Dietary patterns among European children and their association with adiposity-related outcomes: a multi-country study.

BACKGROUND/OBJECTIVE: Children's diets in school-age are inherently unhealthy, with few meeting dietary recommendations. Yet, little is known about similarities and differences on dietary patterns across countries and their association with obesity. We aimed to derive dietary patterns in childhood and explore their association with adiposity-related outcomes in childhood and adolescence. SUBJCTS/METHODS: This study included data from six European countries (Spain, France, UK, Greece, Lithuania and Norway) during childhood (n = 1597) and adolescence (n = 803). Using a food frequency questionnaire, we derived data-driven dietary patterns through exploratory factor analyses and calculated the Mediterranean KIDMED index. We assessed body mass index z-score (zBMI), fat mass proportion and waist-to-height ratio at both visits. Associations were estimated using generalized linear regressions, adjusted for key-confounders. RESULTS: "Meat", "Dairy", "Western", "Healthy" and "Sweets and fats" dietary patterns were derived. Norwegian children showed better diet quality, with higher consumption of fruits and vegetables, and highest "Healthy pattern" adherence, and Lithuanian children, the worst, with higher sweets consumption, and highest "Western pattern" adherence. Children with lower intake of healthy foods (vegetables, fruits, fish) tended to have higher adiposity, e.g., children with average or low "Healthy pattern" adherence (vs. high) had higher fat mass proportion in childhood (average: ß (95% CI) 1.44 (0.48; 2.39), low: 1.10 (0.09; 2.12)). Low adherence to a "Healthy pattern" (vs. high) was associated with increased adolescent zBMI, and child and adolescent waist-to-height ratio. Low "Dairy pattern" adherence (vs. high), was associated with lower zBMI and fat mass in childhood, but not in adolescence. No significant associations were seen with the KIDMED index. CONCLUSIONS: Many European children have poor diets and a low adherence to a healthy diet pattern may be of concern for adiposity-related outcomes. Assessment of children's dietary patterns can help tailor dietary advice and provide support for families aiming to prevent future excess weight gain.

Intra-breath changes in respiratory mechanics are sensitive to history of respiratory illness in preschool children: the SEPAGES cohort.

BACKGROUND: Intra-breath oscillometry has been proposed as a sensitive means of detecting airway obstruction in young children. We aimed to assess the impact of early life wheezing and lower respiratory tract illness on lung function, using both standard and intra-breath oscillometry in 3 year old children. METHODS: History of doctor-diagnosed asthma, wheezing, bronchiolitis and bronchitis and hospitalisation for respiratory problems were assessed by questionnaires in 384 population-based children. Association of respiratory history with standard and intra-breath oscillometry parameters, including resistance at 7 Hz (R7), frequency-dependence of resistance (R7 - 19), reactance at 7 Hz (X7), area of the reactance curve (AX), end-inspiratory and end-expiratory R (ReI, ReE) and X (XeI, XeE), and volume-dependence of resistance (ΔR = ReE-ReI) was estimated by linear regression adjusted on confounders. RESULTS: Among the 320 children who accepted the oscillometry test, 281 (88%) performed 3 technically acceptable and reproducible standard oscillometry measurements and 251 children also performed one intra-breath oscillometry measurement. Asthma was associated with higher ReI, ReE, ΔR and R7 and wheezing was associated with higher ΔR. Bronchiolitis was associated with higher R7 and AX and lower XeI and bronchitis with higher ReI. No statistically significant association was observed for hospitalisation. CONCLUSIONS: Our findings confirm the good success rate of oscillometry in 3-year-old children and indicate an association between a history of early-life wheezing and lower respiratory tract illness and lower lung function as assessed by both standard and intra-breath oscillometry. Our study supports the relevance of using intra-breath oscillometry parameters as sensitive outcome measures in preschool children in epidemiological cohorts.

Perinatal Exposure to Phenols and Poly- and Perfluoroalkyl Substances and Gut Microbiota in One-Year-Old Children.

