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1.
Diabetes Care ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601636

RESUMO

OBJECTIVE: Maternal gestational diabetes mellitus (GDM) has been associated with adverse outcomes in the offspring. Growing evidence suggests that the epigenome may play a role, but most previous studies have been small and adjusted for few covariates. The current study meta-analyzed the association between maternal GDM and cord blood DNA methylation in the Pregnancy and Childhood Epigenetics (PACE) consortium. RESEARCH DESIGN AND METHODS: Seven pregnancy cohorts (3,677 mother-newborn pairs [317 with GDM]) contributed results from epigenome-wide association studies, using DNA methylation data acquired by the Infinium HumanMethylation450 BeadChip array. Associations between GDM and DNA methylation were examined using robust linear regression, with adjustment for potential confounders. Fixed-effects meta-analyses were performed using METAL. Differentially methylated regions (DMRs) were identified by taking the intersection of results obtained using two regional approaches: comb-p and DMRcate. RESULTS: Two DMRs were identified by both comb-p and DMRcate. Both regions were hypomethylated in newborns exposed to GDM in utero compared with control subjects. One DMR (chr 1: 248100345-248100614) was located in the OR2L13 promoter, and the other (chr 10: 135341870-135342620) was located in the gene body of CYP2E1. Individual CpG analyses did not reveal any differentially methylated loci based on a false discovery rate-adjusted P value threshold of 0.05. CONCLUSIONS: Maternal GDM was associated with lower cord blood methylation levels within two regions, including the promoter of OR2L13, a gene associated with autism spectrum disorder, and the gene body of CYP2E1, which is upregulated in type 1 and type 2 diabetes. Future studies are needed to understand whether these associations are causal and possible health consequences.

2.
Nat Commun ; 10(1): 3866, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31530803

RESUMO

Particle transfer across the placenta has been suggested but to date, no direct evidence in real-life, human context exists. Here we report the presence of black carbon (BC) particles as part of combustion-derived particulate matter in human placentae using white-light generation under femtosecond pulsed illumination. BC is identified in all screened placentae, with an average (SD) particle count of 0.95 × 104 (0.66 × 104) and 2.09 × 104 (0.9 × 104) particles per mm3 for low and high exposed mothers, respectively. Furthermore, the placental BC load is positively associated with mothers' residential BC exposure during pregnancy (0.63-2.42 µg per m3). Our finding that BC particles accumulate on the fetal side of the placenta suggests that ambient particulates could be transported towards the fetus and represents a potential mechanism explaining the detrimental health effects of pollution from early life onwards.

3.
Environ Res ; 176: 108550, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31260916

RESUMO

INTRODUCTION: Limited evidence suggests that epigenetic mechanisms may partially mediate the adverse effects of air pollution on health. Our aims were to identify new genomic loci showing differential DNA methylation associated with long-term exposure to air pollution and to replicate loci previously identified in other studies. METHODS: A two-stage epigenome-wide association study was designed: 630 individuals from the REGICOR study were included in the discovery and 454 participants of the EPIC-Italy study in the validation stage. DNA methylation was assessed using the Infinium HumanMethylation450 BeadChip. NOX, NO2, PM10, PM2.5, PMcoarse, traffic intensity and traffic load exposure were measured according to the ESCAPE protocol. A systematic review was undertaken to identify those cytosine-phosphate-guanine (CpGs) associated with air pollution in previous studies and we screened for them in the discovery study. RESULTS: In the discovery stage of the epigenome-wide association study, 81 unique CpGs were associated with air pollution (p-value <10-5) but none of them were validated in the replication sample. Furthermore, we identified 15 CpGs in the systematic review showing differential methylation with a p-value fulfilling the Bonferroni criteria and 1673 CpGs fulfilling the false discovery rate criteria, all of which were related to PM2.5 or NO2. None of them was replicated in the discovery study, in which the top hits were located in an intergenic region on chromosome 1 (cg10893043, p-value = 6.79·10-5) and in the LRRC45 and PXK genes (cg05088605, p-value = 2.15·10-04; cg16560256, p-value = 2.23·10-04). CONCLUSIONS: Neither new genomic loci associated with long-term air pollution were identified, nor previously identified loci were replicated. Continued efforts to test this potential association are warranted.

