A multi-resolution ensemble model of three decision-tree-based algorithms to predict daily NO2 concentration in France 2005-2022.

Understanding and managing the health effects of Nitrogen Dioxide (NO2) requires high resolution spatiotemporal exposure maps. Here, we developed a multi-stage multi-resolution ensemble model that predicts daily NO2 concentration across continental France from 2005 to 2022. Innovations of this work include the computation of daily predictions at a 200 m resolution in large urban areas and the use of a spatio-temporal blocking procedure to avoid data leakage and ensure fair performance estimation. Predictions were obtained after three cascading stages of modeling: (1) predicting NO2 total column density from Ozone Monitoring Instrument satellite; (2) predicting daily NO2 concentrations at a 1 km spatial resolution using a large set of potential predictors such as predictions obtained from stage 1, land-cover and road traffic data; and (3) predicting residuals from stage 2 models at a 200 m resolution in large urban areas. The latter two stages used a generalized additive model to ensemble predictions of three decision-tree algorithms (random forest, extreme gradient boosting and categorical boosting). Cross-validated performances of our ensemble models were overall very good, with a ten-fold cross-validated R2 for the 1 km model of 0.83, and of 0.69 for the 200 m model. All three basis learners participated in the ensemble predictions to various degrees depending on time and space. In sum, our multi-stage approach was able to predict daily NO2 concentrations with a relatively low error. Ensembling the predictions maximizes the chance of obtaining accurate values if one basis learner fails in a specific area or at a particular time, by relying on the other learners. To the best of our knowledge, this is the first study aiming to predict NO2 concentrations in France with such a high spatiotemporal resolution, large spatial extent, and long temporal coverage. Exposure estimates are available to investigate NO2 health effects in epidemiological studies.

Childhood exposure to outdoor air pollution in different microenvironments and cognitive and fine motor function in children from six European cohorts.

BACKGROUND: Exposure to air pollution during childhood has been linked with adverse effects on cognitive development and motor function. However, limited research has been done on the associations of air pollution exposure in different microenvironments such as home, school, or while commuting with these outcomes. OBJECTIVE: To analyze the association between childhood air pollution exposure in different microenvironments and cognitive and fine motor function from six European birth cohorts. METHODS: We included 1301 children from six European birth cohorts aged 6-11 years from the HELIX project. Average outdoor air pollutants concentrations (NO2, PM2.5) were estimated using land use regression models for different microenvironments (home, school, and commute), for 1-year before the outcome assessment. Attentional function, cognitive flexibility, non-verbal intelligence, and fine motor function were assessed using the Attention Network Test, Trail Making Test A and B, Raven Colored Progressive Matrices test, and the Finger Tapping test, respectively. Adjusted linear regressions models were run to determine the association between each air pollutant from each microenvironment on each outcome. RESULTS: In pooled analysis we observed high correlation (rs = 0.9) between air pollution exposures levels at home and school. However, the cohort-by-cohort analysis revealed correlations ranging from low to moderate. Air pollution exposure levels while commuting were higher than at home or school. Exposure to air pollution in the different microenvironments was not associated with working memory, attentional function, non-verbal intelligence, and fine motor function. Results remained consistently null in random-effects meta-analysis. CONCLUSIONS: No association was observed between outdoor air pollution exposure in different microenvironments (home, school, commute) and cognitive and fine motor function in children from six European birth cohorts. Future research should include a more detailed exposure assessment, considering personal measurements and time spent in different microenvironments.

Placental DNA methylation signatures of prenatal air pollution exposure and potential effects on birth outcomes: an analysis of three prospective cohorts.

