Background: More than 80% of the Canadian population lives in urban settings. Urban areas usually bring exposure to poorer air quality, less access to green spaces, and higher building density. These environmental factors may endanger child development. Objective: To assess the relationship of urban environmental exposures during pregnancy with cognitive abilities, motor function, externalizing and internalizing symptoms in children. Method: We included 6,279 mother-child pairs from 3 Canadian population-based birth-cohorts (3D Cohort Study in Montreal, Quebec City, and Sherbrooke, AOF Study in Calgary, CHILD Study in Edmonton, Vancouver, Toronto, and Winnipeg). We estimated 7 environmental exposures of the built environment, surrounding greenness, and air pollution, around participant's home addresses during pregnancy. Validated neuropsychological tests were used to assess non-verbal and verbal abilities, gross and fine motor function, externalizing and internalizing symptoms at child's age 2 to 5 years. We assessed associations of each environmental exposure indicator with each of the 6 outcomes, using multivariate linear regression models. We conducted analyses separately by city of recruitment and combined estimates in meta-analyses. Results: Overall, urban environment during pregnancy was not associated with cognitive abilities (e.g., -0.81 non-verbal points 95 %CI [-2.10; 0.48] per 1 mu g/m3 increase in PM2.5), motor function, or externalizing and internalizing symptoms. In individual cohorts, we found associations of some environmental exposures, in particular building density, fine particles, and nitrogen dioxide with non-verbal abilities, verbal abilities, and fine motor function, but overall confidence intervals in the meta-analyses included the null. Conclusion: We found no evidence of a relationship of prenatal built environment, surrounding greenness, and air pollution with cognitive abilities, motor functions or externalizing and internalizing symptoms in childhood.Urban environment has been shown to influence health across the lifecourse, however, specific exposures during pregnancy do not seem associated with poorer neurodevelopment in children of 2- to 5- year.

Emerging evidence suggests that air pollution exposure is associated with child's brain morphology, but the relationship between air pollution and longitudinal changes in the development of brain volumes has yet to be investigated. We studied the association of exposure to air pollution in pregnancy and childhood with the change of brain volumes from childhood into adolescence, using repeated assessments of brain volumes. We used data from 4243 children of a large Dutch population-based birth cohort. Exposure to 14 air pollutants during pregnancy and childhood was estimated using land-use regression models. We obtained structural brain MRI data at 3 timepoints, resulting in 6059 useable scans of white matter, cortical grey matter, cerebellum, and 7 subcortical volumes. For 1191 participants we had data on both last two timepoints. We conducted single-pollutant analyses for each air pollutant and brain volume, using linear mixed models adjusted for life-style and socioeconomic status variables. Then we performed multi-pollutant analyses with the least absolute shrinkage and selection operator for mixed models. Air pollution exposure was not associated with changes in white matter, cortical grey matter, and cerebellar volumes. Higher exposure to copper and particulate matter with aerodynamic diameter <2.5 μm (PM2.5) during pregnancy was associated with a smaller hippocampal volume at the first neuroimaging assessment, followed by faster growth of hippocampal volume (e.g. 25.1 mm3 increase of hippocampal volume [95 % CI 8.6; 41.7] per 5 ng/m3 increase in copper exposure per year of age). Results were comparable when restricting the analyses to children with complete data for the last two timepoints. Exposure to copper and PM2.5 during pregnancy was related with a smaller hippocampal volume in mid childhood, followed by catch-up growth. Plasticity of the hippocampus might mitigate adverse effects of air pollution early in life.