The role of the gut microbiota in human health calls for a better understanding of its determinants. In particular, the possible effects of chemicals with widespread exposure other than pharmaceuticals are little known. Our aim was to characterize the sensitivity of the early-life gut microbiota to specific chemicals with possible antimicrobial action. Within the SEPAGES French couple-child cohort, we assessed 12 phenols in repeated urine samples from 356 pregnant women and their offspring and 19 poly- and perfluoroalkyl substances (PFASs) in serum from the pregnant women. We collected stool samples from the children at one year of age, in which the V3-V4 region of the 16S rRNA gene was sequenced, allowing for gut bacterial profiling. Associations of each chemical with α- and ß-diversity indices of the gut microbiota and with the relative abundance of the most abundant taxa were assessed using single-pollutant and mixture (BKMR) models. Perinatal exposure to certain parabens was associated with gut microbiota α- and ß-diversity and with Firmicutes and Proteobacteria. Suggestive associations of certain phenols with genera of the Lachnospiraceae and Enterobacteriaceae families were observed, but these were not maintained after correction for multiple testing. Parabens, which have known antimicrobial properties, might disrupt the child gut microbiota, but larger studies are required to confirm these findings.

Chemical exposome and children health: Identification of dose-response relationships from meta-analyses and epidemiological studies.

BACKGROUND: Health impact assessment studies quantifying the impact of the chemical exposome on children's health generally consider a small fraction of the exposome. Synthetizing available dose-response relationships is an essential step to fill this gap. We reviewed the literature for dose-response relationships relating the chemical exposome with children health. METHOD: We focused on 78 substance-outcome pairs for which the level of evidence had previously been classified as 'likely' or 'very likely'. We searched for dose-response relationships for these pairs from meta-analyses and, if none was available, from single epidemiological studies, from which we conducted meta-analyses whenever possible. RESULTS: We identified dose-response relationships for 50 of the 78 prioritized substance-outcome pairs (64%). Dose-response relationships stemmed from meta-analyses for 21 pairs, from de novo meta-analyses for 1 pair and single studies for 28 pairs. Dose-response relationships were available for tobacco (fetal and infant death, congenital heart defects, birth outcomes, orofacial clefts, respiratory health), lead (asthma, cognition, delayed puberty onset and iron deficiency anaemia), polychlorobiphenyls (PCBs) (cognition, respiratory infections and birth outcomes), bisphenol A (cognition), hexachlorobenzene (HCB) (respiratory health), Polybrominated diphenyl ethers (neurodevelopment), DDT (hypospadias, cryptorchidism, miscarriage), pesticides (neurodevelopment), methylmercury (cognition), PFAS (immune system, birth weight, behavior, miscarriage), arsenic (cognition, birth weight, death, respiratory health), cadmium (cognition, birth weight), manganese (behavior), sodium (blood pressure) and thallium (birth weight). For 28 of the 78 substance-outcome pairs (36%), no dose-response relationship was available from epidemiological studies in children. CONCLUSIONS: We identified dose-response relationships for 50 substance-outcome pairs, corresponding to 20 chemicals and 17 health outcomes. These can be used to perform more comprehensive quantitative health impact assessment of the exposome on child health. We also identified 28 substance-outcome pairs corresponding to 'likely' or 'very likely' effects for which research generating dose-response functions in children would be relevant.

Urban environment and children's health: An umbrella review of exposure response functions for health impact assessment.

BACKGROUND: Urban settlements have become the main living environment. Understanding the impact of urban exposures on human health has therefore become a growing area of research. Up-to-date knowledge about the influence of urban exposures on pregnant women's and children's health is especially relevant, as they are particularly vulnerable to certain external influences. AIM: This review aims to provide a synthesis of systematic reviews with meta-analyses reporting on an association between the urban environmental risk factors and health outcomes in pregnancy, infants, children and adolescents. METHODS: We conducted an umbrella review, methodically analysing systematic reviews with meta-analyses, published between January 2016 and December 2022 in PubMed or Scopus. Adhering to the PRISMA checklist, we searched for free text using Medical Subject Headings (MeSH) terms related to air pollution, noise pollution, temperature, green space exposure, built and food environment, health outcomes, children (aged 0-18 years), pregnancy and systematic reviews with meta-analyses. We extracted key characteristics of each included study and assessed the quality of the included studies via the R-AMSTAR 2 tool. RESULTS: Twenty-four studies met our inclusion criteria and identified 104 associations including 15 exposures and 60 health outcomes. The most frequently studied associations were related to air pollutants, followed by the built and food environment and noise. Birth outcomes (including low birth weight, pre-term birth or stillbirth) were the most commonly affected health outcomes, followed by respiratory outcomes such as asthma or respiratory infections. A total of 45 exposure-response function were reported to be statistically significant, including 10 exposures and 23 health effects. CONCLUSION: This umbrella review provides an overview of the evidence and availability of exposure response functions between selected urban exposures and child health outcomes. This helps to identify research gaps and to build the basis for health impact assessment.