BACKGROUND: Pregnancy air pollution exposure (PAPE) has been linked to a wide range of adverse birth and childhood outcomes, but there is a paucity of data on its influence on the placental epigenome, which can regulate the programming of physiological functions and affect child development. This study aimed to investigate the association between prenatal air pollutant exposure concentrations and changes in placental DNA methylation patterns, and to explore the potential windows of susceptibility and sex-specific alterations. METHODS: This multi-site study used three prospective population-based mother-child cohorts: EDEN, PELAGIE, and SEPAGES, originating from four French geographical regions (Nancy, Poitiers, Brittany, and Grenoble). Pregnant women were included between 2003 and 2006 for EDEN and PELAGIE, and between 2014 and 2017 for SEPAGES. The main eligibility criteria were: being older than 18 years, having a singleton pregnancy, and living and planning to deliver in one of the maternity clinics in one of the study areas. A total of 1539 mother-child pairs were analysed, measuring placental DNA methylation using Illumina BeadChips. We used validated spatiotemporally resolved models to estimate PM2·5, PM10, and NO2 exposure over each trimester of pregnancy at the maternal residential address. We conducted a pooled adjusted epigenome-wide association study to identify differentially methylated 5'-C-phosphate-G-3' (CpG) sites and regions (assessed using the Infinium HumanMethylationEPIC BeadChip array, n=871), including sex-specific and sex-linked alterations, and independently validated our results (assessed using the Infinium HumanMethylation450 BeadChip array, n=668). FINDINGS: We identified four CpGs and 28 regions associated with PAPE in the total population, 469 CpGs and 87 regions in male infants, and 150 CpGs and 66 regions in female infants. We validated 35% of the CpGs available. More than 30% of the identified CpGs were related to one (or more) birth outcome and most significant alterations were enriched for neural development, immunity, and metabolism related genes. The 28 regions identified for both sexes overlapped with imprinted genes (four genes), and were associated with neurodevelopment (nine genes), immune system (seven genes), and metabolism (five genes). Most associations were observed for the third trimester for female infants (134 of 150 CpGs), and throughout pregnancy (281 of 469 CpGs) and the first trimester (237 of 469 CpGs) for male infants. INTERPRETATION: These findings highlight the molecular pathways through which PAPE might affect child health in a widespread and sex-specific manner, identifying the genes involved in the major physiological functions of a developing child. Further studies are needed to elucidate whether these epigenetic changes persist and affect health later in life. FUNDING: French Agency for National Research, Fondation pour la Recherche Médicale, Fondation de France, and the Plan Cancer.

Environmental and social inequities in continental France: an analysis of exposure to heat, air pollution, and lack of vegetation.

BACKGROUND: Cumulative environmental exposures and social deprivation increase health vulnerability and limit the capacity of populations to adapt to climate change. OBJECTIVE: Our study aimed at providing a fine-scale characterization of exposure to heat, air pollution, and lack of vegetation in continental France between 2000 and 2018, describing spatiotemporal trends and environmental hotspots (i.e., areas that cumulate the highest levels of overexposure), and exploring any associations with social deprivation. METHODS: The European (EDI) and French (FDep) social deprivation indices, the normalized difference vegetation index, daily ambient temperatures, particulate matter (PM2.5 and PM10), nitrogen dioxide, and ozone (O3) concentrations were estimated for 48,185 French census districts. Reference values were chosen to characterize (over-)exposure. Hotspots were defined as the areas cumulating the highest overexposure to temperature, air pollution, and lack of vegetation. Associations between heat overexposure or hotspots and social deprivation were assessed using logistic regressions. RESULTS: Overexposure to heat was higher in 2015-2018 compared with 2000-2014. Exposure to all air pollutants except for O3 decreased during the study period. In 2018, more than 79% of the urban census districts exceeded the 2021 WHO air quality guidelines. The evolution of vegetation density between 2000 and 2018 was heterogeneous across continental France. In urban areas, the most deprived census districts were at a higher risk of being hotspots (odds ratio (OR): 10.86, 95% CI: 9.87-11.98 using EDI and OR: 1.07, 95% CI: 1.04-1.11 using FDep). IMPACT STATEMENT: We studied cumulative environmental exposures and social deprivation in French census districts. The 2015-2018 period showed the highest overexposure to heat between 2000 and 2018. In 2018, the air quality did not meet the 2021 WHO guidelines in most census districts and 8.6 million people lived in environmental hotspots. Highly socially deprived urban areas had a higher risk of being in a hotspot. This study proposes for the first time, a methodology to identify hotspots of exposure to heat, air pollution, and lack of vegetation and their associations with social deprivation at a national level.

