Associations of four biological age markers with child development: a multi-omic analysis in the European HELIX cohort

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 age, smoke exposure with greater DNA methylation Δ age and high family affluence with longer telomere length. Among associations with child developmental measures, all biological age markers were associated with greater BMI and fat mass, and all markers except telomere length were associated with greater height, at least at nominal significance (p<0.05). Immunometabolic Δ age was associated with better working memory (p = 4e -3) and reduced inattentiveness (p= 4e -4), while DNA methylation Δ age was associated with greater inattentiveness (p=0.03) and poorer externalizing behaviours (p= 0.01). Shorter telomere length was also associated with poorer externalizing behaviours (p=0.03). Conclusions: In children, as in adults, biological ageing appears to be a multi-faceted process and adiposity is an important correlate of accelerated biological ageing. Patterns of associations suggested that accelerated immunometabolic age may be beneficial for some aspects of child development while accelerated DNA methylation age and telomere attrition may reflect early detrimental aspects of biological ageing, apparent even in children. Funding: UK Research and Innovation (MR/S03532X/1); European Commission (grant agreement numbers: 308333; 874583)

Investigating the process of ethical approval in citizen science research. The case of public health

Undertaking citizen science research in Public Health involving human subjects poses significant challenges concerning the traditional process of ethical approval. It requires an extension of the ethics of protection of research subjects in order to include the empowerment of citizens as citizen scientists. This paper investigates these challenges and illustrates the ethical framework and the strategies developed within the CitieS-Health project. It also proposes first recommendations generated from the experiences of five citizen science pilot studies in environmental epidemiology within this project

Understanding correlates of neighborhood aesthetic ratings: A European-based Four City comparison

Evidence of associations between nature and health behaviors and health status is mounting. However, there is a need to deconstruct “natural space” to capture the qualities of green and blue space and the various ways people experience these natural outdoor environments. These experiences influence and sustain changes in health and social behaviors such as physical activity, diet, and social connectedness. In this paper, we examine the social, cultural, and emotional factors that influence people´s perceptions of natural outdoor environments, also referred to as neighborhood aesthetics. Using a population-based sample of 2948 adults in four European cities who participated in the PHENOTYPE study, we developed a quality-based aesthetics index of nearby nature to represent our study outcome. The scale had high internal consistency (Cronbach’s alpha 0.86). We assessed its association with common measures of the natural environment (Normalized Difference Vegetation Index (NDVI)), and examined factors that may influence aesthetic ratings. Hypothesized correlates of neighborhood aesthetics including presence of and time in neighborhood nature, perceived environmental stressors and neighborhood social cohesion and attachment were generally confirmed. Contrary to our expectations, respondents born in the country of current residence rated neighborhood aesthetics lower than those born elsewhere and associations with length of residence were not consistent across countries. Interventions designed to influence social, cultural, and emotional processes could improve aesthetics ratings and potentially contribute to better health and wellbeing

The Effect of Park and Urban Environments on Coronary Artery Disease Patients: A Randomized Trial

© 2015 Regina Grazuleviciene et al. Aim. To test the hypothesis that walking in a park has a greater positive effect on coronary artery disease (CAD) patients' hemodynamic parameters than walking in an urban environment. Methods. Twenty stable CAD patients were randomized into two groups: 30-minute walk on 7 consecutive days in either a city park or busy urban street. Wilcoxon signed-rank test was employed to study short-term (30 min) and cumulative changes (following 7 consecutive days of exposure) in resting hemodynamic parameters in different environments. Results. There were no statistically significant differences in the baseline and peak exercise systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), exercise duration, or HR recovery in urban versus park exposure groups. Seven days of walking slightly improved all hemodynamic parameters in both groups. Compared to baseline, the city park group exhibited statistically significantly greater reductions in HR and DBP and increases in exercise duration and HR recovery. The SBP and DBP changes in the urban exposed group were lower than in the park exposed group. Conclusions. Walking in a park had a greater positive effect on CAD patients' cardiac function than walking in an urban environment, suggesting that rehabilitation through walking in green environments after coronary events should be encouraged

The human early-life exposome (HELIX): project rationale and design

Background: Developmental periods in early life may be particularly vulnerable to impacts of environmental exposures. Human research on this topic has generally focused on single exposure–health effect relationships. The “exposome” concept encompasses the totality of exposures from conception onward, complementing the genome. Objectives: The Human Early-Life Exposome (HELIX) project is a new collaborative research project that aims to implement novel exposure assessment and biomarker methods to characterize early-life exposure to multiple environmental factors and associate these with omics biomarkers and child health outcomes, thus characterizing the “early-life exposome.” Here we describe the general design of the project. Methods: In six existing birth cohort studies in Europe, HELIX will estimate prenatal and postnatal exposure to a broad range of chemical and physical exposures. Exposure models will be developed for the full cohorts totaling 32,000 mother–child pairs, and biomarkers will be measured in a subset of 1,200 mother–child pairs. Nested repeat-sampling panel studies (n = 150) will collect data on biomarker variability, use smartphones to assess mobility and physical activity, and perform personal exposure monitoring. Omics techniques will determine molecular profiles (metabolome, proteome, transcriptome, epigenome) associated with exposures. Statistical methods for multiple exposures will provide exposure–response estimates for fetal and child growth, obesity, neurodevelopment, and respiratory outcomes. A health impact assessment exercise will evaluate risks and benefits of combined exposures. Conclusions: HELIX is one of the first attempts to describe the early-life exposome of European populations and unravel its relation to omics markers and health in childhood. As proof of concept, it will form an important first step toward the life-course exposome