Associations between combined urban and lifestyle factors and respiratory health in European children.

INTRODUCTION: Previous studies identified some environmental and lifestyle factors independently associated with children respiratory health, but few focused on exposure mixture effects. This study aimed at identifying, in pregnancy and in childhood, combined urban and lifestyle environment profiles associated with respiratory health in children. METHODS: This study is based on the European Human Early-Life Exposome (HELIX) project, combining six birth cohorts. Associations between profiles of pregnancy (38 exposures) and childhood (84 exposures) urban and lifestyle factors, identified by clustering analysis, and respiratory health were estimated by regression models adjusted for confounders. RESULTS: Among the 1033 included children (mean ± standard-deviation (SD) age: 8.2 ± 1.6 years old, 47% girls) the mean ± SD forced expiratory volume in 1s (FEV1) and forced vital capacity (FVC) were 99 ± 13% and 101 ± 14%, respectively, and 12%, 12% and 24% reported ever-asthma, wheezing and rhinitis, respectively. Four profiles of pregnancy exposures and four profiles of childhood exposures were identified. Compared to the reference childhood exposure profile (low exposures), two exposure profiles were associated with lower levels of FEV1. One profile was characterized by few natural spaces in the surroundings and high exposure to the built environment and road traffic. The second profile was characterized by high exposure to meteorological factors and low levels of all other exposures and was also associated with an increased risk of ever-asthma and wheezing. A pregnancy exposure profile characterized by high exposure levels to all risk factors, but a healthy maternal lifestyle, was associated with a lower risk of wheezing and rhinitis in children, compared to the reference pregnancy profile (low exposures). CONCLUSION: This comprehensive approach revealed pregnancy and childhood profiles of urban and lifestyle exposures associated with lung function and/or respiratory conditions in children. Our findings highlight the need to pursue the study of combined exposures to improve prevention strategies for multifactorial diseases such as asthma.

The methodology of quantitative risk assessment studies.

Once an external factor has been deemed likely to influence human health and a dose response function is available, an assessment of its health impact or that of policies aimed at influencing this and possibly other factors in a specific population can be obtained through a quantitative risk assessment, or health impact assessment (HIA) study. The health impact is usually expressed as a number of disease cases or disability-adjusted life-years (DALYs) attributable to or expected from the exposure or policy. We review the methodology of quantitative risk assessment studies based on human data. The main steps of such studies include definition of counterfactual scenarios related to the exposure or policy, exposure(s) assessment, quantification of risks (usually relying on literature-based dose response functions), possibly economic assessment, followed by uncertainty analyses. We discuss issues and make recommendations relative to the accuracy and geographic scale at which factors are assessed, which can strongly influence the study results. If several factors are considered simultaneously, then correlation, mutual influences and possibly synergy between them should be taken into account. Gaps or issues in the methodology of quantitative risk assessment studies include 1) proposing a formal approach to the quantitative handling of the level of evidence regarding each exposure-health pair (essential to consider emerging factors); 2) contrasting risk assessment based on human dose-response functions with that relying on toxicological data; 3) clarification of terminology of health impact assessment and human-based risk assessment studies, which are actually very similar, and 4) other technical issues related to the simultaneous consideration of several factors, in particular when they are causally linked.

Urinary metabolite quantitative trait loci in children and their interaction with dietary factors.

