Nitrogen dioxide exposure, attentional function, and working memory in children from 4 to 8 years: Periods of susceptibility from pregnancy to childhood.

BACKGROUND: Air pollution exposure during pregnancy and childhood has been linked to executive function impairment in children, however, very few studies have assessed these two exposure periods jointly to identify susceptible periods of exposure. We sought to identify potential periods of susceptibility of nitrogen dioxide (NO2) exposure from conception to childhood on attentional function and working memory in school-aged children. METHODS: Within the Spanish INMA Project, we estimated residential daily NO2 exposures during pregnancy and up to 6 years of childhood using land use regression models (n = 1,703). We assessed attentional function at 4-6 years and 6-8 years, using the Conners Kiddie Continuous Performance Test and the Attention Network Test, respectively, and working memory at 6-8 years, using the N-back task. We used distributed lag non-linear models to assess the periods of susceptibility of each outcome, adjusting for potential confounders and correcting for multiple testing. We also stratified all models by sex. RESULTS: Higher exposure to NO2 between 1.3 and 1.6 years of age was associated with higher hit reaction time standard error (HRT-SE) (0.14 ms (95 % CI 0.05; 0.22) per 10 µg/m3 increase in NO2) and between 1.5 and 2.2 years of age with more omission errors (1.02 (95 % CI 1.01; 1.03) of the attentional function test at 4-6 years. Higher exposure to NO2 between 0.3 and 2.2 years was associated with higher HRT-SE (10.61 ms (95 % CI 3.46; 17.75) at 6-8 years only in boys. We found no associations between exposure to NO2 and working memory at 6-8 years. CONCLUSION: Our findings suggest that NO2 exposure during the first two years of life is associated with poorer attentional function in children from 4 to 8 years of age, especially in boys. These findings highlight the importance of exploring long-term effects of traffic-related air pollution exposure in older age groups.

Urban environment and health: a cross-sectional multiregional project based on population health surveys in Spain (DAS-EP project) - study protocol.

INTRODUCTION: The European Environment Agency estimates that 75% of the European population lives in cities. Despite the many advantages of city life, the risks and challenges to health arising from urbanisation need to be addressed in order to tackle the growing burden of disease and health inequalities in cities. This study, Urban environment and health: a cross-sectional multiregional project based on population health surveys in Spain (DAS-EP project), aims to investigate the complex association between the urban environmental exposures (UrbEEs) and health. METHODS AND ANALYSIS: DAS-EP is a Spanish multiregional cross-sectional project that combines population health surveys (PHS) and geographical information systems (GIS) allowing to collect rich individual-level data from 17 000 adult citizens participating in the PHS conducted in the autonomous regions of the Basque Country, Andalusia, and the Valencian Community, and the city of Barcelona in the years 2021-2023. This study focuses on the population living in cities or metropolitan areas with more than 100 000 inhabitants. UrbEEs are described by objective estimates at participants' home addresses by GIS, and subjective indicators present in PHS. The health outcomes included in the PHS and selected for this study are self-perceived health (general and mental), prevalence of chronic mental disorders, health-related quality of life, consumption of medication for common mental disorders and sleep quality. We aim to further understand the direct and indirect effects between UrbEEs and health, as well as to estimate the impact at the population level, taking respondents' sociodemographic and socioeconomic characteristics, and lifestyle into consideration. ETHICS AND DISSEMINATION: The study was approved by the regional Research Ethics Committee of the Basque Country (Ethics Committee for Research Involving Medicinal Products in the Basque Country; PI2022138), Andalusia (Biomedical Research Ethics Committee of the Province of Granada; 2078-N-22), Barcelona (CEIC-PSMar; 2022/10667) and the Valencian Community (Ethics Committee for Clinical Research of the Directorate General of Public Health and Center for Advanced Research in Public Health; 20221125/04). The results will be communicated to the general population, health professionals, and institutions through conferences, reports and scientific articles.