Intergenerational transmission of tobacco smoking: The role of the child's behavioral difficulties. Data from the Danish National Birth cohort (DNBC).

AIMS: This study explores the role of offspring behavioral difficulties in the intergeneration transmission of tobacco smoking. METHODS: This longitudinal cohort study is based on children born in Denmark in 1996-2003 participating in the Danish National Birth Cohort (DNBC), followed-up until 18years of age. We included mother-child pairs with complete data regarding the exposure (4 trajectories of maternal daily smoking quantity during pregnancy: low, intermediate/stable, intermediate/decreasing and high), outcome (offspring daily smoking status at 18 years) and mediator (offspring symptoms of hyperactivity-inattention at 11 years), that is 24,588 mother-child pairs. RESULTS: In our study population, during pregnancy respectively 86.2%, 6.80%, 4.08% and 2.97% mothers belonged to the low, intermediate/stable, intermediate/decreasing and high smoking trajectory groups. After controlling for covariates using propensity scores, the direct effect of maternal smoking in pregnancy on offspring smoking in adolescence was statistically significant, especially when the mother belonged to the intermediate/stable smoking trajectory group (ORIPW = 2.09, 95% CI: 1.70 - 2.61) or to the high smoking trajectory group (ORIPW = 2.08, 95% CI: 1.52 - 3.11) compared to the low smoking trajectory group. None of the indirect effects of maternal smoking in pregnancy were statistically significant, and neither were the proportions mediated. CONCLUSION: Maternal pregnancy smoking seems to have an influence on offspring smoking in early adulthood, which does not appear to be mediated by offspring behavioral difficulties. Women should be strongly encouraged to quit smoking in pregnancy to reduce both short and long-term health risks among their offspring.

Analyzing effect modifiers of the temperature-mortality relationship in the Paris region to identify social and environmental levers for more effective adaptation to heat.

Adaptation to heat is a major challenge for the Paris region (France). Based on fine-scale data for the 1,287 municipalities of the region over 2000-2017, we analyzed (time-serie design) the temperature-mortality relationship by territories (urban, suburban, rural), age (15-64 and ≥ 65) and sex, and explored how it was modified by vegetation and socio-economic indicators. Heat was associated with an increased mortality risk for all territories, age groups, sex, and mortality causes. Women aged 65 and over residing in the most deprived municipalities had a relative risk (RR) of deaths at 29.4 °C (compared to 16.6 °C) of 4.2 [3.8:4.5], while the RR was 3.4 [3.2:3.7] for women living in less deprived municipalities. Actions to reduce such sex and social inequities should be central in heat adaptation policy.

Epigenetic footprints: Investigating placental DNA methylation in the context of prenatal exposure to phenols and phthalates.

BACKGROUND: Endocrine disrupting compounds (EDCs) such as phthalates and phenols can affect placental functioning and fetal health, potentially via epigenetic modifications. We investigated the associations between pregnancy exposure to synthetic phenols and phthalates estimated from repeated urine sampling and genome wide placental DNA methylation. METHODS: The study is based on 387 women with placental DNA methylation assessed with Infinium MethylationEPIC arrays and with 7 phenols, 13 phthalates, and two non-phthalate plasticizer metabolites measured in pools of urine samples collected twice during pregnancy. We conducted an exploratory analysis on individual CpGs (EWAS) and differentially methylated regions (DMRs) as well as a candidate analysis focusing on 20 previously identified CpGs. Sex-stratified analyses were also performed. RESULTS: In the exploratory analysis, when both sexes were studied together no association was observed in the EWAS. In the sex-stratified analysis, 114 individual CpGs (68 in males, 46 in females) were differentially methylated, encompassing 74 genes (36 for males and 38 for females). We additionally identified 28 DMRs in the entire cohort, 40 for females and 42 for males. Associations were mostly positive (for DMRs: 93% positive associations in the entire cohort, 60% in the sex-stratified analysis), with the exception of several associations for bisphenols and DINCH metabolites that were negative. Biomarkers associated with most DMRs were parabens, DEHP, and DiNP metabolite concentrations. Some DMRs encompassed imprinted genes including APC (associated with parabens and DiNP metabolites), GNAS (bisphenols), ZIM2;PEG3;MIMT1 (parabens, monoethyl phthalate), and SGCE;PEG10 (parabens, DINCH metabolites). Terms related to adiposity, lipid and glucose metabolism, and cardiovascular function were among the enriched phenotypes associated with differentially methylated CpGs. The candidate analysis identified one CpG mapping to imprinted LGALS8 gene, negatively associated with ethylparaben. CONCLUSIONS: By combining improved exposure assessment and extensive placental epigenome coverage, we identified several novel genes associated with the exposure, possibly in a sex-specific manner.