Human metabolism is influenced by genetic and environmental factors. Previous studies have identified over 23 loci associated with more than 26 urine metabolites levels in adults, which are known as urinary metabolite quantitative trait loci (metabQTLs). The aim of the present study is the identification for the first time of urinary metabQTLs in children and their interaction with dietary patterns. Association between genome-wide genotyping data and 44 urine metabolite levels measured by proton nuclear magnetic resonance spectroscopy was tested in 996 children from the Human Early Life Exposome project. Twelve statistically significant urine metabQTLs were identified, involving 11 unique loci and 10 different metabolites. Comparison with previous findings in adults revealed that six metabQTLs were already known, and one had been described in serum and three were involved the same locus as other reported metabQTLs but had different urinary metabolites. The remaining two metabQTLs represent novel urine metabolite-locus associations, which are reported for the first time in this study [single nucleotide polymorphism (SNP) rs12575496 for taurine, and the missense SNP rs2274870 for 3-hydroxyisobutyrate]. Moreover, it was found that urinary taurine levels were affected by the combined action of genetic variation and dietary patterns of meat intake as well as by the interaction of this SNP with beverage intake dietary patterns. Overall, we identified 12 urinary metabQTLs in children, including two novel associations. While a substantial part of the identified loci affected urinary metabolite levels both in children and in adults, the metabQTL for taurine seemed to be specific to children and interacted with dietary patterns.

Prenatal environmental exposures associated with sex differences in childhood obesity and neurodevelopment.

BACKGROUND: Obesity and neurodevelopmental delay are complex traits that often co-occur and differ between boys and girls. Prenatal exposures are believed to influence children's obesity, but it is unknown whether exposures of pregnant mothers can confer a different risk of obesity between sexes, and whether they can affect neurodevelopment. METHODS: We analyzed data from 1044 children from the HELIX project, comprising 93 exposures during pregnancy, and clinical, neuropsychological, and methylation data during childhood (5-11 years). Using exposome-wide interaction analyses, we identified prenatal exposures with the highest sexual dimorphism in obesity risk, which were used to create a multiexposure profile. We applied causal random forest to classify individuals into two environments: E1 and E0. E1 consists of a combination of exposure levels where girls have significantly less risk of obesity than boys, as compared to E0, which consists of the remaining combination of exposure levels. We investigated whether the association between sex and neurodevelopmental delay also differed between E0 and E1. We used methylation data to perform an epigenome-wide association study between the environments to see the effect of belonging to E1 or E0 at the molecular level. RESULTS: We observed that E1 was defined by the combination of low dairy consumption, non-smokers' cotinine levels in blood, low facility richness, and the presence of green spaces during pregnancy (ORinteraction = 0.070, P = 2.59 × 10-5). E1 was also associated with a lower risk of neurodevelopmental delay in girls, based on neuropsychological tests of non-verbal intelligence (ORinteraction = 0.42, P = 0.047) and working memory (ORinteraction = 0.31, P = 0.02). In line with this, several neurodevelopmental functions were enriched in significant differentially methylated probes between E1 and E0. CONCLUSIONS: The risk of obesity can be different for boys and girls in certain prenatal environments. We identified an environment combining four exposure levels that protect girls from obesity and neurodevelopment delay. The combination of single exposures into multiexposure profiles using causal inference can help determine populations at risk.

Statistical Approaches to Study Exposome-Health Associations in the Context of Repeated Exposure Data: A Simulation Study.

The exposome concept aims to consider all environmental stressors simultaneously. The dimension of the data and the correlation that may exist between exposures lead to various statistical challenges. Some methodological studies have provided insight regarding the efficiency of specific modeling approaches in the context of exposome data assessed once for each subject. However, few studies have considered the situation in which environmental exposures are assessed repeatedly. Here, we conduct a simulation study to compare the performance of statistical approaches to assess exposome-health associations in the context of multiple exposure variables. Different scenarios were tested, assuming different types and numbers of exposure-outcome causal relationships. An application study using real data collected within the INMA mother-child cohort (Spain) is also presented. In the simulation experiment, assessed methods showed varying performance across scenarios, making it challenging to recommend a one-size-fits-all strategy. Generally, methods such as sparse partial least-squares and the deletion-substitution-addition algorithm tended to outperform the other tested methods (ExWAS, Elastic-Net, DLNM, or sNPLS). Notably, as the number of true predictors increased, the performance of all methods declined. The absence of a clearly superior approach underscores the additional challenges posed by repeated exposome data, such as the presence of more complex correlation structures and interdependencies between variables, and highlights that careful consideration is essential when selecting the appropriate statistical method. In this regard, we provide recommendations based on the expected scenario. Given the heightened risk of reporting false positive or negative associations when applying these techniques to repeated exposome data, we advise interpreting the results with caution, particularly in compromised contexts such as those with a limited sample size.