Urban environment during pregnancy and childhood and white matter microstructure in preadolescence in two European birth cohorts.

Growing evidence suggests that urban environment may influence cognition and behavior in children, but the underlying pollutant and neurobiological mechanisms are unclear. We evaluated the association of built environment and urban natural space indicators during pregnancy and childhood with brain white matter microstructure in preadolescents, and examined the potential mediating role of air pollution and road-traffic noise. We used data of the Generation R Study, a population-based birth cohort in Rotterdam, the Netherlands (n = 2725; 2002-2006) for the primary analyses. Replication of the main findings was attempted on an independent neuroimaging dataset from the PELAGIE birth cohort, France (n = 95; 2002-2006). We assessed exposures to 12 built environment and 4 urban natural spaces indicators from conception up to 9 years of age. We computed 2 white matter microstructure outcomes (i.e., average of fractional anisotropy (FA) and mean diffusivity (MD) from 12 white matte tracts) from diffusion tensor imaging data. Greater distance to the nearest major green space during pregnancy was associated with higher whole-brain FA (0.001 (95%CI 0.000; 0.002) per 7 m increase), and higher land use diversity during childhood was associated with lower whole-brain MD (-0.001 (95%CI -0.002; -0.000) per 0.12-point increase), with no evidence of mediation by air pollution nor road-traffic noise. Higher percentage of transport and lower surrounding greenness during pregnancy were associated with lower whole-brain FA, and road-traffic noise mediated 19% and 52% of these associations, respectively. We found estimates in the same direction in the PELAGIE cohort, although confidence intervals were larger and included the null. This study suggests an association between urban environment and white matter microstructure, mainly through road-traffic noise, indicating that greater access to green space nearby might promote white matter development.

DNA methylation at birth and fine motor ability in childhood: an epigenome-wide association study with replication.

Lower fine motor performance in childhood has been associated with poorer cognitive development and neurodevelopmental conditions such as autism spectrum disorder, yet, biological underpinnings remain unclear. DNA methylation (DNAm), an essential process for healthy neurodevelopment, is a key molecular system of interest. In this study, we conducted the first epigenome-wide association study of neonatal DNAm with childhood fine motor ability and further examined the replicability of epigenetic markers in an independent cohort. The discovery study was embedded in Generation R, a large population-based prospective cohort, including a subsample of 924 ~ 1026 European-ancestry singletons with available data on DNAm in cord blood and fine motor ability at a mean (SD) age of 9.8 (0.4) years. Fine motor ability was measured using a finger-tapping test (3 subtests including left-, right-hand and bimanual), one of the most frequently used neuropsychological instruments of fine motor function. The replication study comprised 326 children with a mean (SD) age of 6.8 (0.4) years from an independent cohort, the INfancia Medio Ambiente (INMA) study. Four CpG sites at birth were prospectively associated with childhood fine motor ability after genome-wide correction. Of these, one CpG (cg07783800 in GNG4) was replicated in INMA, showing that lower levels of methylation at this site were associated with lower fine motor performance in both cohorts. GNG4 is highly expressed in the brain and has been implicated in cognitive decline. Our findings support a prospective, reproducible association between DNAm at birth and fine motor ability in childhood, pointing to GNG4 methylation at birth as a potential biomarker of fine motor ability.

Air pollution exposure during pregnancy and childhood, APOE ε4 status and Alzheimer polygenic risk score, and brain structural morphology in preadolescents.

