92 results found
Robinson O, Lau CE, 2023, How do metabolic processes age: Evidence from human metabolomic studies, Current Opinion in Chemical Biology, Vol: 76, Pages: 1-7, ISSN: 1367-5931
Metabolomics, the global profiling of small molecules in the body, has emerged as a promising analytical approach for assessing molecular changes associated with ageing at the population level. Understanding root metabolic ageing pathways may have important implications for managing age-related disease risk. In this short review, relevant studies published in the last few years that have made valuable contributions to this field will be discussed. These include large-scale studies investigating metabolic changes with age, metabolomic clocks, and metabolic pathways associated with ageing phenotypes. Recent significant advances include the use of longitudinal study designs, populations spanning the whole life course, standardised analytical platforms of enhanced metabolome coverage and development of multivariate analyses. While many challenges remain, recent studies have demonstrated the considerable promise of this field.
Robinson O, Lau C-HE, Joo S, et al., 2023, Associations of four biological age markers with child development: a multi-omic analysis in the European HELIX cohort, eLife, Vol: 12, Pages: 1-30, ISSN: 2050-084X
Background: While biological age in adults is often understood as representing general health and resilience, the conceptual interpretation of accelerated biological age in children and its relationship to development remains unclear. We aimed to clarify the relationship of accelerated biological age, assessed through two established biological age indicators, telomere length and DNA methylation age, and two novel candidate biological age indicators , to child developmental outcomes, including growth and adiposity, cognition, behaviour, lung function and onset of puberty, among European school-age children participating in the HELIX exposome cohort.Methods: The study population included up to 1,173 children, aged between 5 and 12 years, from study centres in the UK, France, Spain, Norway, Lithuania, and Greece. Telomere length was measured through qPCR, blood DNA methylation and gene expression was measured using microarray, and proteins and metabolites were measured by a range of targeted assays. DNA methylation age was assessed using Horvath's skin and blood clock, while novel blood transcriptome and 'immunometabolic' (based on plasma protein and urinary and serum metabolite data) clocks were derived and tested in a subset of children assessed six months after the main follow-up visit. Associations between biological age indicators with child developmental measures as well as health risk factors were estimated using linear regression, adjusted for chronological age, sex, ethnicity and study centre. The clock derived markers were expressed as Δ age (i.e., predicted minus chronological age).Results: Transcriptome and immunometabolic clocks predicted chronological age well in the test set (r= 0.93 and r= 0.84 respectively). Generally, weak correlations were observed, after adjustment for chronological age, between the biological age indicators. Among associations with health risk factors, higher birthweight was associated with greater immunometabolic Δ ag
Vineis P, Handakas E, Alfano R, et al., 2023, The contribution to policies of an exposome-based approach to childhood obesity, Exposome, Vol: https://academic.oup.com/exposome/advance-article/doi/10.1093/exposome/osad006/7180277, ISSN: 2635-2265
Childhood obesity is an increasingly severe public health problem, with a prospective impact on health. We propose an exposome approach to identifying actionable risk factors for this condition. Our assumption is that relationships between external exposures and outcomes such as rapid growth, overweight or obesity in children can be better understood through a “meet-in-the-middle” model. This is based on a combination of external and internal exposome-based approaches, i.e. the study of multiple exposures (in our case dietary patterns) and molecular pathways (metabolomics and epigenetics). This may strengthen causal reasoning by identifying intermediate markers that are associated with both exposures and outcomes. Our biomarker-based studies in the STOP consortium suggest (in several ways, including mediation analysis) that Branched-Chain Amino Acids (BCAAs) could be mediators of the effect of dietary risk factors on childhood overweight/obesity. This is consistent with intervention and animal studies showing that higher intake of BCAAs has a positive impact on body composition, glycemia and satiety. Concerning food, of particular concern is the trend of increasing intake of ultra-processed food (UPF), including among children. Several mechanisms have been proposed to explain the impact of UPF on obesity and overweight, including nutrient intake (particularly proteins), changes in appetite or the role of additives. Research from the ALSPAC cohort has shown a relationship between UPF intake and trajectories in childhood adiposity, while UPF was related to lower blood levels of BCAAs. We suggest that an exposome-based approach can help strengthening causal reasoning and support policies. Intake of UPF in children should be restricted to prevent obesity.
Huybrechts I, Rauber F, Nicolas G, et al., 2023, Corrigendum: characterization of the degree of food processing in the European Prospective Investigation into Cancer and Nutrition: application of the Nova classification and validation using selected biomarkers of food processing, Frontiers in Nutrition, Vol: 10, Pages: 1-4, ISSN: 2296-861X
[This corrects the article DOI: 10.3389/fnut.2022.1035580.]