Longitudinal Associations between Prenatal Exposure to Phthalates and Steroid Hormones in Maternal Hair Samples from the SEPAGES Cohort.

We assessed phthalate-hormone associations in 382 pregnant women of the new-generation SEPAGES cohort (2014-2017, France) using improved exposure and outcome assessments. Metabolites from seven phthalate compounds and the replacement di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH) were measured in within-subject pools of repeated urine samples collected at the second and third pregnancy trimesters (≈21 samples/trimester). Metabolites from five steroid hormones were measured in maternal hair samples collected at delivery, reflecting cumulative levels over the previous weeks to months. Adjusted linear regression and Bayesian weighted quantile sum (BWQS) mixture models were performed. Each doubling in third-trimester urinary mono-benzyl phthalate (MBzP) concentrations was associated with an average increase of 13.3% (95% CI: 2.65, 24.9) for ∑cortisol, 10.0% (95% CI: 0.26, 20.7) for ∑cortisone, 17.3% (95% CI: 1.67, 35.4) for 11-dehydrocorticosterone, and 16.2% (95% CI: 2.20, 32.1) for testosterone, together with a suggestive 10.5% (95% CI: -1.57, 24.1) increase in progesterone levels. Each doubling in second-trimester urinary di-isononyl phthalate (DiNP) concentrations was inversely associated with testosterone levels (-11.6%; 95% CI: -21.6, -0.31). For most hormones, a nonsignificant trend toward a positive phthalate mixture effect was observed in the third but not in the second trimester. Our study showed that exposure to some phthalate metabolites, especially MBzP, may affect adrenal and reproductive hormone levels during pregnancy.

Cytokines as mediators of the associations of prenatal exposure to phenols, parabens, and phthalates with internalizing behaviours at age 3 in boys: A mixture exposure and mediation approach.

Childhood internalizing disorders refer to inwardly focused negative behaviours such as anxiety, depression, and somatic complains. Interactions between psychosocial, genetic, and environmental risk factors adversely impact neurodevelopment and can contribute to internalizing disorders. While prenatal exposure to single endocrine disruptors (EDs) is associated with internalizing behaviours in infants, the associations with prenatal exposure to EDs in mixture remain poorly addressed. In addition, the biological mediators of EDs in mixture effects on internalizing behaviours remain unexplored. EDs do not only interfere with endocrine function, but also with immune function and inflammatory processes. Based on this body of evidence, we hypothetised that inflammation at birth is a plausible biological pathway through which prenatal exposure to EDs in mixture could operate to influence offspring internalizing behaviours. Based on the EDEN birth cohort, we investigated whether exposure to a mixture of EDs increased the odds of internalizing disorders in 459 boy infants at age 3, and whether the pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α measured at birth were mediators of this effect. To determine both the joint and individual associations of prenatal exposure to EDs with infant internalizing behaviours and the possible mediating role of cytokines, we used the counterfactual hierarchical Bayesian Kernel Machine Regression (BKMR) regression-causal mediation analysis. We show that prenatal exposure to a complex mixture of EDs has limited effects on internalizing behaviours in boys at age 3. We also show that IL-1ß, IL-6, and TNF-α are unlikely mediators or suppressors of ED mixture effects on internalizing behaviours in boys at age 3. Further studies on larger cohorts are warranted to refine the deleterious effects of EDs in mixtures on internalizing behaviours and identify possible mediating pathways.

Effects of early exposure to phthalates on cognitive development and visual behavior at 24 months.