BACKGROUND: Air pollution exposure is associated with impaired neurodevelopment, altered structural brain morphology in children, and neurodegenerative disorders. Differential susceptibility to air pollution may be influenced by genetic features. OBJECTIVES: To evaluate whether the apolipoprotein E (APOE) genotype or the polygenic risk score (PRS) for Alzheimer's Disease (AD) modify the association between air pollution exposure during pregnancy and childhood and structural brain morphology in preadolescents. METHODS: We included 1186 children from the Generation R Study. Concentrations of fourteen air pollutants were calculated at participants' home addresses during pregnancy and childhood using land-use-regression models. Structural brain images were collected at age 9-12 years to assess cortical and subcortical brain volumes. APOE status and PRS for AD were examined as genetic modifiers. Linear regression models were used to conduct single-pollutant and multi-pollutant (using the Deletion/Substitution/Addition algorithm) analyses with a two-way interaction between air pollution and each genetic modifier. RESULTS: Higher pregnancy coarse particulate matter (PMcoarse) and childhood polycyclic aromatic hydrocarbons exposure was differentially associated with larger cerebral white matter volume in APOE ε4 carriers compared to non-carriers (29,485 mm3 (95% CI 6,189; 52,781) and 18,663 mm3 (469; 36,856), respectively). Higher pregnancy PMcoarse exposure was differentially associated with larger cortical grey matter volume in children with higher compared to lower PRS for AD (19436 mm3 (825, 38,046)). DISCUSSION: APOE status and PRS for AD possibly modify the association between air pollution exposure and brain structural morphology in preadolescents. Higher air pollution exposure is associated with larger cortical volumes in APOE ε4 carriers and children with a high PRS for AD. This is in line with typical brain development, suggesting an antagonistic pleiotropic effect of these genetic features (i.e., protective effect in early-life, but neurodegenerative effect in adulthood). However, we cannot discard chance findings. Future studies should evaluate trajectorial brain development using a longitudinal design.

Air pollution, white matter microstructure, and brain volumes: Periods of susceptibility from pregnancy to preadolescence.

Air pollution exposure during early-life is associated with altered brain development, but the precise periods of susceptibility are unknown. We aimed to investigate whether there are periods of susceptibility of air pollution between conception and preadolescence in relation to white matter microstructure and brain volumes at 9-12 years old. We used data of 3515 children from the Generation R Study, a population-based birth cohort from Rotterdam, the Netherlands (2002-2006). We estimated daily levels of nitrogen dioxide (NO2), and particulate matter (PM2.5 and PM2.5absorbance) at participants' homes during pregnancy and childhood using land-use regression models. Diffusion tensor and structural brain images were obtained when children were 9-12 years of age, and we calculated fractional anisotropy and mean diffusivity, and several brain structure volumes. We performed distributed lag non-linear modeling adjusting for socioeconomic and lifestyle characteristics. We observed specific periods of susceptibility to all air pollutants from conception to age 5 years in association with lower fractional anisotropy and higher mean diffusivity that survived correction for multiple testing (e.g., -0.85 fractional anisotropy (95%CI -1.43; -0.27) per 5 µg/m3 increase in PM2.5 between conception and 4 years of age). We also observed certain periods of susceptibility to some air pollutants in relation to global brain and some subcortical brain volumes, but only the association between PM2.5 and putamen survived correction for multiple testing (172 mm3 (95%CI 57; 286) per 5 µg/m3 increase in PM2.5 between 4 months and 1.8 year of age). This study suggested that conception, pregnancy, infancy, toddlerhood, and early childhood seem to be susceptible periods to air pollution exposure for the development of white matter microstructure and the putamen volume. Longitudinal studies with repeated brain outcome measurements are needed for understanding the trajectories and the long-term effects of exposure to air pollution.

Longitudinal associations of DNA methylation and sleep in children: a meta-analysis.

