposure scenarios, with Oxford Street characterized by diesel vehicles and Barcelona by normal mixed urban traffic. Levels of five and four pollutants were measured, respectively, using personal exposure monitoring devices. Serum samples were used for metabolomic profiling. The association between TRAP and levels of each metabolic feature was assessed. All pollutant levels were significantly higher at the high pollution sites. 29 and 77 metabolic features were associated with at least one pollutant in the Oxford Street II and TAPAS II studies, respectively, which related to 17 and 30 metabolic compounds. Little overlap was observed across pollutants for metabolic features, suggesting that different pollutants may affect levels of different metabolic features. After observing the annotated compounds, the main pathway suggested in Oxford Street II in association with NO2 was the acyl-carnitine pathway, previously found to be associated with cardio-respiratory disease. No overlap was found between the metabolic features identified in the two studies.
•Two randomized crossover trials were used to assess the relationship between TRAP and metabolic features with MS-based metabolomics (MWAS)•The locations represent different exposure scenarios, with London characterized by diesel vehicles and Barcelona by normal mixed urban traffic•Levels of 17 and 30 metabolic compounds associated with different air pollutants in the studies, with little overlap in features across pollutants•No overlap found between metabolomic features identified in the two studies, possibly due to different levels of single pollutants•The acyl-carnitine pathway, involved in cardio-respiratory disease, was suggested as a potential pathway in association with NO2 in one study
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Persistent organic pollutants (POPs) are synthetic chemical substances that accumulate in our environment. POPs such as polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB) and ...dichlorodiphenyltrichloroethane (DDT) have been classified as carcinogenic to humans and animals. Due to their resistance to biodegradation humans are still exposed to these compounds worldwide. We aim to evaluate the miRNA and transcriptomic response of a human population exposed to POPs. The miRNA and transcriptomic response was measured in blood of healthy subjects by microarray technology and associated with the serum concentrations of six PCB congeners, DDE (a common DDT metabolite), and HCB. A total of 93 miRNA levels appeared significantly associated with the POP-exposure (FDR < 0.05). The miRNA profile includes four tumor suppressor miRNAs, namely miR-193a-3p, miR-152, miR-31-5p and miR-34a-5p. Integration of the miRNA profile with the transcriptome profile suggests an interaction with oncogenes such as MYC, CCND1, BCL2 and VEGFA. We have shown that exposure to POPs is associated with human miRNA and transcriptomic responses. The identified miRNAs and target genes are related to various types of cancer and involved in relevant signaling pathways like wnt and p53. Therefore, these miRNAs may have great potential to contribute to biomarker-based environmental health risk assessment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Persistent organic pollutants (POPs) are a group of diverse substances, including polychlorinated biphenyls (PCBs) and organochlorine pesticides that are resistant to biodegradation and ubiquitously ...present in our environment. Exposure to endocrine disrupting chemicals such as POPs has been linked to type 2 diabetes and metabolic disturbances in epidemiological and animal studies, but little is known about POPs exposure during pregnancy and the development of gestational diabetes mellitus (GDM). The purpose of this study was to determine the extent to which exposure to current low levels of different POPs in the first trimester of pregnancy is associated with GDM risk in 939 women from the “Rhea” pregnancy cohort in Crete, Greece.
Concentrations of several PCBs, dichlorodiphenyldichloroethene (DDE), and hexachlorobenzene (HCB) were determined in first trimester maternal serum by triple quadrupole mass spectrometry. We defined total PCBs as the sum of all congeners, nondioxin-like PCBs as the sum of PCB 153, 138, 170 and 180, and dioxin-like PCBs as the sum of PCB 118 and 156. Pregnant women were screened for gestational diabetes mellitus (GDM) between 24 and 28weeks of gestation, and GDM was defined by the criteria proposed by Carpenter and Coustan. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression models.
Of the 939 women, 68 (7%) developed GDM. Serum concentrations of POPs were higher in women with GDM. Women in the medium and high tertiles of PCBs had 3.90 (95% CI: 1.37, 11.06) and 3.60 (95% CI: 1.14, 11.39) fold respectively higher odds of developing GDM compared to women in the lowest tertile of PCB exposure after adjusting for pre-pregnancy BMI and several other confounders. Odds of GDM for women in the medium and high tertiles of dioxin-like PCBs was 5.63 (95% CI: 1.81, 17.51) and 4.71 (95% CI: 1.38, 16.01) and for nondioxin-like PCBs 2.36 (95% CI: 0.89, 6.23) and 2.26 (95% CI: 0.77, 6.68) respectively. Prenatal DDE and HCB exposure were not significantly associated GDM risk.
These findings suggest that women with high PCBs levels in early pregnancy had higher risk for GDM. Further studies are needed to replicate these results and to evaluate potential biological mechanisms underlying the observed associations.