Robinson O, 2023, Mediators of the association between childhood body mass index and educational attainment: analysis of a UK prospective cohort study, Pediatric Obesity, Vol: 18, Pages: 1-9, ISSN: 2047-6302
BackgroundHigher body mass index (BMI) in childhood is associated with lower academic achievement.ObjectiveTo explore potential pathways linking childhood BMI with educational attainment.MethodsUsing data from the Avon Longitudinal Study of Parents and Children prospective cohort study (N = 6949), we assessed the association between BMI z-scores at 11.7 years and educational attainment at 16 (General Certificate of Secondary Education [GCSE] results). Depressive symptoms, externalizing behaviours, bullying and school enjoyment were considered as potential mediators. Mediators were examined individually and jointly using sequential causal mediation.ResultsHigher BMI z-scores were associated with lower GCSE scores (females β = −3.47 95% CI −5.54, −1.41 males β = −4.33 95% CI −6.73, −1.94). Together, bullying, externalizing symptoms, depressive symptoms and school enjoyment mediated 41.9% of this association in females, and 23.3% in males. In males, evidence for mediation was weak (confidence intervals for all indirect effects spanned the null). In both females and males, most of the mediation was driven by externalizing symptoms.ConclusionsThe detrimental effect of higher BMI on educational attainment appears to be partly explained by externalizing behaviours, particularly in females. Interventions to support behavioural problems may help the academic achievement of children with a higher body weight.
Robinson O, 2023, The exposome approach to study children's health, Current Opinion in Environmental Science & Health, Vol: 32, Pages: 1-7, ISSN: 2468-5844
The exposome represents an interdisciplinary science and promising field of research that can identify how multiple facets of the environment influences health across the lifespan. A particular sensitive and critical window for environmental exposures and exposure-associated health is during early life, especially childhood. Previous studies of the exposome during childhood are highlighted, including the external and internal exposome. Challenges, and potential ways to overcome them, of the childhood exposome are presented with the aims to improve exposome studies during early life.
Alfano R, Zugna D, Barros H, et al., 2023, Cord blood epigenome-wide meta-analysis in six European-based child cohorts identifies signatures linked to rapid weight growth, BMC Medicine, Vol: 21, ISSN: 1741-7015
BACKGROUND: Rapid postnatal growth may result from exposure in utero or early life to adverse conditions and has been associated with diseases later in life and, in particular, with childhood obesity. DNA methylation, interfacing early-life exposures and subsequent diseases, is a possible mechanism underlying early-life programming. METHODS: Here, a meta-analysis of Illumina HumanMethylation 450K/EPIC-array associations of cord blood DNA methylation at single CpG sites and CpG genomic regions with rapid weight growth at 1 year of age (defined with reference to WHO growth charts) was conducted in six European-based child cohorts (ALSPAC, ENVIRONAGE, Generation XXI, INMA, Piccolipiù, and RHEA, N = 2003). The association of gestational age acceleration (calculated using the Bohlin epigenetic clock) with rapid weight growth was also explored via meta-analysis. Follow-up analyses of identified DNA methylation signals included prediction of rapid weight growth, mediation of the effect of conventional risk factors on rapid weight growth, integration with transcriptomics and metabolomics, association with overweight in childhood (between 4 and 8 years), and comparison with previous findings. RESULTS: Forty-seven CpGs were associated with rapid weight growth at suggestive p-value <1e-05 and, among them, three CpGs (cg14459032, cg25953130 annotated to ARID5B, and cg00049440 annotated to KLF9) passed the genome-wide significance level (p-value <1.25e-07). Sixteen differentially methylated regions (DMRs) were identified as associated with rapid weight growth at false discovery rate (FDR)-adjusted/Siddak p-values < 0.01. Gestational age acceleration was associated with decreasing risk of rapid weight growth (p-value = 9.75e-04). Identified DNA methylation signals slightly increased the prediction of rapid weight growth in addition to conventional risk factors. Among the identified signals, three CpGs partially mediated the effect of gestational age on rapid weigh
Huybrechts I, Rauber F, Nicolas G, et al., 2022, Characterization of the degree of food processing in the European Prospective Investigation into Cancer and Nutrition: Application of the Nova classification and validation using selected biomarkers of food processing, Frontiers in Nutrition, Vol: 9, ISSN: 2296-861X
Background: Epidemiological studies have demonstrated an association between the degree of food processing in our diet and the risk of various chronic diseases. Much of this evidence is based on the international Nova classification system, which classifies food into four groups based on the type of processing: (1) Unprocessed and minimally processed foods, (2) Processed culinary ingredients, (3) Processed foods, and (4) “Ultra-processed” foods (UPF). The ability of the Nova classification to accurately characterise the degree of food processing across consumption patterns in various European populations has not been investigated so far. Therefore, we applied the Nova coding to data from the European Prospective Investigation into Cancer and Nutrition (EPIC) in order to characterize the degree of food processing in our diet across European populations with diverse cultural and socio-economic backgrounds and to validate this Nova classification through comparison with objective biomarker