Prenatal Urban Environment and Blood Pressure Trajectories From Childhood to Early Adulthood.

Background: Prenatal urban environmental exposures have been associated with blood pressure in children. The dynamic of these associations across childhood and later ages is unknown. Objectives: The purpose of this study was to assess associations of prenatal urban environmental exposures with blood pressure trajectories from childhood to early adulthood. Methods: Repeated measures of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were collected in up to 7,454 participants from a UK birth cohort. Prenatal urban exposures (n = 43) covered measures of noise, air pollution, built environment, natural spaces, traffic, meteorology, and food environment. An exposome-wide association study approach was used. Linear spline mixed-effects models were used to model associations of each exposure with trajectories of blood pressure. Replication was sought in 4 independent European cohorts (up to 9,261). Results: In discovery analyses, higher humidity was associated with a faster increase (mean yearly change in SBP for an interquartile range increase in humidity: 0.29 mm Hg/y, 95% CI: 0.20-0.39) and higher temperature with a slower increase (mean yearly change in SBP per interquartile range increase in temperature: -0.17 mm Hg/y, 95% CI: -0.28 to -0.07) in SBP in childhood. Higher levels of humidity and air pollution were associated with faster increase in DBP in childhood and slower increase in adolescence. There was little evidence of an association of other exposures with change in SBP or DBP. Results for humidity and temperature, but not for air pollution, were replicated in other cohorts. Conclusions: Replicated findings suggest that higher prenatal humidity and temperature could modulate blood pressure changes across childhood.

Early life exposure to mercury and relationships with telomere length and mitochondrial DNA content in European children.

BACKGROUND: Telomere length (TL) and mitochondrial function expressed as mitochondrial DNA copy number (mtDNAcn) are biomarkers of aging and oxidative stress and inflammation, respectively. Methylmercury (MeHg), a common pollutant in fish, induces oxidative stress. We hypothesized that elevated oxidative stress from exposure to MeHg decreases mtDNAcn and shortens TL. METHODS: Study participants are 6-11-year-old children from the HELIX multi-center birth cohort study, comprising six European countries. Prenatal and postnatal total mercury (THg) concentrations were measured in blood samples, TL and mtDNAcn were determined in child DNA. Covariates and confounders were obtained by questionnaires. Robust regression models were run, considering sociodemographic and lifestyle covariates, as well as fish consumption. Sex, ethnicity, and fish consumption interaction models were also run. RESULTS: We found longer TL with higher pre- and postnatal THg blood concentrations, even at low-level THg exposure according to the RfD proposed by the US EPA. The prenatal association showed a significant linear relationship with a 3.46 % increase in TL for each unit increased THg. The postnatal association followed an inverted U-shaped marginal non-linear relationship with 1.38 % an increase in TL for each unit increased THg until reaching a cut-point at 0.96 µg/L blood THg, from which TL attrition was observed. Higher pre- and postnatal blood THg concentrations were consistently related to longer TL among cohorts and no modification effect of fish consumption nor children's sex was observed. No association between THg exposure and mtDNAcn was found. DISCUSSION: We found evidence that THg is associated with TL but the associations seem to be time- and concentration-dependent. Further studies are needed to clarify the mechanism behind the telomere changes of THg and related health effects.

Urban environment in pregnancy and postpartum depression: An individual participant data meta-analysis of 12 European birth cohorts.