Context Maternal vitamin D level is an important determinant of pregnancy and child health outcomes. Exposure to air pollution is suspected to increase the risk of vitamin D deficiency, but the evidence is scarce. Objective We investigated the association between air pollution during pregnancy and maternal vitamin D levels. Methods A total of 15 935 pregnant women from 5 birth cohorts in Europe and the United States were included. Averaged concentrations of nitrogen oxides, fine and coarse particles, and composition of fine particles from conception until vitamin D measurement were estimated at participants’ residential addresses using land-use regression or other spatiotemporal models. Cohorts measured vitamin D as 25(OH)D or 25(OH)D3 levels in serum or plasma at early or mid-pregnancy. We defined suboptimal vitamin D levels as levels below 20 ng/mL. We performed logistic regression models for each cohort to estimate the association between air pollution exposure and suboptimal vitamin D levels and pooled cohort-specific estimates in a random-effect meta-analysis. Models were adjusted for sociodemographic and lifestyle characteristics and month of conception. Results We found an association between particulate matter (PM)2.5 and higher odds of suboptimal vitamin D levels (ie, below 20 ng/mL) (odds ratio per 5 μg/m3 increase in PM2.5, 1.43; 95% CI: 1.02, 1.99). There was no association between other air pollutant exposure and vitamin D levels. Conclusion PM2.5 exposure might contribute to suboptimal levels of vitamin D in pregnancy. Reducing air pollution exposure should be a priority because vitamin D deficiency may adversely influence offspring development.

Abstract Background Night shift work during pregnancy has been associated with differential DNA methylation in placental tissue, but no studies have explored this association in cord blood. We aimed to examine associations of maternal night shift work with cord blood DNA methylation. Methods A total of 4487 mother–newborn pairs from 7 studies were included. Maternal night shift work during pregnancy was ascertained via questionnaires and harmonized into “any” versus “no”. DNA methylation was measured in cord blood using the Illumina Infinium Methylation arrays. Robust linear regression models adjusted for relevant confounders were run in the individual cohorts, and results were meta-analyzed. Results Maternal night shift work during pregnancy ranged from 3.4% to 26.3%. Three CpGs were differentially methylated in relation to maternal night shift work during pregnancy at a false discovery rate adjusted P < 0.05: cg10945885 (estimate (β) 0.38%, standard error (SE) 0.07), cg00773359 (β 0.25%, SE 0.05), and cg21836426 (β − 0.29%, SE 0.05). Associations of the identified CpGs were found in previous literature for gestational age and childhood and adolescent BMI. In a mouse model of prenatal jet lag exposure, information on offspring DNA methylation of ten homologous genes annotated to the 16 CpGs with P < 1 × 10−5 in our analysis was available, of which eight were associated (enrichment P: 1.62 × 10−11). Conclusion Maternal night shift work during pregnancy was associated with newborn DNA methylation at 3 CpGs. Top findings overlapped with those in a mouse model of gestational jet lag. This work strengthens evidence that DNA methylation could be a marker or mediator of impacts of circadian rhythm disturbances.

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.

Background: Recent evidence suggests an association of air pollution exposure with brain development, but evidence on white matter microstructure in children is scarce. We investigated how air pollution exposure during pregnancy and childhood impacts longitudinal development of white matter microstructure throughout adolescence. Methods: Our study population consisted of 4108 participants of Generation R, a large population-based birth cohort from Rotterdam, the Netherlands. Residential air pollution exposure to 14 air pollutants during pregnancy and childhood was estimated with land-use regression models. Diffusion tensor images were obtained around age 10 and 14, resulting in a total of 5422 useable scans (n = 3082 for wave 1 and n = 2340 for wave 2; n = 1314 for participants with data on both waves). We calculated whole-brain fractional anisotropy (FA) and mean diffusivity (MD) and performed single- and multi-pollutant analyses using mixed effects models adjusted for life-style and socioeconomic status variables. Results: Higher exposure to PM2.5 during pregnancy, and PM10, PM2.5, PM2.5-10, and NOX during childhood was associated with a consistently lower whole-brain FA throughout adolescence (e.g. - 0.07 x 10-2 FA [95%CI -0.12; -0.02] per 1 standard deviation higher PM2.5 exposure during pregnancy). Higher exposure to silicon (Si) in PM2.5 and oxidative potential of PM2.5 during pregnancy, and PM2.5 during childhood was associated with an initial higher MD followed by a faster decrease in MD throughout adolescence (e.g. - 0.02 x 10-5 mm2/s MD [95%CI -0.03; -0.00] per year of age per 1 standard deviation higher Si exposure during pregnancy). Results were comparable when performing the analysis in children with complete data on the outcome for both neuroimaging assessments. Conclusions: Exposure to several pollutants was associated with a consistently lower whole-brain FA throughout adolescence. The association of few pollutants with whole-brain MD at baseline attenuated throughout adolescence. These findings suggest both persistent and age-limited associations of air pollution exposure with white matter microstructure.