•Exposure to environmental pollutants has been linked to type 2 diabetes.•Environmental chemicals may be associated with glucose disorders during pregnancy.•We explored effects of exposure to POPs on the development of gestational diabetes.•Exposure to PCBs during pregnancy was associated with increased risk for GDM.•DDE and HCB exposure was not significantly associated GDM risk.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Low socioeconomic status (SES) is associated with earlier onset of age-related chronic conditions and reduced life-expectancy, but the underlying biomolecular mechanisms remain unclear. Evidence of ...DNA-methylation differences by SES suggests a possible association of SES with epigenetic age acceleration (AA). We investigated the association of SES with AA in more than 5,000 individuals belonging to three independent prospective cohorts from Italy, Australia, and Ireland. Low SES was associated with greater AA (β = 0.99 years; 95% CI 0.39,1.59; p = 0.002; comparing extreme categories). The results were consistent across different SES indicators. The associations were only partially modulated by the unhealthy lifestyle habits of individuals with lower SES. Individuals who experienced life-course SES improvement had intermediate AA compared to extreme SES categories, suggesting reversibility of the effect and supporting the relative importance of the early childhood social environment. Socioeconomic adversity is associated with accelerated epigenetic aging, implicating biomolecular mechanisms that may link SES to age-related diseases and longevity.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cadmium bioaccumulates in the body and causes several adverse health effects. Understanding the primary sources of exposure is critical in order to implement effective prevention measures.
We ...included 454 adults enrolled in the Florence cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) during 1992–98. At enrolment, information was collected on demographics, lifestyle and dietary habits using validated questionnaires; anthropometric measures were taken; and a blood sample was collected from each study participant. Information on the residential and occupational history prior to enrolment was reconstructed by phone interviews. Cadmium levels were measured in erythrocytes using inductively coupled plasma-mass spectrometry. We used multiple linear regression models to investigate the main determinants of cadmium levels.
Median erythrocyte cadmium levels were 0.66 μg/L (inter-quartile range 0.43–1.07 μg/L). Cadmium levels were lowest in never smokers (0.50 μg/L) and highest in current smokers (1.38 μg/L). Smoking status and the number of pack-years were the strongest predictors of cadmium levels in multivariable analysis, together with erythrocyte levels of lead, and biking to work, while an inverse association emerged with consumption of red meat and dairy products and physical activity levels. Cadmium levels were higher among women than men (0.66 vs. 0.58 μg/L), and, among the former, positively associated with late menopause, nulliparity, and use of hormones for menopause. The predictors included in the multivariable model explained >40% of the variability in erythrocyte cadmium levels.
Smoking was the most important determinant of erythrocyte cadmium levels, which were also affected by dietary habits, physical activity levels, biking, and (among women) hormone-related variables. Our results are important to inform public health actions aimed at reducing the impact of potentially modifiable sources of exposure to cadmium.
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•We studied the predictors of erythrocyte Cd levels among 454 Italian adults.•Smoking and the number of pack-years were the strongest predictor of Cd levels.•Lifestyle (e.g. diet and physical activity) also played a significant role.•Cd levels were higher among women and correlated with exposure to sex hormones.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Despite the advances in the treatment of OC with combinatorial regimens, including surgery and platinum-based chemotherapy, ...patients generally exhibit poor prognosis due to high chemotherapy resistance. Herein, we tested the hypothesis that DNA damage response (DDR) pathways are involved in resistance of OC patients to platinum chemotherapy. Selected DDR signals were evaluated in two human ovarian carcinoma cell lines, one sensitive (A2780) and one resistant (A2780/C30) to platinum treatment as well as in peripheral blood mononuclear cells (PBMCs) from OC patients, sensitive (n = 7) or resistant (n = 4) to subsequent chemotherapy. PBMCs from healthy volunteers (n = 9) were studied in parallel. DNA damage was evaluated by immunofluorescence γH2AX staining and comet assay. Higher levels of intrinsic DNA damage were found in A2780 than in A2780/C30 cells. Moreover, the intrinsic DNA damage levels were significantly higher in OC patients relative to healthy volunteers, as well as in platinum-sensitive patients relative to platinum-resistant ones (all P<0.05). Following carboplatin treatment, A2780 cells showed lower DNA repair efficiency than A2780/C30 cells. Also, following carboplatin treatment of PBMCs ex vivo, the DNA repair efficiency was significantly higher in healthy volunteers than in platinum-resistant patients and lowest in platinum-sensitive ones (t1/2 for loss of γH2AX foci: 2.7±0.5h, 8.8±1.9h and 15.4±3.2h, respectively; using comet assay, t1/2 of platinum-induced damage repair: 4.8±1.4h, 12.9±1.9h and 21.4±2.6h, respectively; all P<0.03). Additionally, the carboplatin-induced apoptosis rate was higher in A2780 than in A2780/C30 cells. In PBMCs, apoptosis rates were inversely correlated with DNA repair efficiencies of these cells, being significantly higher in platinum-sensitive than in platinum-resistant patients and lowest in healthy volunteers (all P<0.05). We conclude that perturbations of DNA repair pathways as measured in PBMCs from OC patients correlate with the drug sensitivity of these cells and reflect the individualized response to platinum-based chemotherapy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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