Exposure to natural environments during pregnancy and birth outcomes in 11 european birth cohorts

Research suggests that maternal exposure to natural environments (i.e., green and blue spaces) promotes healthy fetal growth. However, the available evidence is heterogeneous across regions, with very few studies on the effects of blue spaces. This study evaluated associations between maternal exposure to natural environments and birth outcomes in 11 birth cohorts across nine European countries. This study, part of the LifeCycle project, was based on a total sample size of 69,683 newborns with harmonised data. For each participant, we calculated seven indicators of residential exposure to natural environments: surrounding greenspace in 100m, 300m, and 500m using Normalised Difference Vegetation Index (NDVI) buffers, distance to the nearest green space, accessibility to green space, distance to the nearest blue space, and accessibility to blue space. Measures of birth weight and small for gestational age (SGA) were extracted from hospital records. We used pooled linear and logistic regression models to estimate associations between exposure to the natural environment and birth outcomes, controlling for the relevant covariates. We evaluated the potential effect modification by socioeconomic status (SES) and region of Europe and the influence of ambient air pollution on the associations. In the pooled analyses, residential surrounding greenspace in 100m, 300m, and 500m buffer was associated with increased birth weight and lower odds for SGA. Higher residential distance to green space was associated with lower birth weight and higher odds for SGA. We observed close to null associations for accessibility to green space and exposure to blue space. We found stronger estimated magnitudes for those participants with lower educational levels, from more deprived areas, and living in the northern European region. Our associations did not change notably after adjustment for air pollution. These findings may support implementing policies to promote natural environments in our cities, starting in more deprived areas. © 2022Funding text 1: This project received funding from the European Union's Horizon 2020 research and innovation programme (LIFECYCLE, grant agreement No 733206; EUCAN-Connect grant agreement No 824989). ISGlobal acknowledges support from the Spanish Ministry of Science and Innovation and State Research Agency through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. For more information of each cohort individual funding, see Supplementary Material s, Information S2. ; Funding text 2: We would like to thanks to all the mothers, fathers, and children for their generous contribution as participants in the cohorts that are part of the LifeCycle project. For more information of each cohort individual acknowledgment, see Supplementary Materials, Information S1. This project received funding from the European Union's Horizon 2020 research and innovation programme (LIFECYCLE, grant agreement No 733206; EUCAN-Connect grant agreement No 824989). ISGlobal acknowledges support from the Spanish Ministry of Science and Innovation and State Research Agency through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. For more information of each cohort individual funding, see Supplementary Materials, Information S2. DAL has received support from Medtronic Ltd and Roche Diagnostics for research unrelated to this study. All the other authors declare that they have no competing interests

In utero and childhood exposure to tobacco smoke and multi-layer molecular signatures in children

Background The adverse health effects of early life exposure to tobacco smoking have been widely reported. In spite of this, the underlying molecular mechanisms of in utero and postnatal exposure to tobacco smoke are only partially understood. Here, we aimed to identify multi-layer molecular signatures associated with exposure to tobacco smoke in these two exposure windows. Methods We investigated the associations of maternal smoking during pregnancy and childhood secondhand smoke (SHS) exposure with molecular features measured in 1203 European children (mean age 8.1 years) from the Human Early Life Exposome (HELIX) project. Molecular features, covering 4 layers, included blood DNA methylation and gene and miRNA transcription, plasma proteins, and sera and urinary metabolites. Results Maternal smoking during pregnancy was associated with DNA methylation changes at 18 loci in child blood. DNA methylation at 5 of these loci was related to expression of the nearby genes. However, the expression of these genes themselves was only weakly associated with maternal smoking. Conversely, childhood SHS was not associated with blood DNA methylation or transcription patterns, but with reduced levels of several serum metabolites and with increased plasma PAI1 (plasminogen activator inhibitor-1), a protein that inhibits fibrinolysis. Some of the in utero and childhood smoking-related molecular marks showed dose-response trends, with stronger effects with higher dose or longer duration of the exposure. Conclusion In this first study covering multi-layer molecular features, pregnancy and childhood exposure to tobacco smoke were associated with distinct molecular phenotypes in children. The persistent and dose-dependent changes in the methylome make CpGs good candidates to develop biomarkers of past exposure. Moreover, compared to methylation, the weak association of maternal smoking in pregnancy with gene expression suggests different reversal rates and a methylation-based memory to past exposures. Finally, certain metabolites and protein markers evidenced potential early biological effects of postnatal SHS, such as fibrinolysis

Gaseous air pollution and emergency hospital visits for hypertension in Beijing, China: a time-stratified case-crossover study