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 (β = 0.06; 95 %CI: 0.03, 0.09 I2 = 4.03 %, p < 0.001) and FVC (β = 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 (β = -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.

IntroductionThe 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 analysisDAS-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 disseminationThe 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.

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.

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 child-hood 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 epsilon 4 carriers compared to non-carriers (29,485 mm3 (95% CI 6,189; 52,781) and 18,663 mm3 (469; 36,856), respectively). Higher preg-nancy 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 epsilon 4 carriers and children with a high PRS for AD. This is in line with typical brain development, sug-gesting 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.

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.

Cell migration plays a critical role during the development of most organisms and the process of malignant tumor metastasis. In the present study, we investigated the role of PTPIP51 (protein tyrosine phosphatase interacting protein 51) in cell motility. Overexpression of PTPIP51 induced cell elongation, increased cell migration, adhesion, and spreading, while downregulation of PTPIP51 had the opposite effects. We demonstrated here, that PTPIP51 could regulate ERK activity on Raf level, since MEK inhibitor and dominant-negative Raf-1 but not Ras could inhibit the ERK activation induced by PTPIP51. Further studies proved that PTPIP51 could interact with Raf-1 through 14–3–3, suggesting that PTPIP51 is a regulator of the Raf–MEK–ERK cascade through modulation of Raf-1 by 14–3–3. In addition, two redundant 14–3–3 binding domains in the PTPIP51 protein have been identified by deletion/mutation studies. We conclude that PTPIP51 regulates cell morphology and cell motility via interaction with Raf-1 through 14–3–3, and that PTPIP51 binds to 14–3–3 through two redundant binding domains.

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 mu m (PM2.5), <10 mu m (PM10) and 2.5-10 mu m (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.

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. 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. 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). 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.

Recent studies have linked air pollution to brain characteristics in children, but few studies have considered associations with other urban exposures. We investigated the associations between urban exposome and white matter microstructure and brain volumes in preadolescents. We used data from 3,315 children of the Generation R cohort, The Netherlands. Residential levels of 20 built environment metrics, 6 natural spaces indicators, 12 air pollutants, and road-traffic noise were assessed during pregnancy and childhood. Diffusion tensor and structural brain images were obtained at 9–12 years. We estimated fractional anisotropy (FA) and mean diffusivity (MD) and several brain structure volumes. We ran multi-pollutant analysis between built environment and natural spaces indicators and each outcome using Deletion/Substitution/Addition algorithm. When an association was found, we ran mediation analyses to estimate whether the association was mediated by air pollution or noise. Built environment and natural spaces indicators during pregnancy were not associated with FA nor MD. During childhood, building density and industrial or commercial land use (LU) were related to higher MD, and LU diversity was associated with lower MD (e.g., -0.02 95%CI (0,03; -0,01)). Total effects of building density and LU diversity were partially mediated by fine particulate matter elemental zinc (9.0% and 23.2%, respectively). Surrounding greenness during pregnancy was associated with smaller subcortical gray matter, pallidum and thalamus volumes, with no mediation by air pollution nor noise. Built environment indicators, including LU diversity and unhealthy food facilities density during pregnancy or childhood were associated with smaller hippocampus, larger amygdala and nucleus accumbens volumes, with a mediation up to 6.9% by elemental zinc or polycyclic aromatic hydrocarbons. Early-life built environment and natural space indicators were related to brain structural connectivity and morphology in preadolescence, with a partial mediation by air pollution levels. Birth cohort, urban exposome, air pollution, natural spaces, neuroimaging, child development

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.