measurements.Methods: After grouping foods in the EPIC dataset according to the Nova classification, a total of 476,768 participants in the EPIC cohort (71.5% women; mean age 51 [standard deviation (SD) 9.93]; median age 52 [percentile (p)25–p75: 58–66] years) were included in the cross-sectional analysis that characterised consumption patterns based on the Nova classification. The consumption of food products classified as different Nova categories were compared to relevant circulating biomarkers denoting food processing, measured in various subsamples (N between 417 and 9,460) within the EPIC cohort via (partial) correlation analyses (unadjusted and adjusted by sex, age, BMI and country). These biomarkers included an industrial transfatty acid (ITFA) isomer (elaidic acid; exogenous fatty acid generated during oil hydrogenation and heating) and urinary 4-methyl syringol sulfate (an indicator for the consumption of smoked food and a component of liquid smoke u
Maitre L, Bustamante M, Hernandez-Ferrer C, et al., 2022, Multi-omics signatures of the human early life exposome, Nature Communications, Vol: 13, Pages: 1-18, ISSN: 2041-1723
Environmental exposures during early life play a critical role in life-course health, yet the molecular phenotypes underlying environmental effects on health are poorly understood. In the Human Early Life Exposome (HELIX) project, a multi-centre cohort of 1301 mother-child pairs, we associate individual exposomes consisting of >100 chemical, outdoor, social and lifestyle exposures assessed in pregnancy and childhood, with multi-omics profiles (methylome, transcriptome, proteins and metabolites) in childhood. We identify 1170 associations, 249 in pregnancy and 921 in childhood, which reveal potential biological responses and sources of exposure. Pregnancy exposures, including maternal smoking, cadmium and molybdenum, are predominantly associated with child DNA methylation changes. In contrast, childhood exposures are associated with features across all omics layers, most frequently the serum metabolome, revealing signatures for diet, toxic chemical compounds, essential trace elements, and weather conditions, among others. Our comprehensive and unique resource of all associations (https://helixomics.isglobal.org/) will serve to guide future investigation into the biological imprints of the early life exposome.
Handakas E, Chang K, Khandpur N, et al., 2022, Metabolic profiles of ultra-processed food consumption and their role in obesity risk in British children, Clinical Nutrition, Vol: 41, Pages: 2537-2548, ISSN: 0261-5614
Background & aimsHigher consumption of ultra-processed foods (UPF) has been associated with childhood obesity, but underlying mechanisms remain unclear. We investigated plasma nuclear magnetic resonance metabolic profiles of higher UPF consumption and their role in obesity risk in the British ALSPAC cohort.MethodsWe performed cross-sectional and prospective metabolome wide association analyses of UPF, calculated from food diaries using the NOVA classification. In cross-sectional analysis, we tested the association between UPF consumption and metabolic profile at 7 years (N = 4528), and in the prospective analysis we tested the association between UPF consumption at 13 years and metabolic profile at 17 years (N = 3086). Effects of UPF-associated metabolites at 7 years on subsequent fat mass accumulation were assessed using growth curve models.ResultsAt 7 years, UPF was associated with 115 metabolic traits including lower levels of branched-chain and aromatic amino acids and higher levels of citrate, glutamine, and monounsaturated fatty acids, which were also associated with greater fat mass accumulation. Reported intake of nutrients mediated associations with most metabolites, except for citrate.ConclusionsUPF consumption among British children is associated with perturbation of multiple metabolic traits, many of which contribute to child obesity risk.
Freni Sterrantino A, Fiorito G, D'errico A, et al., 2022, Association between work characteristics and epigenetic age acceleration: cross-sectional results from UK – Understanding Society study, Aging, Vol: 14, Pages: 7752-7773, ISSN: 1945-4589
Occupation-related stress and work characteristics are possible determinants of social inequalities in epigenetic aging but have been little investigated. Here, we investigate the association of several work characteristics with epigenetic age acceleration (AA) biomarkers.The study population included employed and unemployed men and women (n=631) from UK Understanding Society study. We evaluated the association of employment and work characteristics related to job type, job stability; job schedule; autonomy and influence at work; occupational physical activity; and feelings regarding the job with four epigenetic age acceleration biomarkers (Hannum, Horvath, PhenoAge, GrimAge) and pace of aging (DunedinPoAm, DunedinPACE). We fitted linear regression models, unadjusted and adjusted for established risk factors, and found the following associations for unemployment (years of acceleration): HorvathAA (1.51, 95%CI 0.08,2.95), GrimAgeAA (1.53, 95%CI 0.16,2.90) and 3.21 years for PhenoAA (95%CI 0.89,5.33). Job insecurity increased PhenoAA (1.83, 95%CI 0.003,3.67), while working at night was associated with an increase of 2.12 years in GrimAgeAA (95%CI 0.69,3.55). We found effects of unemployment to be stronger in men and effects of night shift work to be stronger in women. These results provide evidence of associations between unemployment with accelerated ageing and suggest that insecure employment and night work may also increase age acceleration. Our findings have implications for policies relating to current changes in working conditions and highlight the utility of biological age biomarkers in studies in younger populations without long-term health information.