4.
Environ Health Perspect ; 127(5): 57012, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31148503

RESUMO

BACKGROUND: Prenatal exposure to air pollution has been associated with childhood respiratory disease and other adverse outcomes. Epigenetics is a suggested link between exposures and health outcomes. OBJECTIVES: We aimed to investigate associations between prenatal exposure to particulate matter (PM) with diameter [Formula: see text] ([Formula: see text]) or [Formula: see text] ([Formula: see text]) and DNA methylation in newborns and children. METHODS: We meta-analyzed associations between exposure to [Formula: see text] ([Formula: see text]) and [Formula: see text] ([Formula: see text]) at maternal home addresses during pregnancy and newborn DNA methylation assessed by Illumina Infinium HumanMethylation450K BeadChip in nine European and American studies, with replication in 688 independent newborns and look-up analyses in 2,118 older children. We used two approaches, one focusing on single cytosine-phosphate-guanine (CpG) sites and another on differentially methylated regions (DMRs). We also related PM exposures to blood mRNA expression. RESULTS: Six CpGs were significantly associated [false discovery rate (FDR) [Formula: see text]] with prenatal [Formula: see text] and 14 with [Formula: see text] exposure. Two of the [Formula: see text] CpGs mapped to FAM13A (cg00905156) and NOTCH4 (cg06849931) previously associated with lung function and asthma. Although these associations did not replicate in the smaller newborn sample, both CpGs were significant ([Formula: see text]) in 7- to 9-y-olds. For cg06849931, however, the direction of the association was inconsistent. Concurrent [Formula: see text] exposure was associated with a significantly higher NOTCH4 expression at age 16 y. We also identified several DMRs associated with either prenatal [Formula: see text] and or [Formula: see text] exposure, of which two [Formula: see text] DMRs, including H19 and MARCH11, replicated in newborns. CONCLUSIONS: Several differentially methylated CpGs and DMRs associated with prenatal PM exposure were identified in newborns, with annotation to genes previously implicated in lung-related outcomes. https://doi.org/10.1289/EHP4522.

5.
Environ Sci Technol ; 53(10): 5966-5976, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31041867

RESUMO

Mitochondrial DNA (mtDNA) content and telomere length are putative aging biomarkers and are sensitive to environmental stressors, including pollutants. Our objective was to identify, from a set of environmental exposures, which exposure is associated with leukocyte mtDNA content and telomere length in adults. This study includes 175 adults from 50 to 65 years old from the cross-sectional Flemish Environment and Health study, of whom leukocyte telomere length and mtDNA content were determined using qPCR. The levels of exposure of seven metals, 11 organohalogens, and four perfluorinated compounds (PFHxS, PFNA, PFOA, PFOS) were measured. We performed sparse partial least-squares regression analyses followed by ordinary least-squares regression to assess the multipollutant associations. While accounting for possible confounders and coexposures, we identified that urinary cadmium (6.52%, 95% confidence interval, 1.06, 12.28), serum hexachlorobenzene (2.89%, 018, 5.68), and perfluorooctanesulfonic acid (11.38%, 5.97, 17.08) exposure were positively associated ( p < 0.05) with mtDNA content, while urinary copper (-9.88%, -14.82, -4.66) and serum perfluorohexanesulfonic acid (-4.75%, -8.79, -0.54) exposure were inversely associated with mtDNA content. Urinary antimony (2.69%, 0.45, 4.99) and mercury (1.91%, 0.42, 3.43) exposure were positively associated with leukocyte telomere length, while urinary copper (-3.52%, -6.60, -0.34) and serum perfluorooctanesulfonic acid (-3.64%, -6.60, -0.60) showed an inverse association. Our findings support the hypothesis that environmental pollutants interact with molecular hallmarks of aging.