BACKGROUND AND OBJECTIVES: Studies focusing on the neurodevelopmental effects of phthalates seldom consider exposure during infancy, a critical period for brain development. Most rely on parent-completed questionnaires to assess child neurodevelopment, which may be subject to reporting error. We studied the associations between prenatal and infancy exposure to phthalates and objective measures of neurodevelopment at the age of two. METHODS: We relied on 151 mother-child pairs from the SEPAGES mother-child cohort. Women were asked to collect three spot urine samples per day over seven consecutive days during the second (median: 18.0 gestational weeks) and third (median: 34.2 gestational weeks) trimesters of pregnancy. They then collected one urine sample per day over seven consecutive days from their infants around the age of 12 months. Metabolites of phthalates and non-phthalate plasticizers were measured in within-subject and within-period pools of repeated urine samples. Eye tracking tasks were performed at two years allowing to compute four indicators linked with cognitive development and visual behavior: mean fixation duration, novelty preference, percent time spent looking at the eyes and mean reaction time. RESULTS: Pre-natal exposure to monobenzyl phthalate at the second and third trimesters was associated with shorter fixation durations. In models allowing for interaction with child sex, these associations were only observed among girls. Exposure to di(2-ethylhexyl) phthalate at the third but not the second trimester was associated with increased time spent looking at a novel face and eyes. We observed faster reaction times and decreased time spent looking at the eyes in a face recognition task, with increased post-natal exposure to monoethyl, mono-iso-butyl and mono-n-butyl phthalates. DISCUSSION: Relying on improved exposure assessment, we highlighted associations of pre- and post-natal exposure to phthalates with indicators derived from eye tracking tasks, mainly in girls. Some of these indicators have been affected in individuals with neurodevelopmental disorders.

Pre-natal exposure to NO2 and PM2.5 and newborn lung function: An approach based on repeated personal exposure measurements.

CONTEXT: While strong evidence supports adverse effects of pre-natal air pollution on child's lung function, previous studies rarely considered fine particulate matter (PM2.5) or the potential role of offspring sex and no study examined the effects of pre-natal PM2.5 on the lung function of the newborn. AIM: We examined overall and sex-specific associations of personal pre-natal exposure to PM2.5 and nitrogen (NO2) with newborn lung function measurements. METHODS: This study relied on 391 mother-child pairs from the French SEPAGES cohort. PM2.5 and NO2 exposure was estimated by the average concentration of pollutants measured by sensors carried by the pregnant women during repeated periods of one week. Lung function was assessed with tidal breathing analysis (TBFVL) and nitrogen multiple breath washout (N2MBW) test, performed at 7 weeks. Associations between pre-natal exposure to air pollutants and lung function indicators were estimated by linear regression models adjusted for potential confounders, and then stratified by sex. RESULTS: Mean exposure to NO2 and PM2.5 during pregnancy was 20.2 µg/m3 and 14.3 µg/m3, respectively. A 10 µg/m3 increase in PM2.5 maternal personal exposure during pregnancy was associated with an adjusted 2.5 ml (2.3%) decrease in the functional residual capacity of the newborn (p-value = 0.11). In females, functional residual capacity was decreased by 5.2 ml (5.0%) (p = 0.02) and tidal volume by 1.6 ml (p = 0.08) for each 10 µg/m3 increase in PM2.5. No association was found between maternal NO2 exposure and newborns lung function. CONCLUSIONS: Personal pre-natal PM2.5 exposure was associated with lower lung volumes in female newborns, but not in males. Our results provide evidence that pulmonary effects of air pollution exposure can be initiated in utero. These findings have long term implications for respiratory health and may provide insights into the underlying mechanisms of PM2.5 effects.

Prenatal and childhood exposure to ambient air pollution and cognitive function in school-age children: Examining sensitive windows and sex-specific associations.

BACKGROUND: Combined effect of both prenatal and early postnatal exposure to ambient air pollution on child cognition has rarely been investigated and periods of sensitivity are unknown. This study explores the temporal relationship between pre- and postnatal exposure to PM10, PM2.5, NO2 and child cognitive function. METHODS: Using validated spatiotemporally resolved exposure models, pre- and postnatal daily PM2.5, PM10 (satellite based, 1 km resolution) and NO2 (chemistry-transport model, 4 km resolution) concentrations at the mother's residence were estimated for 1271 mother-child pairs from the French EDEN and PELAGIE cohorts. Scores representative of children's General, Verbal and Non-Verbal abilities at 5-6 years were constructed based on subscale scores from the WPPSI-III, WISC-IV or NEPSY-II batteries, using confirmatory factor analysis (CFA). Associations of both prenatal (first 35 gestational weeks) and postnatal (60 months after birth) exposure to air pollutants with child cognition were explored using Distributed Lag Non-linear Models adjusted for confounders. RESULTS: Increased maternal exposure to PM10, PM2.5 and NO2, during sensitive windows comprised between the 15th and the 33rd gestational weeks, was associated with lower males' General and Non-verbal abilities. Higher postnatal exposure to PM2.5 between the 35th and 52nd month of life was associated with lower males' General, Verbal and Non-verbal abilities. Some protective associations were punctually observed for the very first gestational weeks or months of life for both males and females and the different pollutants and cognitive scores. DISCUSSION: These results suggest poorer cognitive function at 5-6 years among males following increased maternal exposure to PM10, PM2.5 and NO2 during mid-pregnancy and child exposure to PM2.5 around 3-4 years. Apparent protective associations observed are unlikely to be causal and might be due to live birth selection bias, chance finding or residual confounding.