Cappozzo A, McCrory C, Robinson O, et al., 2022, A blood DNA methylation biomarker for predicting short-term risk of cardiovascular events, Clinical Epigenetics, Vol: 14, ISSN: 1868-7083
Background:Recent evidence highlights the epidemiological value of blood DNA methylation (DNAm) as surrogate biomarker for exposure to risk factors for non-communicable diseases (NCD). DNAm surrogate of exposures predicts diseases and longevity better than self-reported or measured exposures in many cases. Consequently, disease prediction models based on blood DNAm surrogates may outperform current state-of-the-art prediction models. This study aims to develop novel DNAm surrogates for cardiovascular diseases (CVD) risk factors and develop a composite biomarker predictive of CVD risk. We compared the prediction performance of our newly developed risk score with the state-of-the-art DNAm risk scores for cardiovascular diseases, the ‘next-generation’ epigenetic clock DNAmGrimAge, and the prediction model based on traditional risk factors SCORE2.Results:Using data from the EPIC Italy cohort, we derived novel DNAm surrogates for BMI, blood pressure, fasting glucose and insulin, cholesterol, triglycerides, and coagulation biomarkers. We validated them in four independent data sets from Europe and the USA. Further, we derived a DNAmCVDscore predictive of the time-to-CVD event as a combination of several DNAm surrogates. ROC curve analyses show that DNAmCVDscore outperforms previously developed DNAm scores for CVD risk and SCORE2 for short-term CVD risk. Interestingly, the performance of DNAmGrimAge and DNAmCVDscore was comparable (slightly lower for DNAmGrimAge, although the differences were not statistically significant).Conclusions:We described novel DNAm surrogates for CVD risk factors useful for future molecular epidemiology research, and we described a blood DNAm-based composite biomarker, DNAmCVDscore, predictive of short-term cardiovascular events. Our results highlight the usefulness of DNAm surrogate biomarkers of risk factors in epigenetic epidemiology to identify high-risk populations. In addition, we provide further evidence on the effectiveness of
Handakas E, Xu Y, Blair Segal A, et al., 2022, Molecular mediators of the association between child obesity and mental health, Frontiers in Genetics, Vol: 13, Pages: 1-18, ISSN: 1664-8021
Biological mechanisms underlying the association between obesity and depression remain unclear. We investigated the role of metabolites and DNA methylation as mediators of the relationship between childhood obesity and subsequent poor mental health in the English Avon Longitudinal Study of Parents and Children. Obesity was defined according to United Kingdom Growth charts at age 7 years and mental health through the Short Mood and Feelings Questionnaire (SMFQ) completed at age 11 years. Metabolites and DNA methylation were measured by nuclear magnetic resonance spectroscopy and Illumina array in blood at the age of 7 years. The associations between obesity and SMFQ score, as continuous count data or using cut-offs to define depressive symptoms (SMFQ >7) or depression (SMFQ >11), were tested using adjusted Poisson and logistic regression. Candidate metabolite mediators were identified through metabolome-wide association scans for obesity and SMFQ score, correcting for false-discovery rate. Candidate DNA methylation mediators were identified through testing the association of putative BMI-associated CpG sites with SMFQ scores, correcting for look-up false-discovery rate. Mediation by candidate molecular markers was tested. Two-sample Mendelian randomization (MR) analyses were additionally applied to test causal associations of metabolites with depression in independent adult samples. 4,018 and 768 children were included for metabolomics and epigenetics analyses, respectively. Obesity at 7 years was associated with a 14% increase in SMFQ score (95% CI: 1.04, 1.25) and greater odds of depression (OR: 1.46 (95% CI: 0.78, 2.38) at 11 years. Natural indirect effects (mediating pathways) between obesity and depression for tyrosine, leucine and conjugated linoleic acid were 1.06 (95% CI: 1.00, 1.13, proportion mediated (PM): 15%), 1.04 (95% CI: 0.99, 1.10, PM: 9.6%) and 1.06 (95% CI: 1.00, 1.12, PM: 13.9%) respectively. In MR analysis, one unit increase in tyrosine was
Fernández-Barrés S, Robinson O, Fossati S, et al., 2022, Urban environment and health behaviours in children from six European countries, Environment International, Vol: 165, ISSN: 0160-4120
Background:Urban environmental design is increasingly considered influential for health and wellbeing, but evidence is mostly based on adults and single exposure studies. We evaluated the association between a wide range of urban environment characteristics and health behaviours in childhood.Methods:We estimated exposure to 32 urban environment characteristics (related to the built environment, traffic, and natural spaces) for home and school addresses of 1,581 children aged 6-11 years from six European cohorts. We collected information on health behaviours including total amount of overall moderate-to-vigorous physical activity, physical activity outside school hours, active transport, sedentary behaviours and sleep duration, and developed patterns of behaviours with principal component analysis. We used an exposure-wide association study to screen all exposure-outcome associations, and the deletion-substitution-addition algorithm to build a final multi-exposure model.Results:In multi-exposure models, green spaces (Normalized Difference Vegetation Index, NDVI) were positively associated with active transport, and inversely associated with sedentary time (22.71 min/day less (95%CI -39.90, -5.51) per interquartile range increase in NDVI). Residence in densely built areas was associated with more physical activity and less sedentary time, and densely populated areas with less physical activity outside school hours and more sedentary time. Presence of a major road was associated with lower sleep duration (-4.80 min/day (95%CI -9.11, -0.48); compared with no major road). Results for the behavioural patterns were similar.Conclusions:This multicohort study suggests that areas with more vegetation, more building density, less population density and without major roads are associated with improved health behaviours in childhood.