Assuntos
Poluentes Ambientais , Fluorcarbonetos , Adulto , Idoso , Biomarcadores , Estudos Transversais , DNA Mitocondrial , Exposição Ambiental , Humanos , Pessoa de Meia-Idade
6.
Nat Commun ; 10(1): 1893, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015461

RESUMO

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.


Assuntos
Peso ao Nascer/genética , DNA/metabolismo , Epigênese Genética , Genoma Humano , Adolescente , Adulto , Índice de Massa Corporal , Criança , Ilhas de CpG , DNA/genética , Metilação de DNA , Feminino , Desenvolvimento Fetal/genética , Feto , Ácido Fólico/sangue , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fumar/efeitos adversos , Fumar/sangue , Fumar/genética
7.
Int J Epidemiol ; 48(1): 30-44, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30590607

RESUMO

BACKGROUND: Socioeconomic experiences are recognized determinants of health, and recent work has shown that social disadvantages in early life may induce sustained biological changes at molecular level that are detectable later in life. However, the dynamics and persistence of biological embedding of socioeconomic position (SEP) remains vastly unexplored. METHODS: Using the data from the ALSPAC birth cohort, we performed epigenome-wide association studies of DNA methylation changes at three life stages (birth, n = 914; childhood at mean age 7.5 years, n = 973; and adolescence at mean age 15.5 years, n = 974), measured using the Illumina HumanMethylation450 Beadchip, in relation to pregnancy SEP indicators (maternal and paternal education and occupation). RESULTS: Across the four early life SEP metrics investigated, only maternal education was associated with methylation levels at birth, and four CpGs mapped to SULF1, GLB1L2 and RPUSD1 genes were identified [false discovery rate (FDR)-corrected P-value <0.05]. No epigenetic signature was found associated with maternal education in child samples, but methylation levels at 20 CpG loci were found significantly associated with maternal education in adolescence. Although no overlap was found between the differentially methylated CpG sites at different ages, we identified two CpG sites at birth and during adolescence which are 219 bp apart in the SULF1 gene that encodes an heparan sulphatase involved in modulation of signalling pathways. Using data from an independent birth cohort, the ENVIRONAGE cohort, we were not able to replicate these findings. CONCLUSIONS: Taken together, our results suggest that parental SEP, and particularly maternal education, may influence the offspring's methylome at birth and adolescence.

8.
Environ Int ; 123: 39-49, 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30496980

RESUMO

BACKGROUND: Studies investigating short-term exposure to ambient air pollution and heart rate variability (HRV) suggest that particulate matter (PM) exposure is associated with reductions in measures of HRV. Mitochondria are sensitive to PM exposure and may represent a biologically relevant underlying mechanism. However, evidence in children is lacking. OBJECTIVES: Here we examine whether PM has an influence on children's HRV and evaluate whether mitochondrial DNA content (mtDNAc) reflects individual susceptibility. METHODS: Within a panel study in primary school children (aged 9-12 years), we measured HRV in a subset of 60 children on three different days during school-time using four indicators: normal-to-normal intervals (SDNN), square root of mean squared difference of normal-to-normal intervals (rMSSD), high frequency (HF), and low frequency (LF). This resulted in a total number of 150 visits (median number of visits per child: 2.5/child). MtDNAc was measured using qPCR in buccal cells. We measured recent PM exposure at the school. Residential 24-hour mean exposure to PM was modelled with a high resolution spatial temporal model. Mixed-effects models were used to estimate the association between HRV and recent PM exposure and potential effect-modification by mtDNAc. RESULTS: Children were on average [SD] 9.9 [1.2] years and comprised 39 girls. Median [25th-75th] recent outdoor PM2.5 and PM10 exposure at school was 6.20 [2.8-12.8] µg/m3 and 29.3 [24.7-42.0] µg/m3, respectively. In children with low mtDNAc (25th percentile), we observed for each 10 µg/m3 increment in recent PM2.5 exposure a lowering in the LF parameter with 9.76% (95% CI: -16.9 to -1.99%, p = 0.02; pint = 0.007). Children with high mtDNAc did not show this association. For PM10 exposure, we observed an inverse association with three HRV indicators in children with low mtDNAc: -2.24% (95% CI: -4.27 to -0.16%; p = 0.04; pint = 0.02) for SDNN, -5.67% (95% CI: -10.5 to -0.59%; p = 0.03; pint = 0.04) for HF and -6.64% (95% CI: -10.7 to -2.38%; p = 0.003; pint = 0.005) for LF. CONCLUSIONS: HRV is inversely associated with recent PM air pollution, especially in children with low mtDNAc. Our data revealed that mtDNAc determines susceptibility to adverse autonomic effects of recent PM exposure in children.