In utero exposure to poly- and perfluoroalkyl substances and children respiratory health in the three first years of life.

BACKGROUND: Poly- and perfluoroalkyl substances (PFAS) are used in a wide range of products. Experimental studies suggested impaired lung development and pro-inflammatory response following exposure to some PFAS. We aimed to assess the associations between prenatal exposure to PFAS and children respiratory health. METHODS: The study is based on 433 mother-child pairs. 26 PFAS were measured in maternal serum collected during pregnancy. Lung function parameters were measured at 2 months using tidal breathing flow-volume loops and multiple-breath nitrogen washout and at 36 months using oscillometry. Incidence of respiratory health diseases (asthma, wheeze, bronchitis, bronchiolitis) in the first 36 months of life was assessed by repeated questionnaires. A cluster-based analysis was applied to identify prenatal PFAS exposure patterns. Adjusted linear and logistic regressions were performed to assess the associations between PFAS exposure patterns as well as individual PFAS, and each respiratory health parameter. RESULTS: We excluded 13 PFAS due to low quantification (<5%). Relying on the 13 remaining PFAS, we identified three exposure clusters, characterized by low (N = 163), medium (N = 236) and high (N = 51) pregnancy PFAS concentrations. Compared to children belonging to the low exposure group, children in the moderate exposure group had higher reactance at 7 Hz (X7) and lower frequency dependence of resistance between 7 Hz and 19 Hz (R7-19) at 36 months, suggesting better lung function. No association of any exposure metric was detected with respiratory diseases in the first 3 years of life. CONCLUSIONS: Our study relying on both mixture and uni-pollutant analyses, does not provide evidence for a deleterious effect of prenatal PFAS exposure on respiratory health at an early age.

Environmental exposures in early-life and general health in childhood.

BACKGROUND: Early-life environmental exposures are suspected to be involved in the development of chronic diseases later in life. Most studies conducted so far considered single or few exposures and single-health parameter. Our study aimed to identify a childhood general health score and assess its association with a wide range of pre- and post-natal environmental exposures. METHODS: The analysis is based on 870 children (6-12 years) from six European birth cohorts participating in the Human Early-Life Exposome project. A total of 53 prenatal and 105 childhood environmental factors were considered, including lifestyle, social, urban and chemical exposures. We built a general health score by averaging three sub-scores (cardiometabolic, respiratory/allergy and mental) built from 15 health parameters. By construct, a child with a low score has a low general health status. Penalized multivariable regression through Least Absolute Shrinkage and Selection Operator (LASSO) was fitted in order to identify exposures associated with the general health score. FINDINGS: The results of LASSO show that a lower general health score was associated with maternal passive and active smoking during pregnancy and postnatal exposure to methylparaben, copper, indoor air pollutants, high intake of caffeinated drinks and few contacts with friends and family. Higher child's general health score was associated with prenatal exposure to a bluespace near residency and postnatal exposures to pets, cobalt, high intakes of vegetables and more physical activity. Against our hypotheses, postnatal exposure to organochlorine compounds and perfluorooctanoate were associated with a higher child's general health score. CONCLUSION: By using a general health score summarizing the child cardiometabolic, respiratory/allergy and mental health, this study reinforced previously suspected environmental factors associated with various child health parameters (e.g. tobacco, air pollutants) and identified new factors (e.g. pets, bluespace) warranting further investigations.

Association of Daily Temperature With Suicide Mortality: A Comparison With Other Causes of Death and Characterization of Possible Attenuation Across 5 Decades.