Robinson O, 2022, Cord blood metabolites and rapid postnatal growth as multiple mediators in the prenatal propensity to childhood overweight, International Journal of Obesity, Vol: 46, Pages: 1384-1393, ISSN: 0307-0565
BACKGROUND: The mechanisms underlying childhood overweight and obesity are poorly known. Here, we investigated the direct and indirect effects of different prenatal exposures on offspring rapid postnatal growth and overweight in childhood, mediated through cord blood metabolites. Additionally, rapid postnatal growth was considered a potential mediator on childhood overweight, alone and sequentially to each metabolite.METHODS: Within four European birth-cohorts (N=375 mother-child dyads), information on seven prenatal exposures (maternal education, pre-pregnancy BMI, weight gain and tobacco smoke during pregnancy, age at delivery, parity, and child gestational age), selected as obesogenic according to a-priori knowledge, was collected. Cord blood levels of 31 metabolites, associated with rapid postnatal growth and/or childhood overweight in a previous study, were measured via liquid-chromatography-quadrupole-time-of-flight-mass-spectrometry. Rapid growth at 12 months and childhood overweight (including obesity) between four and eight years were defined with reference to WHO growth charts. Single mediation analysis was performed using the imputation approach and multiple mediation analysis using the extended-imputation approach.RESULTS: Single mediation suggested that the effect of maternal education, pregnancy weight gain, parity, and gestational age on rapid postnatal growth but not on childhood overweight was partly mediated by seven metabolites, including cholestenone, decenoylcarnitine(C10:1), phosphatidylcholine(C34:3), progesterone and three unidentified metabolites; and the effect of gestational age on childhood overweight was mainly mediated by rapid postnatal growth. Multiple mediation suggested that the effect of gestational age on childhood overweight was mainly mediated by rapid postnatal growth and that the mediating role of the metabolites was marginal. CONCLUSION: Our findings provide evidence of the involvement of in utero metabolism in the propensity
Jarvelin M-R, 2022, DNA methylation signature of chronic low-gradeinflammation and its role in cardio-respiratorydiseases, Nature Communications, Vol: 13, ISSN: 2041-1723
We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.
Ribeiro AI, Fraga S, Severo M, et al., 2022, Association of neighbourhood disadvantage and individual socioeconomic position with all-cause mortality: a longitudinal multicohort analysis, LANCET PUBLIC HEALTH, Vol: 7, Pages: E447-E457, ISSN: 2468-2667
Freni Sterrantino A, Fiorito G, D'errico A, et al., 2022, Work-related stress and well-being in association with epigenetic age acceleration: a Northern Finland Birth Cohort 1966 Study, Aging, Vol: 14, Pages: 1128-1156, ISSN: 1945-4589
Recent evidence indicates consistent association of low socioeconomic status with epigenetic age acceleration, measured from DNA methylation. As work characteristics and job stressors are crucial components of socioeconomic status, we investigated their association with various measures of epigenetic age acceleration.The study population included employed and unemployed men and women (n=604) from the Northern Finland Birth Cohort 1966. We investigated the association of job strain, effort-reward imbalance and work characteristics with five biomarkers of epigenetic aging (Hannum, Horvath, PhenoAge, GrimAge, and DunedinPoAm).Our results indicate few significant associations between work stress indicators and epigenetic age acceleration, limited to a range of ±2 years, and smoking recording the highest effect on GrimAge age acceleration biomarker between current and no smokers (median difference 4.73 years (IQR 1.18, 8.41). PhenoAgeAA was associated with job strain active work (β=-1.301 95%CI -2.391, -0.212), slowing aging of less than 1.5 years, and working as white-collar slowed aging six months (GrimAgeAA β=-0.683, 95%CI -1.264, -0.102) when compared to blue collars. Association was found for working for more than 40 hours per week that increased the aging over 1.5 years, (HorvathAA β =2.058 95%CI 0.517,3.599, HannumAA β=1.567, 95%CI 0.415,2.719).The pattern of associations was different between women and men and some of the estimated effects are inconsistent with current literature. Our results provide the first evidence of association of work conditions with epigenetic aging biomarkers. However, further epidemiological research is needed to fully understand how work-related stress affects epigenetic age acceleration in men and women in different societies.
Stratakis N, Siskos AP, Papadopoulou E, et al., 2022, Urinary metabolic biomarkers of diet quality in European children are associated with metabolic health, eLife, Vol: 11, Pages: 1-20, ISSN: 2050-084X
Urinary metabolic profiling is a promising powerful tool to reflect dietary intake and can help understand metabolic alterations in response to diet quality. Here, we used 1H NMR spectroscopy in a multicountry study in European children (1147 children from 6 different cohorts) and identified a common panel of 4 urinary metabolites (hippurate, N-methylnicotinic acid, urea, and sucrose) that was predictive of Mediterranean diet adherence (KIDMED) and ultra-processed food consumption and also had higher capacity in discriminating children’s diet quality than that of established sociodemographic determinants. Further, we showed that the identified metabolite panel also reflected the associations of these diet quality indicators with C-peptide, a stable and accurate marker of insulin resistance and future risk of metabolic disease. This methodology enables objective assessment of dietary patterns in European child populations, complementary to traditional questionary methods, and can be used in future studies to evaluate diet quality. Moreover, this knowledge can provide mechanistic evidence of common biological pathways that characterize healthy and unhealthy dietary patterns, and diet-related molecular alterations that could associate to metabolic disease.