9.
Artigo em Inglês | MEDLINE | ID: mdl-30361985

RESUMO

PURPOSE OF REVIEW: This systematic review evaluated existing evidence linking air pollution exposure in humans to major epigenetic mechanisms: DNA methylation, microRNAs, long noncoding RNAs, and chromatin regulation. RECENT FINDINGS: Eighty-two manuscripts were eligible, most of which were observational (85%), conducted in adults (66%) and based on DNA methylation (79%). Most observational studies, except panel, demonstrated modest effects of air pollution on the methylome. Panel and experimental studies revealed a relatively large number of significant methylome alterations, though based on smaller sample sizes. Particulate matter levels were positively associated in several studies with global or LINE-1 hypomethylation, a hallmark of several diseases, and with decondensed chromatin structure. Several air pollution species altered the DNA methylation clock, inducing accelerated biological aging. The causal nature of identified associations is not clear, however, especially that most originate from countries with low air pollution levels. Existing evidence, gaps, and perspectives are highlighted herein.

10.
J Transl Med ; 16(1): 224, 2018 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-30103773

RESUMO

BACKGROUND: The developmental origins of health and disease theory states that a disturbance in the early life environment can contribute to disease risk in later life. Leptin and insulin are anorectic hormones involved in energy homeostasis and are crucial for foetal growth. Disturbances in the levels of these hormones contribute to obesity and diabetes. In adults, altered mitochondrial function is an important hallmark of metabolic disorders, including obesity and diabetes. However, the mitochondrial effects of early life metabolic variation are unexplored. We investigated whether there is an association between metabolic hormones and mitochondrial DNA (mtDNA) content in early life. METHODS: The study included 236 newborns from the FLEHS III birth cohort, Flanders (Belgium). Relative mtDNA content of cord blood leukocytes was determined using quantitative PCR. Cord blood levels of leptin and insulin were determined using immunoassays. We studied the association between these metabolic hormones and mtDNA content using multiple linear regression models, while accounting for covariates and potential confounders. RESULTS: Leptin and insulin levels were positively associated with cord blood mtDNA content. mtDNA content was respectively 4.49% (95% CI 1.15-7.93; p = 0.008) and 1.60% (95% CI 0.31-2.91; p = 0.02) higher for a interquartile range increase of respectively cord blood leptin and insulin levels. In a sensitivity analysis, we observed that insulin and leptin were independently associated to mtDNA content and that insulin was stronger associated to mtDNA content in boys than in girls. CONCLUSION: Neonatal metabolic hormones were associated with cord blood mtDNA content, which suggests that in early life the variation of mtDNA content might accommodate or reflect changes in the metabolic status.