BACKGROUND: Sleep is important for healthy functioning in children. Numerous genetic and environmental factors, from conception onwards, may influence this phenotype. Epigenetic mechanisms such as DNA methylation have been proposed to underlie variation in sleep or may be an early-life marker of sleep disturbances. We examined if DNA methylation at birth or in school age is associated with parent-reported and actigraphy-estimated sleep outcomes in children. METHODS: We meta-analysed epigenome-wide association study results. DNA methylation was measured from cord blood at birth in 11 cohorts and from peripheral blood in children (4-13 years) in 8 cohorts. Outcomes included parent-reported sleep duration, sleep initiation and fragmentation problems, and actigraphy-estimated sleep duration, sleep onset latency and wake-after-sleep-onset duration. RESULTS: We found no associations between DNA methylation at birth and parent-reported sleep duration (n = 3658), initiation problems (n = 2504), or fragmentation (n = 1681) (p values above cut-off 4.0 × 10-8). Lower methylation at cg24815001 and cg02753354 at birth was associated with longer actigraphy-estimated sleep duration (p = 3.31 × 10-8, n = 577) and sleep onset latency (p = 8.8 × 10-9, n = 580), respectively. DNA methylation in childhood was not cross-sectionally associated with any sleep outcomes (n = 716-2539). CONCLUSION: DNA methylation, at birth or in childhood, was not associated with parent-reported sleep. Associations observed with objectively measured sleep outcomes could be studied further if additional data sets become available.

Exposure to DDT and DDE and functional neuroimaging in adolescents from the CHAMACOS cohort.

BACKGROUND: Epidemiological studies suggest that exposure to p,p'-dichloro-diphenyl-trichloroethane (p,p'-DDT) is associated with poorer cognitive function in children and adolescents, but the neural mechanisms underlying this association remain unclear. OBJECTIVE: We investigated associations of prenatal and childhood exposure to p,p'-DDT and its metabolite p,p'-dichloro-diphenyl-dichloroethylene (p,p'-DDE) with cortical activation in adolescents using functional near-infrared spectroscopy (fNIRS). METHODS: We administered fNIRS to 95 adolescents from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) aged 15-17 years. We assessed cortical activity in the frontal, temporal, and parietal brain regions while participants completed tasks of executive function, language comprehension, and social cognition. We measured serum p,p'-DDT and -DDE concentrations at age 9 years and then estimated exposure-outcome associations using linear regression models adjusted for sociodemographic characteristics. In secondary analyses, we back-extrapolated prenatal concentrations using prediction models and examined their association with cortical activation. RESULTS: Median (P25-P75) p,p'-DDT and -DDE concentrations in childhood were 1.4 (1-2.3) and 141.5 (75.0-281.3) ng/g lipid, respectively. We found that childhood exposure to p,p'-DDT and -DDE was associated with altered patterns of brain activation during tasks of cognition and executive functions. For example, we observed increased activity in the left frontal lobe during a language comprehension task (ß per 10 ng/g lipid increase of serum p,p'-DDE at age 9 years = 3.4; 95% CI: 0.0, 6.9 in the left inferior frontal lobe; and ß = 4.2; 95% CI: 0.9, 7.5 in the left superior frontal lobe). We found no sex differences in the associations of childhood p,p'-DDT and -DDE concentrations with neural activity. Associations between prenatal p,p'-DDT and p,p'-DDE concentrations and brain activity were similar to those observed for child p,p'-DDT and -DDE concentrations. CONCLUSIONS: Childhood p,p'-DDT and -DDE exposure may impact cortical brain activation, which could be an underlying mechanism for its previously reported associations with poorer cognitive function.

Maternal exposure to air pollution during pregnancy and child's cognitive, language, and motor function: ECLIPSES study.

Prenatal exposure to air pollution, even at low levels, has been associated with negative effects on a child's neuropsychological functioning. The present work aimed to investigate the associations between prenatal exposure to air pollution on a child's cognitive, language, and motor function at 40 days of age in a highly exposed area of Spain. From the ECLIPSES study population, the present work counted 473 mother-child pairs. Traffic-related air pollution levels at home addresses during the whole pregnancy were estimated including particulate matter (PM) with an aerodynamic diameter <2.5 µm (PM2.5), <10 µm (PM10) and 2.5-10 µm (PMcoarse), PM2.5absorbance, nitrogen dioxide (NO2), other nitrogen oxides (NOx), and ozone (O3) using land-use regression models developed within ESCAPE and ELAPSE projects. Children's cognitive, language, and motor functions were assessed using the Bayley Scales of Infant Development 3rd edition (BSID-III) at around 40 days of age. Linear regression models were adjusted for maternal biological, sociodemographic and lifestyle characteristics, area deprivation index, and amount of greenness around the home's address. All air pollutants assessed, except PM2.5 absorbance, were associated with lower motor function in children, while no association was observed between prenatal exposure to air pollution and cognitive and language functions. This finding highlights the need to continue raising awareness of the population-level impact that maternal exposure to air pollution even at low levels can have on the neuropsychological functions of children.