Keski-Rahkonen P, Robinson O, Alfano R, et al., 2022, Commentary: Data processing thresholds for abundance and sparsity and missed biological insights in an untargeted chemical analysis of blood specimens for exposomics, Frontiers in Public Health, Vol: 9, ISSN: 2296-2565
A Commentary onData Processing Thresholds for Abundance and Sparsity and Missed Biological Insights in an Untargeted Chemical Analysis of Blood Specimens for Exposomicsby Barupal, D. K., Baygi, S. F., Wright, R. O., and Arora, M. (2021). Front. Public Health 9:653599. doi: 10.3389/fpubh.2021.653599
Handakas E, Lau CH, Alfano R, et al., 2022, A systematic review of metabolomic studies of childhood obesity: State of the evidence for metabolic determinants and consequences, Obesity Reviews, Vol: 23, Pages: 1-13, ISSN: 1467-7881
Childhood obesity has become a global epidemic and carries significant long-term consequences to physical and mental health. Metabolomics, the global profiling of small molecules or metabolites, may reveal the mechanisms of development of childhood obesity and clarify links between obesity and metabolic disease. A systematic review of metabolomic studies of childhood obesity was conducted, following Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines, searching across Scopus, Ovid, Web of Science and PubMed databases for articles published from January 1, 2005 to July 8, 2020, retrieving 1271 different records and retaining 41 articles for qualitative synthesis. Study quality was assessed using a modified Newcastle–Ottawa Scale. Thirty-three studies were conducted on blood, six on urine, three on umbilical cord blood, and one on saliva. Thirty studies were primarily cross-sectional, five studies were primarily longitudinal, and seven studies examined effects of weight-loss following a life-style intervention. A consistent metabolic profile of childhood obesity was observed including amino acids (particularly branched chain and aromatic), carnitines, lipids, and steroids. Although the use of metabolomics in childhood obesity research is still developing, the identified metabolites have provided additional insight into the pathogenesis of many obesity-related diseases. Further longitudinal research is needed into the role of metabolic profiles and child obesity risk.
Malacarne D, Chandakas E, Robinson O, et al., 2022, The built environment as determinant of childhood obesity: a systematic literature review, Obesity Reviews, Vol: 23, Pages: 1-11, ISSN: 1467-7881
We evaluated the epidemiological evidence on the built environment and its link to childhood obesity, focusing on environmental factors such as traffic noise and air pollution, as well as physical factors potentially driving obesity-related behaviours, such as neighbourhood walkability and availability and accessibility of parks and playgrounds. Eligible studies were i) conducted on human children below the age of 18 years, ii) focused on body size measurements in childhood, iii) examined at least one built environment characteristic, iv) reported effect sizes and associated confidence intervals, and v) were published in English language. A z-Test, as alternative to the meta-analysis, was used to quantify associations due to heterogeneity in exposure and outcome definition. We found strong evidence for an association of traffic-related air pollution (nitrogen dioxide and nitrogen oxides exposure; p<0.001) and built environment characteristics supportive of walking (street intersection density; p<0.01 and access to parks; p<0.001) with childhood obesity. We identified a lack of studies which account for interactions between different built environment exposures or verify the role and mechanism of important effect modifiers such as age.
Alfano R, Robinson O, Handakas E, et al., 2022, Perspectives and challenges of epigenetic determinants of childhood obesity: A systematic review, Obesity Reviews, Vol: 23, Pages: 1-13, ISSN: 1467-7881
The tremendous increase in childhood obesity prevalence over the last few decades cannot merely be explained by genetics and evolutionary changes in the genome, implying that gene–environment interactions, such as epigenetic modifications, likely play a major role. This systematic review aims to summarize the evidence of the association between epigenetics and childhood obesity. A literature search was performed via PubMed and Scopus engines using a combination of terms related to epigenetics and pediatric obesity. Articles studying the association between epigenetic mechanisms (including DNA methylation and hydroxymethylation, non-coding RNAs, and chromatin and histones modification) and obesity and/or overweight (or any related anthropometric parameters) in children (0–18 years) were included. The risk of bias was assessed with a modified Newcastle–Ottawa scale for non-randomized studies. One hundred twenty-one studies explored epigenetic changes related to childhood obesity. DNA methylation was the most widely investigated mechanism (N = 101 studies), followed by non-coding RNAs (N = 19 studies) with evidence suggestive of an association with childhood obesity for DNA methylation of specific genes and microRNAs (miRNAs). One study, focusing on histones modification, was identified. Heterogeneity of findings may have hindered more insights into the epigenetic changes related to childhood obesity. Gaps and challenges that future research should face are herein described.