11.
Environ Res ; 166: 310-323, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29908461

RESUMO

BACKGROUND: Fetal development is a crucial window of susceptibility in which exposure-related alterations can be induced on the molecular level, leading to potential changes in metabolism and development. The placenta serves as a gatekeeper between mother and fetus, and is in contact with environmental stressors throughout pregnancy. This makes the placenta as a temporary organ an informative non-invasive matrix suitable to investigate omics-related aberrations in association with in utero exposures such as ambient air pollution. OBJECTIVES: To summarize and discuss the current evidence and define the gaps of knowledge concerning human placental -omics markers in association with prenatal exposure to ambient air pollution. METHODS: Two investigators independently searched the PubMed, ScienceDirect, and Scopus databases to identify all studies published until January 2017 with an emphasis on epidemiological research on prenatal exposure to ambient air pollution and the effect on placental -omics signatures. RESULTS: From the initial 386 articles, 25 were retained following an a priori set inclusion and exclusion criteria. We identified eleven studies on the genome, two on the transcriptome, five on the epigenome, five on the proteome category, one study with both genomic and proteomic topics, and one study with both genomic and transcriptomic topics. Six studies discussed the triple relationship between exposure to air pollution during pregnancy, the associated placental -omics marker(s), and the potential effect on disease development later in life. So far, no metabolomic or exposomic data discussing associations between the placenta and prenatal exposure to air pollution have been published. CONCLUSIONS: Integration of placental biomarkers in an environmental epidemiological context enables researchers to address fundamental questions essential in unraveling the fetal origin of disease and helps to better define the pregnancy exposome of air pollution.

12.
Sci Rep ; 8(1): 8209, 2018 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-29844486

RESUMO

An imbalance between energy uptake and energy expenditure is the most important reason for increasing trends in obesity starting from early in life. Extracellular miRNAs are expressed in all bodily fluids and their expression is influenced by a broad range of stimuli. We examined whether screen time, physical activity and BMI are associated with children's salivary extracellular miR-222 and miR-146a expression. In 80 children the extracellular fraction of saliva was obtained by means of differential centrifugation and ultracentrifugation. Expression levels of miR-222 and miR-146a were profiled by qPCR. We studied the association between children's salivary extracellular miRNA expression and screen time, physical activity and BMI using mixed models, while accounting for potential confounders. We found that higher screen time was positively associated with salivary extracellular miR-222 and miR-146a levels. On average, one hour more screen time use per week was associated with a 3.44% higher miR-222 (95% CI: 1.34 to 5.58; p = 0.002) and 1.84% higher miR-146a (95% CI: -0.04 to 3.75; p = 0.055) level in saliva. BMI and physical activity of the child were not significantly associated with either miR-222 or miR-146a. A sedentary behaviour, represented by screen time use in children, is associated with discernible changes in salivary expression of miR-146a and or miR-222. These miRNA targets may emerge attractive candidates to explore the role of these exposures in developmental processes of children's health.

13.
Sci Rep ; 8(1): 7095, 2018 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-29728662

RESUMO

Retinal arteriolar narrowing increases with age and predict adverse cardiovascular outcomes. Telomere length keeps track of the division of somatic cells and is a biomarker of biological age. We investigated to what extent retinal arteriolar diameters are associated with biological age, as captured by leukocyte telomere length (LTL). In 168 randomly selected Flemish participants from the family-based population study FLEMENGHO (mean age, 46.2 years) at baseline, of whom 85 underwent a follow-up examination (median, 4.1 years), we post-processed nonmydriatic retinal photographs and measured LTL. In men only, central retinal arteriolar equivalents (CRAE) and arteriole-to-venule ratio (AVR) were associated with LTL with stronger associations at higher age and body mass index. In men aged 57.6 years (75th percentile) a 20% shorter LTL was associated with a decrease in CRAE of 4.57 µm. A 20% shorter LTL was associated with a decrease of 5.88 µm in CRAE at a BMI of 29.9 kg/m2 (75th percentile). Similar associations were observed between AVR and LTL. In women, no retinal microvascular traits were associated with LTL. Retinal arteriolar narrowing in men but not in women is associated with biological age. Our findings support the idea that avoiding overweight contributes to maintaining a healthier microcirculation.

