Long-term exposure to ambient air pollution can lead to chronic health effects such as cancer, cardiovascular and respiratory disease. Systemic inflammation has been hypothesized as a putative ...biological mechanism contributing to these adverse health effects. We evaluated the effect of long-term exposure to air pollution on blood markers of systemic inflammation.
We measured a panel of 28 inflammatory markers in peripheral blood samples from 587 individuals that were biobanked as part of a prospective study. Participants were from Varese and Turin (Italy) and Umea (Sweden). Long-term air pollution estimates of nitrogen oxides (NOx) were available from the European Study of Cohorts for Air Pollution Effects (ESCAPE). Linear mixed models adjusted for potential confounders were applied to assess the association between NOx and the markers of inflammation.
Long-term exposure to NOx was associated with decreased levels of interleukin (IL)-2, IL-8, IL-10 and tumor necrosis factor-α in Italy, but not in Sweden. NOx exposure levels were considerably lower in Sweden than in Italy (Sweden: median (5th, 95th percentiles) 6.65μg/m3 (4.8, 19.7); Italy: median (5th, 95th percentiles) 94.2μg/m3 (7.8, 124.5)). Combining data from Italy and Sweden we only observed a significant association between long-term exposure to NOx and decreased levels of circulating IL-8.
We observed some indication for perturbations in the inflammatory markers due to long-term exposure to NOx. Effects were stronger in Italy than in Sweden, potentially reflecting the difference in air pollution levels between the two cohorts.
•We assessed the association between long-term exposure to NOx and plasma concentration of a panel of inflammatory markers.•We included data from two prospective cohorts from Italy and Sweden (n=587 individuals).•Our panel of inflammatory markers includes 28 cytokines, chemokines, and growth factors.•We used a state of the art long-term air pollution exposure assessment developed within the ESCAPE project.•We observed indications for an association between NOx and interleukin 2, 8, 10, and tumor necrosis factor alpha.
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.
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.
Prenatal exposure to endocrine-disrupting chemicals such as persistent organic pollutants (POPs) may increase risk of obesity later in life.
We examined the relation of in utero POPs exposure to ...offspring obesity and cardiometabolic risk factors at 4 years of age in the Rhea mother-child cohort in Crete, Greece (n = 689).
We determined concentrations of polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethylene (DDE), and hexachlorobenzene (HCB) in first-trimester maternal serum. We measured child weight, height, waist circumference, skinfold thicknesses, blood pressure (BP), blood levels of lipids, C-reactive protein, and adipokines at 4 years of age. Childhood obesity was defined using age- and sex-specific cut points for body mass index (BMI) as recommended by the International Obesity Task Force.
On multivariable regression analyses, a 10-fold increase in HCB was associated with a higher BMI z-score (adjusted β = 0.49; 95% CI: 0.12, 0.86), obesity relative risk (RR) = 8.14; 95% CI: 1.85, 35.81, abdominal obesity (RR = 3.49; 95% CI: 1.08, 11.28), greater sum of skinfold thickness (β = 7.71 mm; 95% CI: 2.04, 13.39), and higher systolic BP (β = 4.34 mmHg; 95% CI: 0.63, 8.05) at 4 years of age. Prenatal DDE exposure was associated with higher BMI z-score (β = 0.27; 95% CI: 0.04, 0.5), abdominal obesity (RR = 3.76; 95% CI: 1.70, 8.30), and higher diastolic BP (β = 1.79 mmHg; 95% CI: 0.13, 3.46). PCBs were not significantly associated with offspring obesity or cardiometabolic risk factors.
Prenatal exposure to DDE and HCB was associated with excess adiposity and higher blood pressure levels in early childhood.
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.
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.
Obesity is an established risk factor for several common chronic diseases such as breast and colorectal cancer, metabolic and cardiovascular diseases; however, the biological basis for these ...relationships is not fully understood. To explore the association of obesity with these conditions, we investigated peripheral blood leucocyte (PBL) DNA methylation markers for adiposity and their contribution to risk of incident breast and colorectal cancer and myocardial infarction.
DNA methylation profiles (Illumina Infinium
HumanMethylation450 BeadChip) from 1941 individuals from four population-based European cohorts were analysed in relation to body mass index, waist circumference, waist-hip and waist-height ratio within a meta-analytical framework. In a subset of these individuals, data on genome-wide gene expression level, biomarkers of glucose and lipid metabolism were also available. Validation of methylation markers associated with all adiposity measures was performed in 358 individuals. Finally, we investigated the association of obesity-related methylation marks with breast, colorectal cancer and myocardial infarction within relevant subsets of the discovery population.
We identified 40 CpG loci with methylation levels associated with at least one adiposity measure. Of these, one CpG locus (cg06500161) in ABCG1 was associated with all four adiposity measures (P = 9.07×10
to 3.27×10
) and lower transcriptional activity of the full-length isoform of ABCG1 (P = 6.00×10
), higher triglyceride levels (P = 5.37×10
) and higher triglycerides-to-HDL cholesterol ratio (P = 1.03×10
). Of the 40 informative and obesity-related CpG loci, two (in IL2RB and FGF18) were significantly associated with colorectal cancer (inversely, P < 1.6×10
) and one intergenic locus on chromosome 1 was inversely associated with myocardial infarction (P < 1.25×10
), independently of obesity and established risk factors.
Our results suggest that epigenetic changes, in particular altered DNA methylation patterns, may be an intermediate biomarker at the intersection of obesity and obesity-related diseases, and could offer clues as to underlying biological mechanisms.
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.
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.
ABSTRACT
Exposure to environmental stressors, toxicants, and nutrient deficiencies can affect DNA in several ways. Some exposures cause damage and alter the structure of DNA, but there is increasing ...evidence that the same or other environmental exposures, including those that occur during fetal development in utero, can cause epigenetic effects that modulate DNA function and gene expression. Some epigenetic changes to DNA that affect gene transcription are at least partially reversible (i.e., they can be enzymatically reversed after cessation of exposure to environmental agents), but some epigenetic modifications seem to persist, even for decades. To explain the effects of early life experiences (such as famine and exposures to other stressors) on the long‐term persistence of specific patterns of epigenetic modifications, such as DNA methylation, we propose an analogy with immune memory. We propose that an epigenetic memory can be established and maintained in self‐renewing stem cell compartments. We suggest that the observations on early life effects on adult diseases and the persistence of methylation changes in smokers support our hypothesis, for which a mechanistic basis, however, needs to be further clarified. We outline a new model based on methylation changes. Although these changes seem to be mainly adaptive, they are also implicated in the pathogenesis and onset of diseases, depending on individual genotypic background and types of subsequent exposures. Elucidating the relationships between the adaptive and maladaptive consequences of the epigenetic modifications that result from complex environmental exposures is a major challenge for current and future research in epigenetics.—Vineis, P., Chatziioannou, A., Cunliffe, V. T., Flanagan, J. M., Hanson, M., Kirsch‐Volders, M., Kyrtopoulos, S. Epigenetic memory in response to environmental stressors. FASEB J. 31, 2241–2251 (2017). www.fasebj.org
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