Urban environment and cognitive and motor function in children from four European birth cohorts.

BACKGROUND: The urban environment may influence neurodevelopment from conception onwards, but there is no evaluation of the impact of multiple groups of exposures simultaneously. We investigated the association between early-life urban environment and cognitive and motor function in children. METHODS: We used data from 5403 mother-child pairs from four population-based birth-cohorts (UK, France, Spain, and Greece). We estimated thirteen urban home exposures during pregnancy and childhood, including: built environment, natural spaces, and air pollution. Verbal, non-verbal, gross motor, and fine motor functions were assessed using validated tests at five years old. We ran adjusted multi-exposure models using the Deletion-Substitution-Addition algorithm. RESULTS: Higher greenness exposure within 300 m during pregnancy was associated with higher verbal abilities (1.5 points (95% confidence interval 0.4, 2.7) per 0.20 unit increase in greenness). Higher connectivity density within 100 m and land use diversity during pregnancy were related to lower verbal abilities. Childhood exposure to PM2.5 mediated 74% of the association between greenness during childhood and verbal abilities. Higher exposure to PM2.5 during pregnancy was related to lower fine motor function (-1.2 points (-2.1, -0.4) per 3.2 µg/m3 increase in PM2.5). No associations were found with non-verbal abilities and gross motor function. DISCUSSION: This study suggests that built environment, greenness, and air pollution may impact child cognitive and motor function at five years old. This study adds evidence that well-designed urban planning may benefit children's cognitive and motor development.

Multiple pesticides in mothers' hair samples and children's measurements at birth: Results from the French national birth cohort (ELFE).

BACKGROUND: A growing body of studies now suggests that the general population is continuously and ubiquitously exposed to numerous pesticides. However, studies investigating the possible role of environmental exposure to pesticides on fetal growth have focused on a limited set of substances, despite the hundreds of modern pesticides currently available. AIM: To explore the relation between maternal hair concentrations of 64 pesticides and metabolites and their newborns' measurements at birth, with data from the ELFE French nationwide birth cohort. METHODS: We measured 64 compounds (10-100% detection) in bundles of hair 9 cm long collected at birth from 311 women who gave birth in France in 2011. We assessed their associations with birth weight, length, and head circumference, adjusted for potential confounders, and used elastic net regularization to simultaneously select the strongest predictors of measurements at birth. Selected variables were multiply imputed for missing values, and unpenalized estimators were assessed by standard linear regression. RESULTS: We observed statistically significant associations between maternal hair concentrations of seven pesticides or pesticide metabolites and birth measurements (weight: fipronil sulfone; length: TCPy, bitertanol, DEP, and isoproturon; head circumference: tebuconazole and prochloraz). Analyses restricted to boys identified 12 additional compounds: 8 independently associated with birth weight (3Me4NP, DCPMU, DMST, fipronil, mecoprop, propoxur, fenhexamid, and thiabendazole), 2 with birth length (dieldrin and ß-endosulfan), and 6 with head circumference (ß-endosulfan, ß-HCH, fenuron, DCPMU, propoxur, and thiabendazole). CONCLUSION: Our results suggest that prenatal exposure to 19 pesticides or metabolites from various chemical families may influence measurements at birth. As with any exploratory research findings, results should be interpreted cautiously, until they are replicated or verified by further epidemiological or mechanistic studies.

Prenatal exposure to glycol ethers and motor inhibition function evaluated by functional MRI at the age of 10 to 12 years in the PELAGIE mother-child cohort.