14.
Int J Cancer ; 2018 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-29696642

RESUMO

Air pollution has been classified as carcinogenic to humans. However, to date little is known about the relevance for cancers of the stomach and upper aerodigestive tract (UADT). We investigated the association of long-term exposure to ambient air pollution with incidence of gastric and UADT cancer in 11 European cohorts. Air pollution exposure was assigned by land-use regression models for particulate matter (PM) below 10 µm (PM10 ), below 2.5 µm (PM2.5 ), between 2.5 and 10 µm (PMcoarse ), PM2.5 absorbance and nitrogen oxides (NO2 and NOX ) as well as approximated by traffic indicators. Cox regression models with adjustment for potential confounders were used for cohort-specific analyses. Combined estimates were determined with random effects meta-analyses. During average follow-up of 14.1 years of 305,551 individuals, 744 incident cases of gastric cancer and 933 of UADT cancer occurred. The hazard ratio for an increase of 5 µg/m3 of PM2.5 was 1.38 (95% CI 0.99; 1.92) for gastric and 1.05 (95% CI 0.62; 1.77) for UADT cancers. No associations were found for any of the other exposures considered. Adjustment for additional confounders and restriction to study participants with stable addresses did not influence markedly the effect estimate for PM2.5 and gastric cancer. Higher estimated risks of gastric cancer associated with PM2.5 was found in men (HR 1.98 [1.30; 3.01]) as compared to women (HR 0.85 [0.5; 1.45]). This large multicentre cohort study shows an association between long-term exposure to PM2.5 and gastric cancer, but not UADT cancers, suggesting that air pollution may contribute to gastric cancer risk.

15.
Environ Sci Technol ; 52(9): 5427-5437, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29597345

RESUMO

Maternal exposure to airborne particulate matter (PM) has been associated with restricted fetal growth and reduced birthweight. Here, we performed methylome-wide analyses of cord and children's blood DNA in relation to residential exposure to PM smaller than 10 µm (PM10). This study included participants of the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC, cord blood, n = 780; blood at age 7, n = 757 and age 15-17, n = 850) and the EXPOsOMICS birth cohort consortium including cord blood from ENVIR ONAGE ( n = 197), INMA ( n = 84), Piccolipiù ( n = 99) and Rhea ( n = 75). We could not identify significant CpG sites, by meta-analyzing associations between maternal PM10 exposure during pregnancy and DNA methylation in cord blood, nor by studying DNA methylation and concordant annual exposure at 7 and 15-17 years. The CpG cg21785536 was inversely associated with PM10 exposure using a longitudinal model integrating the three studied age groups (-1.2% per 10 µg/m3; raw p-value = 3.82 × 10-8). Pathway analyses on the corresponding genes of the 100 strongest associated CpG sites of the longitudinal model revealed enriched pathways relating to the GABAergic synapse, p53 signaling and NOTCH1. We provided evidence that residential PM10 exposure in early life affects methylation of the CpG cg21785536 located on the EGF Domain Specific O-Linked N-Acetylglucosamine Transferase gene.

16.
J Proteome Res ; 17(3): 1235-1247, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29401400

RESUMO

Birth weight is an important indicator of maternal and fetal health and a predictor of health in later life. However, the determinants of variance in birth weight are still poorly understood. We aimed to identify the biological pathways, which may be perturbed by environmental exposures, that are important in determining birth weight. We applied untargeted mass-spectrometry-based metabolomics to 481 cord blood samples collected at delivery in four birth cohorts from across Europe: ENVIRONAGE (Belgium), INMA (Spain), Piccolipiu (Italy), and Rhea (Greece). We performed a metabolome-wide association scan for birth weight on over 4000 metabolic features, controlling the false discovery rate at 5%. Annotation of compounds was conducted through reference to authentic standards. We identified 68 metabolites significantly associated with birth weight, including vitamin A, progesterone, docosahexaenoic acid, indolelactic acid, and multiple acylcarnitines and phosphatidylcholines. We observed enrichment (p < 0.05) of the tryptophan metabolism, prostaglandin formation, C21-steroid hormone signaling, carnitine shuttle, and glycerophospholipid metabolism pathways. Vitamin A was associated with both maternal smoking and birth weight, suggesting a mediation pathway. Our findings shed new light on the pathways central to fetal growth and will have implications for antenatal and perinatal care and potentially for health in later life.