Stratakis N, Siskos AP, Papadopoulou E, et al., 2021, Author response: Urinary metabolic biomarkers of diet quality in European children are associated with metabolic health
Papadopoulou E, Stratakis N, Basagaña X, et al., 2021, Prenatal and postnatal exposure to PFAS and cardiometabolic factors and inflammation status in children from six European cohorts, Environment International, Vol: 157, Pages: 106853-106853, ISSN: 0160-4120
Developing children are particularly vulnerable to the effects of exposure to per- and polyfluoroalkyl substances (PFAS), a group of endocrine disrupting chemicals. We hypothesized that early life exposure to PFASs is associated with poor metabolic health in children. We studied the association between prenatal and postnatal PFASs mixture exposure and cardiometabolic health in children, and the role of inflammatory proteins. In 1,101 mothers-child pairs from the Human Early Life Exposome project, we measured the concentrations of PFAS in blood collected in pregnancy and at 8 years (range = 6-12 years). We applied Bayesian Kernel Machine regression (BKMR) to estimate the associations between exposure to PFAS mixture and the cardiometabolic factors as age and sex- specific z-scores of waist circumference (WC), systolic and diastolic blood pressures (BP), and concentrations of triglycerides (TG), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) cholesterol. We measured thirty six inflammatory biomarkers in child plasma and examined the underlying role of inflammatory status for the exposure-outcome association by integrating the three panels into a network. Exposure to the PFAS mixture was positively associated with HDL-C and systolic BP, and negatively associated with WC, LDL-C and TG. When we examined the independent effects of the individual chemicals in the mixture, prenatal PFHxS was negatively associated with HDL-C and prenatal PFNA was positively associated with WC and these were opposing directions from the overall mixture. Further, the network consisted of five distinct communities connected with positive and negative correlations. The selected inflammatory biomarkers were positively, while the postnatal PFAS were negatively related with the included cardiometabolic factors, and only prenatal PFOA was positively related with the pro-inflammatory cytokine IL-1beta and WC. Our study supports that prenatal, rather than post
Stratakis N, Rock S, La Merrill MA, et al., 2021, Prenatal exposure to persistent organic pollutants and childhood obesity: A systematic review and meta-analysis of human studies, Obesity Reviews, Vol: 23, Pages: 1-16, ISSN: 1467-7881
We conducted a systematic review and meta-analysis of the associations between prenatal exposure to persistent organic pollutants (POPs) and childhood obesity. We focused on organochlorines (dichlorodiphenyltrichloroethane [DDT], dichlorodiphenyldichloroethylene [DDE], hexachlorobenzene [HCB], and polychlorinated biphenyls [PCBs]), perfluoroalkyl and polyfluoroalkyl substances (PFAS), and polybrominated diphenyl ethers (PBDEs) that are the POPs more widely studied in environmental birth cohorts so far. We search two databases (PubMed and Embase) through July/09/2021 and identified 33 studies reporting associations with prenatal organochlorine exposure, 21 studies reporting associations with prenatal PFAS, and five studies reporting associations with prenatal PBDEs. We conducted a qualitative review. Additionally, we performed random-effects meta-analyses of POP exposures, with data estimates from at least three prospective studies, and BMI-z. Prenatal DDE and HCB levels were associated with higher BMI z-score in childhood (beta: 0.12, 95% CI: 0.03, 0.21; I2 : 28.1% per study-specific log increase of DDE and beta: 0.31, 95% CI: 0.09, 0.53; I2 : 31.9% per study-specific log increase of HCB). No significant associations between PCB-153, PFOA, PFOS, or pentaPBDEs with childhood BMI were found in meta-analyses. In individual studies, there was inconclusive evidence that POP levels were positively associated with other obesity indicators (e.g., waist circumference).
de Prado-Bert P, Ruiz-Arenas C, Vives-Usano M, et al., 2021, The early-life exposome and epigenetic age acceleration in children, Environment International, Vol: 155, ISSN: 0160-4120
The early-life exposome influences future health and accelerated biological aging has been proposed as one of the underlying biological mechanisms. We investigated the association between more than 100 exposures assessed during pregnancy and in childhood (including indoor and outdoor air pollutants, built environment, green environments, tobacco smoking, lifestyle exposures, and biomarkers of chemical pollutants), and epigenetic age acceleration in 1,173 children aged 7 years old from the Human Early-Life Exposome project. Age acceleration was calculated based on Horvath’s Skin and Blood clock using child blood DNA methylation measured by Infinium HumanMethylation450 BeadChips. We performed an exposure-wide association study between prenatal and childhood exposome and age acceleration. Maternal tobacco smoking during pregnancy was nominally associated with increased age acceleration. For childhood exposures, indoor particulate matter absorbance (PMabs) and parental smoking were nominally associated with an increase in age acceleration. Exposure to the organic pesticide dimethyl dithiophosphate and the persistent pollutant polychlorinated biphenyl-138 (inversely associated with child body mass index) were protective for age acceleration. None of the associations remained significant after multiple-testing correction. Pregnancy and childhood exposure to tobacco smoke and childhood exposure to indoor PMabs may accelerate epigenetic aging from an early age.