BACKGROUND: Urban environmental exposures associate with adult depression, but it is unclear whether they are associated to postpartum depression (PPD). OBJECTIVES: We investigated associations between urban environment exposures during pregnancy and PPD. METHODS: We included women with singleton deliveries to liveborn children from 12 European birth cohorts (N with minimum one exposure = 30,772, analysis N range 17,686-30,716 depending on exposure; representing 26-46 % of the 66,825 eligible women). We estimated maternal exposure during pregnancy to ambient air pollution with nitrogen dioxide (NO2) and particulate matter (PM2.5 and PM10), road traffic noise (Lden), natural spaces (Normalised Difference Vegetation Index; NDVI, proximity to major green or blue spaces) and built environment (population density, facility richness and walkability). Maternal PPD was assessed 3-18 months after birth using self-completed questionnaires. We used adjusted logistic regression models to estimate cohort-specific associations between each exposure and PPD and combined results via meta-analysis using DataSHIELD. RESULTS: Of the 30,772 women included, 3,078 (10 %) reported having PPD. Exposure to PM10 was associated with slightly increased odds of PPD (adjusted odd ratios (OR) of 1.08 [95 % Confidence Intervals (CI): 0.99, 1.17] per inter quartile range increment of PM10) whilst associations for exposure to NO2 and PM2.5 were close to null. Exposure to high levels of road traffic noise (≥65 dB vs. < 65 dB) was associated with an OR of 1.12 [CI: 0.95, 1.32]. Associations between green spaces and PPD were close to null; whilst proximity to major blue spaces was associated with increased risk of PPD (OR 1.12, 95 %CI: 1.00, 1.26). All associations between built environment and PPD were close to null. Multiple exposure models showed similar results. DISCUSSION: The study findings suggest that exposure to PM10, road traffic noise and blue spaces in pregnancy may increase PPD risk, however future studies should explore this causally.

Green spaces and respiratory, cardiometabolic, and neurodevelopmental outcomes: An individual-participant data meta-analysis of >35.000 European children.

Studies evaluating the benefits and risks of green spaces on children's health are scarce. The present study aimed to examine the associations between exposure to green spaces during pregnancy and early childhood with respiratory, cardiometabolic, and neurodevelopmental outcomes in school-age children. We performed an Individual-Participant Data (IPD) meta-analysis involving 35,000 children from ten European birth cohorts across eight countries. For each participant, we calculated residential Normalized Difference Vegetation Index (NDVI) within a 300 m buffer and the linear distance to green spaces (meters) during prenatal life and childhood. Multiple harmonized health outcomes were selected: asthma and wheezing, lung function, body mass index, diastolic and systolic blood pressure, non-verbal intelligence, internalizing and externalizing problems, and ADHD symptoms. We conducted a two-stage IPD meta-analysis and evaluated effect modification by socioeconomic status (SES) and sex. Between-study heterogeneity was assessed via random-effects meta-regression. Residential surrounding green spaces in childhood, not pregnancy, was associated with improved lung function, particularly higher FEV1 (ß = 0.06; 95 %CI: 0.03, 0.09 I2 = 4.03 %, p < 0.001) and FVC (ß = 0.07; 95 %CI: 0.04, 0.09 I2 = 0 %, p < 0.001) with a stronger association observed in females (p < 0.001). This association remained robust after multiple testing correction and did not change notably after adjusting for ambient air pollution. Increased distance to green spaces showed an association with lower FVC (ß = -0.04; 95 %CI: -0.07, -0.02, I2 = 4.8, p = 0.001), with a stronger effect in children from higher SES backgrounds (p < 0.001). No consistent associations were found between green spaces and asthma, wheezing, cardiometabolic, or neurodevelopmental outcomes, with direction of effect varying across cohorts. Wheezing and neurodevelopmental outcomes showed high between-study heterogeneity, and the age at outcome assessment was only associated with heterogeneity in internalizing problems.. This large European meta-analysis suggests that childhood exposure to green spaces may lead to better lung function. Associations with other respiratory outcomes and selected cardiometabolic and neurodevelopmental outcomes remain inconclusive.