Assuntos
Peso ao Nascer/fisiologia , Sangue Fetal/química , Desenvolvimento Fetal/fisiologia , Metaboloma , Carnitina/análogos & derivados , Carnitina/sangue , Cromatografia Líquida de Alta Pressão , Estudos de Coortes , Ácidos Docosa-Hexaenoicos/sangue , Exposição Ambiental/análise , Europa (Continente) , Feminino , Feto , Humanos , Indóis/sangue , Recém-Nascido , Masculino , Espectrometria de Massas/métodos , Material Particulado/análise , Fosfatidilcolinas/sangue , Gravidez , Progesterona/sangue , Prostaglandinas/sangue , Padrões de Referência , Triptofano/sangue , Vitamina A/sangue
17.
Eur Urol Focus ; 4(1): 113-120, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28753823

RESUMO

BACKGROUND: Ambient air pollution contains low concentrations of carcinogens implicated in the etiology of urinary bladder cancer (BC). Little is known about whether exposure to air pollution influences BC in the general population. OBJECTIVE: To evaluate the association between long-term exposure to ambient air pollution and BC incidence. DESIGN, SETTING, AND PARTICIPANTS: We obtained data from 15 population-based cohorts enrolled between 1985 and 2005 in eight European countries (N=303431; mean follow-up 14.1 yr). We estimated exposure to nitrogen oxides (NO2 and NOx), particulate matter (PM) with diameter <10µm (PM10), <2.5µm (PM2.5), between 2.5 and 10µm (PM2.5-10), PM2.5absorbance (soot), elemental constituents of PM, organic carbon, and traffic density at baseline home addresses using standardized land-use regression models from the European Study of Cohorts for Air Pollution Effects project. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used Cox proportional-hazards models with adjustment for potential confounders for cohort-specific analyses and meta-analyses to estimate summary hazard ratios (HRs) for BC incidence. RESULTS AND LIMITATIONS: During follow-up, 943 incident BC cases were diagnosed. In the meta-analysis, none of the exposures were associated with BC risk. The summary HRs associated with a 10-µg/m3 increase in NO2 and 5-µg/m3 increase in PM2.5 were 0.98 (95% confidence interval [CI] 0.89-1.08) and 0.86 (95% CI 0.63-1.18), respectively. Limitations include the lack of information about lifetime exposure. CONCLUSIONS: There was no evidence of an association between exposure to outdoor air pollution levels at place of residence and risk of BC. PATIENT SUMMARY: We assessed the link between outdoor air pollution at place of residence and bladder cancer using the largest study population to date and extensive assessment of exposure and comprehensive data on personal risk factors such as smoking. We found no association between the levels of outdoor air pollution at place of residence and bladder cancer risk.

18.
Toxicol Sci ; 162(1): 251-263, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29145667

RESUMO

Aiming to in vivo characterize the responses of pluripotent stem cells and regenerative tissues to carcinogenic stress, we employed the highly regenerative organism Schmidtea mediterranea. Its broad regenerative capacities are attributable to a large pool of pluripotent stem cells, which are considered key players in the lower vulnerability toward chemically induced carcinogenesis observed in regenerative organisms. Schmidtea mediterranea is, therefore, an ideal model to study pluripotent stem cell responses with stem cells residing in their natural environment. Including microenvironmental alterations is important, as the surrounding niche influences the onset of oncogenic events. Both short- (3 days) and long-term (17 days) exposures to the genotoxic carcinogen methyl methanesulfonate (50 µM) were evaluated during homeostasis and animal regeneration, two situations that render altered cellular niches. In both cases, MMS-induced DNA damage was observed, which provoked a decrease in proliferation on the short term. The outcome of DNA damage responses following long-term exposure differed between homeostatic and regenerating animals. During regeneration, DNA repair systems were more easily activated than in animals in homeostasis, where apoptosis was an important outcome. Knockdown experiments confirmed the importance of DNA repair systems during carcinogenic exposure in regenerating animals as knockdown of rad51 induced a stem cell-depleted phenotype, after regeneration was completed.