Background: A number of epidemiological studies have been conducted to research the adverse effects of air pollution on mortality and morbidity. Hypertension is the most important risk factor for cardiovascular mortality. However, few previous studies have examined the relationship between gaseous air pollution and morbidity for hypertension. ---------- Methods: Daily data on emergency hospital visits (EHVs) for hypertension were collected from the Peking University Third Hospital. Daily data on gaseous air pollutants (sulfur dioxide (SO2) and nitrogen dioxide (NO2)) and particulate matter less than 10 μm in aerodynamic diameter (PM10) were collected from the Beijing Municipal Environmental Monitoring Center. A time-stratified case-crossover design was conducted to evaluate the relationship between urban gaseous air pollution and EHVs for hypertension. Temperature and relative humidity were controlled for. ---------- Results: In the single air pollutant models, a 10 μg/m3 increase in SO2 and NO2 were significantly associated with EHVs for hypertension. The odds ratios (ORs) were 1.037 (95% confidence interval (CI): 1.004-1.071) for SO2 at lag 0 day, and 1.101 (95% CI: 1.038-1.168) for NO2 at lag 3 day. After controlling for PM10, the ORs associated with SO2 and NO2 were 1.025 (95% CI: 0.987-1.065) and 1.114 (95% CI: 1.037-1.195), respectively.---------- Conclusion: Elevated urban gaseous air pollution was associated with increased EHVs for hypertension in Beijing, China

Exposure to natural environments during pregnancy and birth outcomes in 11 European birth cohorts

Research suggests that maternal exposure to natural environments (i.e., green and blue spaces) promotes healthy fetal growth. However, the available evidence is heterogeneous across regions, with very few studies on the effects of blue spaces. This study evaluated associations between maternal exposure to natural environments and birth outcomes in 11 birth cohorts across nine European countries. This study, part of the LifeCycle project, was based on a total sample size of 69,683 newborns with harmonised data. For each participant, we calculated seven indicators of residential exposure to natural environments: surrounding greenspace in 100m, 300m, and 500m using Normalised Difference Vegetation Index (NDVI) buffers, distance to the nearest green space, accessibility to green space, distance to the nearest blue space, and accessibility to blue space. Measures of birth weight and small for gestational age (SGA) were extracted from hospital records. We used pooled linear and logistic regression models to estimate associations between exposure to the natural environment and birth outcomes, controlling for the relevant covariates. We evaluated the potential effect modification by socioeconomic status (SES) and region of Europe and the influence of ambient air pollution on the associations. In the pooled analyses, residential surrounding greenspace in 100m, 300m, and 500m buffer was associated with increased birth weight and lower odds for SGA. Higher residential distance to green space was associated with lower birth weight and higher odds for SGA. We observed close to null associations for accessibility to green space and exposure to blue space. We found stronger estimated magnitudes for those participants with lower educational levels, from more deprived areas, and living in the northern European region. Our associations did not change notably after adjustment for air pollution. These findings may support implementing policies to promote natural environments in our cities, starting in more deprived areas

Individual exposures to drinking water trihalomethanes, low birth weight and small for gestational age risk: a prospective Kaunas cohort study

<p>Abstract</p> <p>Background</p> <p>Evidence for an association between exposure during pregnancy to trihalomethanes (THMs) in drinking water and impaired fetal growth is still inconsistent and inconclusive, in particular, for various exposure routes. We examined the relationship of individual exposures to THMs in drinking water on low birth weight (LBW), small for gestational age (SGA), and birth weight (BW) in singleton births.</p> <p>Methods</p> <p>We conducted a cohort study of 4,161 pregnant women in Kaunas (Lithuania), using individual information on drinking water, ingestion, showering and bathing, and uptake factors of THMs in blood, to estimate an internal dose of THM. We used regression analysis to evaluate the relationship between internal THM dose and birth outcomes, adjusting for family status, education, smoking, alcohol consumption, body mass index, blood pressure, ethnic group, previous preterm, infant gender, and birth year.</p> <p>Results</p> <p>The estimated internal dose of THMs ranged from 0.0025 to 2.40 mg/d. We found dose-response relationships for the entire pregnancy and trimester-specific THM and chloroform internal dose and risk for LBW and a reduction in BW. The adjusted odds ratio for third tertile vs. first tertile chloroform internal dose of entire pregnancy was 2.17, 95% CI 1.19-3.98 for LBW; the OR per every 0.1 μg/d increase in chloroform internal dose was 1.10, 95% CI 1.01-1.19. Chloroform internal dose was associated with a slightly increased risk of SGA (OR 1.19, 95% CI 0.87-1.63 and OR 1.22, 95% CI 0.89-1.68, respectively, for second and third tertile of third trimester); the risk increased by 4% per every 0.1 μg/d increase in chloroform internal dose (OR 1.04, 95% CI 1.00-1.09).</p> <p>Conclusions</p> <p>THM internal dose in pregnancy varies substantially across individuals, and depends on both water THM levels and water use habits. Increased internal dose may affect fetal growth.</p