BACKGROUND: Pregnant women are ubiquitously exposed to organic solvents, such as glycol ethers. Several studies suggest potential developmental neurotoxicity following exposure to glycol ethers with a lack of clarity of possible brain mechanisms. OBJECTIVES: We investigated the association between urinary levels of glycol ethers of women during early pregnancy and motor inhibition function of their 10- to 12-year-old children by behavioral assessment and brain imaging. METHODS: Exposure to glycol ethers was assessed by measuring six metabolites in urine (<19 weeks of gestation) of 73 pregnant women of the PELAGIE mother-child cohort (France). Maternal urinary levels were classified as low, medium, or high. Children underwent functional magnetic resonance imaging (fMRI) examinations during which motor inhibition function was assessed with a Go/No-Go task. Analyses were performed using linear regression for task performance and generalized linear mixed-effect models for brain activation, FWER-corrected for multiple testing at the spatial cluster level. Confounders were considered by restriction and a priori adjustment. RESULTS: Higher maternal butoxyacetic acid (BAA) urinary concentrations were associated with poorer child performance (ß = -1.1; 95% CI: -1.9, -0.2 for high vs low). There was also a trend for ethoxyacetic acid (EAA) towards poorer performance (ß = -0.3; 95% CI: -0.7, 0.01). Considering inhibition demand, there were increased activity in occipital regions in association with moderate EAA (left cuneus) and moderate methoxyacetic acid (MAA) (right precuneus). When children succeeded to inhibit, high ethoxyethoxyacetic acid (EEAA) and moderate phenoxyacetic acid (PhAA) levels were associated with differential activity in frontal cortex, involved in inhibition network. DISCUSSION: Prenatal urinary levels of two glycol ether metabolites were associated with poorer Go/No-Go task performance. Differential activations were observed in the brain motor inhibition network in relation with successful inhibition, but not with cognitive demand. Nevertheless, there is no consistence between performance indicators and cerebral activity results. Other studies are highly necessary given the ubiquity of glycol ether exposure.

Prenatal exposure to glycol ethers and sex steroid hormones at birth.

BACKGROUND: Glycol ethers (GEs) are oxygenated solvents widely found in occupational and consumer water-based products. Some of them are well-known reproductive and developmental toxicants. OBJECTIVES: To study the variations in circulating sex steroid hormones, measured in cord blood, according to biomarkers of prenatal GE exposure. METHODS: The study population comes from the PELAGIE mother-child cohort, which enrolled pregnant women from Brittany (France, 2002-2006). Maternal urine samples were collected from a random subcohort (n = 338) before 19 weeks' gestation, from which we measured 8 alkoxycarboxylic metabolites of GEs. We subsequently measured 13 sex steroid hormones and sex hormone-binding globulin (SHBG) in cord blood samples. Linear regressions adjusted for potential confounders were used, and nonlinear dose-response associations were investigated. RESULTS: The detection rates of GE metabolites ranged from 4% to 98%; only the 5 most detected (>20%) metabolites were investigated further. Phenoxyacetic acid (detection rate > 95%) was associated with lower levels of SHBG and various steroids (17-alpha-hydroxy-Pregnenolone, delta-5-androstenediol, and dehydroepiandrosterone) among boys and higher SHBG and 16-alpha-hydroxy-dehydroepiandrosterone levels among girls. The two other highly detected metabolites, methoxyetoxyacetic acid and butoxyacetic acid, were associated with variations in estradiol. Butoxyacetic acid was associated with higher delta-5-androstenediol levels while detectable levels of methoxyacetic acid were associated with lower levels of this hormone. CONCLUSION: Our study suggests that prenatal exposure to GE may affect endocrine response patterns, estimated by determining blood levels of sex steroid hormones in newborns. These results raise questions about the potential role of these changes in the pathways between prenatal GE exposure and previously reported adverse developmental outcomes, including impaired neurocognitive performance.