19.
Chem Res Toxicol ; 30(12): 2120-2129, 2017 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-29092396

RESUMO

Covalently modified blood proteins (e.g., serum albumin adducts) are increasingly being viewed as potential biomarkers via which the environmental causes of human diseases may be understood. The notion that some (perhaps many) modifications have yet to be discovered has led to the development of untargeted adductomics methods, which attempt to capture entire populations of adducts. One such method is fixed-step selected reaction monitoring (FS-SRM), which analyses distributions of serum albumin adducts via shifts in the mass of a tryptic peptide [Li et al. (2011) Mol. Cell. Proteomics 10, M110.004606]. Working on the basis that FS-SRM might be able to detect biological variation due to environmental factors, we aimed to scale the methodology for use in an epidemiological setting. Development of sample preparation methods led to a batch workflow with increased throughput and provision for quality control. Challenges posed by technical and biological variation were addressed in the processing and interpretation of the data. A pilot study of 20 smokers and 20 never-smokers provided evidence of an effect of smoking on levels of putative serum albumin adducts. Differences between smokers and never-smokers were most apparent in putative adducts with net gains in mass between 105 and 114 Da (relative to unmodified albumin). The findings suggest that our implementation of FS-SRM could be useful for studying other environmental factors with relevance to human health.


Assuntos
Albumina Sérica/análise , Fumar/sangue , Adulto , Bélgica/epidemiologia , Biomarcadores/sangue , Índice de Massa Corporal , Estudos de Coortes , Humanos , Masculino , Projetos Piloto , Controle de Qualidade , Fumar/epidemiologia , Extração em Fase Sólida
20.
BMC Med ; 15(1): 205, 2017 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-29157235

RESUMO

BACKGROUND: Telomere attrition is extremely rapid during the first years of life, while lifestyle during adulthood exerts a minor impact. This suggests that early life is an important period in the determination of telomere length. We investigated the importance of the early-life environment on both telomere tracking and adult telomere length. METHODS: Among 184 twins of the East Flanders Prospective Twin Survey, telomere length in placental tissue and in buccal cells in young adulthood was measured. Residential addresses at birth and in young adulthood were geocoded and residential traffic and greenness exposure was determined. RESULTS: We investigated individual telomere tracking from birth over a 20 year period (mean age (SD), 22.6 (3.1) years) in association with residential exposure to traffic and greenness. Telomere length in placental tissue and in buccal cells in young adulthood correlated positively (r = 0.31, P < 0.0001). Persons with higher placental telomere length at birth were more likely to have a stronger downward shift in telomere ranking over life (P < 0.0001). Maternal residential traffic exposure correlated inversely with telomere length at birth. Independent of birth placental telomere length, telomere ranking between birth and young adulthood was negatively and significantly associated with residential traffic exposure at the birth address, while traffic exposure at the residential address at adult age was not associated with telomere length. CONCLUSIONS: Longitudinal evidence of telomere length tracking from birth to adulthood shows inverse associations of residential traffic exposure in association with telomere length at birth as well as accelerated telomere shortening in the first two decades of life.


Assuntos
Automóveis , Meio Ambiente , Telômero , Adolescente , Envelhecimento/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Exposição Materna , Mucosa Bucal , Placenta , Gravidez , Estudos Prospectivos , Encurtamento do Telômero , Gêmeos , Adulto Jovem
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