Stratakis N, Siskos AP, Papadopoulou E, et al., 2021, Urinary metabolic biomarkers of diet quality in European children are associated with metabolic health
<jats:title>Abstract</jats:title><jats:p>Urinary metabolic profiling is a promising powerful tool to reflect dietary intake and can help understand metabolic alterations in response to diet quality. Here, we used <jats:sup>1</jats:sup>H-NMR spectroscopy in a multi-country study in European children (1147 children from 6 different cohorts) and identified a common panel of 4 urinary metabolites (hippurate, <jats:italic>N</jats:italic>-methylnicotinic acid, urea and sucrose) that was predictive of Mediterranean diet adherence (KIDMED) and ultra-processed food (UPF) consumption and also had higher capacity in discriminating children’s diet quality than that of established sociodemographic determinants. Further, we showed that the identified metabolite panel also reflected the associations of these diet quality indicators with C-peptide, a stable and accurate marker of insulin resistance and future risk of metabolic disease. This methodology enables objective assessment of dietary patterns in European child populations, complementary to traditional questionary methods, and can be used in future studies to evaluate diet quality. Moreover, this knowledge can provide mechanistic evidence of common biological pathways that characterize healthy and unhealthy dietary patterns, and diet-related molecular alterations that could associate to metabolic disease.</jats:p>
Julvez J, Robinson O, 2021, Early life multiple exposures and child cognitive function: a multi-centric birth cohort study in six European countries, Environmental Pollution, Vol: 284, Pages: 1-11, ISSN: 0269-7491
Epidemiological studies mostly focus on single environmental exposures. This study aims to systematically assess associations between a wide range of prenatal and childhood environmental exposures and cognition. The study sample included data of 1298 mother-child pairs, children were 6–11 years-old, from six European birth cohorts. We measured 87 exposures during pregnancy and 122 cross-sectionally during childhood, including air pollution, built environment, meteorology, natural spaces, traffic, noise, chemicals and life styles. The measured cognitive domains were fluid intelligence (Raven's Coloured Progressive Matrices test, CPM), attention (Attention Network Test, ANT) and working memory (N-Back task). We used two statistical approaches to assess associations between exposure and child cognition: the exposome-wide association study (ExWAS) considering each exposure independently, and the deletion-substitution-addition algorithm (DSA) considering all exposures simultaneously to build a final multiexposure model. Based on this multiexposure model that included the exposure variables selected by ExWAS and DSA models, child organic food intake was associated with higher fluid intelligence (CPM) scores (beta = 1.18; 95% CI = 0.50, 1.87) and higher working memory (N-Back) scores (0.23; 0.05, 0.41), and child fast food intake (−1.25; −2.10, −0.40), house crowding (−0.39; −0.62, −0.16), and child environmental tobacco smoke (ETS) (−0.89; −1.42, −0.35), were all associated with lower CPM scores. Indoor PM2.5 exposure was associated with lower N-Back scores (−0.09; −0.16, −0.02). Additional associations in the unexpected direction were found: Higher prenatal mercury levels, maternal alcohol consumption and child higher perfluorooctane sulfonic acid (PFOS) levels were associated with better cognitive performance; and higher green exposure during pregnancy with lower cognitive performance. This fi
Stratakis N, Golden-Mason L, Margetaki K, et al., 2021, In utero exposure to mercury is associated with increased susceptibility to liver injury and inflammation in childhood, Hepatology, Vol: 74, Pages: 1546-1559, ISSN: 0270-9139
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of liver disease in children. Mercury (Hg), a ubiquitous toxic metal, has been proposed as an environmental factor contributing to toxicant‐associated fatty liver disease. We investigated the effect of prenatal exposure to Hg on childhood liver injury by combining epidemiological results from a multicenter mother‐child cohort with complementary in vitro experiments on monocyte cells that are known to play a key role in liver immune homeostasis and NAFLD. We used data from 872 mothers and their children (median age, 8.1 years; interquartile range [IQR], 6.5‐8.7) from the European Human Early‐Life Exposome (HELIX) cohort. We measured Hg concentration in maternal blood during pregnancy (median, 2.0 μg/L; IQR, 1.1‐3.6). We also assessed serum levels of alanine aminotransferase (ALT), a common screening tool for pediatric NAFLD, and plasma concentrations of inflammation‐related cytokines in children. We found that prenatal Hg exposure was associated with a phenotype in children that was characterized by elevated ALT (≥22.1 U/L for females and ≥25.8 U/L for males) and increased concentrations of circulating interleukin (IL)‐1β, IL‐6, IL‐8, and tumor necrosis factor α (TNF‐α). Consistently, inflammatory monocytes exposed in vitro to a physiologically relevant dose of Hg demonstrated significant up‐regulation of genes encoding these four cytokines and increased concentrations of IL‐8 and TNF‐α in the supernatants.Conclusion:These findings suggest that developmental exposure to Hg can contribute to inflammation and increased NAFLD risk in early life.
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