Suicide is one of the leading causes of death in young adults in many Western countries. We examined the short-term association of temperature with cause-specific mortality, comparing suicide with other causes of death and describing possible attenuation of associations with temperature across decades. We considered all deaths that occurred in France between 1968 and 2016. For each cause of death, we conducted a 2-stage meta-analysis of associations with daily temperature. We stratified the association across time periods. A total of 502,017 deaths by suicide were recorded over 49 years. Temperature was monotonically associated with suicide mortality. The strongest association was found at lag 0 days. The relative risk of suicide mortality at the 99th (compared with the 1st) temperature percentile was 1.54 (95% confidence interval, 1.46, 1.63). Among all causes of death, suicide was the only cause displaying a monotonic trend with temperature and ranked seventh for heat-related mortality; 2 other causes of death implying the nervous system ranked third and fourth. Associations with temperature attenuated between the 1968-1984 and 1985-2000 periods for all-cause mortality and suicide mortality, without clear further attenuation in the 2001-2016 period. The robust short-term monotonic association between temperature and suicide risk could be considered in heat effects- and suicide-related prevention campaigns.

Maternal blood pressure associates with placental DNA methylation both directly and through alterations in cell-type composition.

BACKGROUND: Maternal blood pressure levels reflect cardiovascular adaptation to pregnancy and proper maternal-fetal exchanges through the placenta and are very sensitive to numerous environmental stressors. Maternal hypertension during pregnancy has been associated with impaired placental functions and with an increased risk for children to suffer from cardiovascular and respiratory diseases later on. Investigating changes in placental DNA methylation levels and cell-type composition in association with maternal blood pressure could help elucidate its relationships with placental and fetal development. METHODS: Taking advantage of a large cohort of 666 participants, we investigated the association between epigenome-wide DNA methylation patterns in the placenta, measured using the Infinium HumanMethylation450 BeadChip, placental cell-type composition, estimated in silico, and repeated measurements of maternal steady and pulsatile blood pressure indicators during pregnancy. RESULTS: At the site-specific level, no significant association was found between maternal blood pressure and DNA methylation levels after correction for multiple testing (false discovery rate < 0.05), but 5 out of 24 previously found CpG associations were replicated (p-value < 0.05). At the regional level, our analyses highlighted 64 differentially methylated regions significantly associated with at least one blood pressure component, including 35 regions associated with mean arterial pressure levels during late pregnancy. These regions were found enriched for genes implicated in lung development and diseases. Further mediation analyses show that a significant part of the association between steady blood pressure-but not pulsatile pressure-and placental methylation can be explained by alterations in placental cell-type composition. In particular, elevated blood pressure levels are associated with a decrease in the ratio between mesenchymal stromal cells and syncytiotrophoblasts, even in the absence of preeclampsia. CONCLUSIONS: This study provides the first evidence that the association between maternal steady blood pressure during pregnancy and placental DNA methylation is both direct and partly explained by changes in cell-type composition. These results could hint at molecular mechanisms linking maternal hypertension to lung development and early origins of childhood respiratory problems and at the importance of controlling maternal blood pressure during pregnancy.

Pregnancy Exposure to Phenols and Anthropometric Measures in Gestation and at Birth.

BACKGROUND: Some synthetic phenols alter pathways involved in fetal development. Despite their high within-subject temporal variability, earlier studies relied on spot urine samples to assess pregnancy exposure. In this study, we examined associations between prenatal phenol exposure and fetal growth. METHODS: We measured concentrations of two bisphenols, four parabens, benzophenone-3, and triclosan in 478 pregnant women in two weekly pools of 21 samples each, collected at 18 and 34 gestational weeks. We used adjusted linear regressions to study associations between phenol concentrations and growth outcomes assessed twice during pregnancy and at birth. RESULTS: Benzophenone-3 was positively associated with all ultrasound growth parameters in at least one time point, in males but not females. In females, butylparaben was negatively associated with third-trimester abdominal circumference and weight at birth. We observed isolated associations for triclosan (negative) and for methylparaben and bisphenol S (positive) and late pregnancy fetal growth. CONCLUSIONS: Our results suggest associations between prenatal exposure to phenols and fetal growth. Benzophenone-3 was the exposure most consistently (positively) associated across all growth parameters.