BACKGROUND and AIM Individuals living in areas with higher air pollution have lower levels of vitamin D than residents of areas with lower pollution. Evidence suggests non-optimal gestational vitamin D as an important determinant of pregnancy and child health outcomes. We investigated the association between gestational exposure to air pollution and maternal vitamin D levels. METHODS Participants were 16,553 pregnant women from birth cohorts in the UK (BiB), US (Project Viva), Netherlands (ABCD and Generation R), Poland (REPRO_PL), and Spain (INMA). Averaged concentrations of air pollutants from conception until vitamin D measurement were estimated at participants' residential addresses using land-use regression or other spatiotemporal models. Cohorts measured 25-hydroxy vitamin D [25(OH)D] and/or 25(OH)D3 in serum or plasma at early or mid-pregnancy. We performed linear regression models in each cohort to estimate the association between air pollution exposure and vitamin D levels and pooled cohort-specific results in a random-effect meta-analysis. Models were adjusted for sociodemographic characteristics, smoking and alcohol use, parity, body mass index, and month of conception. RESULTS Concentrations of nitrogen dioxide and fine PM (PM2.5) were lower and had less variation in Project Viva and BiB than other cohorts. In REPRO_PL, 95% of women had vitamin D<20 ng/ml; this rate was 85% in BiB, 52% in Generation R, and <50% in other cohorts. We found an inverse association between PM2.5 and vitamin D levels (-1.4 ng/mL, 95%CI:-2.6,-0.2, per 5 μg/m3 increase in PM2.5). Heterogeneity was high among cohorts, with associations driven by ABCD, BiB, and INMA. There was no association between nitrogen oxide exposure and vitamin D levels. CONCLUSIONS PM2.5 exposure might contribute to non-optimal levels of vitamin D in pregnancy. Future studies should focus on underlying mechanisms, including biological pathways, e.g., inducing metabolism of vitamin D, or other factors, e.g., reduced outdoor activity. KEYWORDS: 25(OH)D; PM2.5; pregnancy; women

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 mu g/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.

BACKGROUND AND AIM: Air pollution exposure has been associated with adverse birth outcomes. However, few studies have investigated potential gestational windows of susceptibility. Further, the extent to which this association differs across socioeconomic status (SES) is underexplored. Therefore, the aim of this study is to investigate windows of susceptibility and explore potential social inequalities in the association between prenatal air pollution exposure and adverse birth outcomes. METHODS: We used a Spanish national-wide birth registry study which includes all newborns born between 2009 and 2010 (n=353,750) and whose mothers resided in the peninsula or the Balearic Islands. Maternal exposures to particulate matter with an aerodynamic diameter of 10 µm (PM10), 2.5 µm (PM2.5), and 2.5-10µm (PMcoarse) were estimated at the residential address throughout pregnancy on a daily basis using spatiotemporal land use machine-learning models. Birth outcomes (i.e., birth weight, gestational age, prematurity, and small or large for gestational age) and SES characteristics of the parents (i.e., education, occupation, ethnicity, area-level deprivation index) were obtained from the registry. Confounder adjusted associations between pollutant concentrations and birth outcomes, windows of susceptibility, and SES disparities were examined using regression models. RESULTS:Higher air pollution concentrations were associated with lower birth weight and increased prematurity [e.g., 20 gram decrease in birth weight (95%CI -25.3, -15.2) per each 10μg/m3 increase in PM10]. Results revealed that exposure during the third trimester were driving these associations and that effect on birth weight and prematurity was greater in magnitude for children from low SES families. Air pollution exposure was not associated with being small or large for gestational age. CONCLUSIONS:Exposure to air pollution during pregnancy was associated with adverse birth outcomes, with the third trimester of pregnancy being the most susceptible window. A pattern of social inequality was observed in this association, with a greater impact on newborns from families with fewer resources. KEYWORDS: Air pollution, birth outcomes, socio-economic inequalities, windows of susceptibility, pregnancy