Ambient air pollution may contribute to childhood obesity through various mechanisms. However, few longitudinal studies examined the relationship between pre- and postnatal exposure to air pollution and obesity outcomes in childhood. We aimed to investigate the association between pre- and postnatal exposure to air pollution and body mass index (BMI) and the risk of overweight/obesity throughout childhood in European cohorts. This study included mother-child pairs from 10 European birth cohorts (n = 37111 (prenatal), 33860 (postnatal)). Exposure to nitrogen dioxide (NO2) and fine particulate matter with aerodynamic diameter < 2.5 µm (PM2.5) was estimated at the home addresses during pre- and postnatal periods (year prior outcome assessment). BMI z-scores (continuous) and overweight/obesity status (categorical: zBMI≥+2 (<5 years) or ≥+1 (≥5 years) standard deviations) were derived at 0-2, 2-5, 5-9, 9-12 years. Associations between air pollution exposure and zBMI were estimated separately for each pollutant and cohort using linear and logistic longitudinal mixed effects models, followed by a random-effects meta-analysis. The overweight/obesity prevalence ranged from 12.3-40.5 % between cohorts at 0-2 years, 16.7-35.3 % at 2-5 years, 12.5-40.7 % at 5-9 years, and 10.7-43.8 % at 9-12 years. Results showed no robust associations between NO2 exposure and zBMI or overweight/obesity risk. Exposure to PM2.5 during pregnancy was associated with 23 % (95%CI 1.05;1.37) higher overweight/obesity risk across childhood, and higher zBMI and overweight/obesity risk at 9-12 years. Heterogeneity between cohorts was considerable (I2:25-89 %), with some cohort-specific associations; e.g., pre- and postnatal exposure to PM2.5 was associated with lower zBMI across age periods in UK cohorts (ALSPAC and BiB), while postnatal exposure to PM2.5 and NO2 was associated with higher zBMI in one Dutch cohort (Generation R). Overall, this large-scale meta-analysis suggests that prenatal PM2.5 exposure may be associated with adverse childhood obesity outcomes, but provides no evidence to support an effect of postnatal air pollution exposure, although cohort-specific associations were observed.

ImportanceClimate change can adversely affect mental health, but the association of ambient temperature with psychiatric symptoms remains poorly understood.ObjectiveTo assess the association of ambient temperature exposure with internalizing, externalizing, and attention problems in adolescents from 2 population-based birth cohorts in Europe.Design, Setting, and ParticipantsThis cohort study analyzed data from the Dutch Generation R Study and the Spanish INMA (Infancia y Medio Ambiente) Project. Generation R recruited 9898 women during pregnancy or shortly after birth, with children born between 2002 and 2006. INMA recruited 2270 pregnant women from Gipuzkoa, Sabadell, and Valencia, Spain, with children born between 2003 and 2008. Individuals born from live singleton births with available outcome and exposure data were included in the study. Data were analyzed between October 2023 and November 2024.ExposureDaily ambient temperature 2 weeks, 1 month, and 2 months preceding outcome assessment was calculated between December 2015 and November 2022 at the residence at 100 × 100 m resolution utilizing the UrbClim model.Main Outcomes and MeasuresThe primary outcomes were internalizing, externalizing, and attention problems, measured with the maternal-reported Child Behavioral Checklist for ages 6 to 18 years; raw scores were square-root transformed, with higher scores indicating more problems. Distributed lag nonlinear models evaluated the associations of temperature exposure with problem scores in each country and region. For Spain, results from the 3 INMA regions were combined using random-effects meta-analysis. Results show the accumulated temperature association over each exposure period.ResultsA total of 3934 participants from Generation R (mean [SD] age at assessment, 13.6 [0.4] years; 1971 female [50%]) and 885 from INMA (mean [SD] age at assessment, 14.9 [1.0] years; 458 female [52%]) were included. Most parents in both cohorts were native to the respective countries of each cohort and had relatively high socioeconomic status. Daily temperatures ranged from −5.2 °C to 32.6 °C in the Netherlands and 3.3 °C to 33.9 °C in Spain. In Generation R, the mean (SD) square-root transformed scores were 2.0 (1.2) for internalizing problems, 1.6 (1.3) for externalizing problems, and 1.5 (1.0) for attention problems, while in INMA these were 2.4 (1.2), 2.1 (1.3), and 1.5 (1.1), respectively. In the Netherlands, cumulative exposure to cold was associated with more internalizing problems (eg, 0.76 [95% CI, 0.20-1.32] higher square-root points at 5.5 °C exposure over a 2-month exposure). In Spain, cumulative exposure to heat was associated with more attention problems (eg, 1.52 [95% CI, 0.39-2.66] higher square-root points at 21.7 °C exposure over a 2-month exposure).Conclusions and RelevanceIn this cohort study, exposure to cold in the Netherlands and heat in Spain were associated with more psychiatric symptoms, highlighting distinct temperature exposure and mental health associations among adolescents. Future studies should explore this across diverse climates to further quantify the intricate and multifactorial association of climate change with mental health.

RATIONALE Atopic diseases are commonly present in childhood. We aimed to create a novel collaborative library of individual-level participant data for research on atopic diseases from birth through adolescence, and to demonstrate its prevalences and general high-risk groups. METHODS We harmonized and standardized individual-level data of 202,475 children from 14 European and Australian pregnancy and birth cohorts participating in the EU CHILD Cohort Network. Sex, geographic region, parental history of atopic diseases, physician-diagnosed current wheezing, asthma and eczema were primarily determined by parental-reported questionnaires, and physician-diagnosed inhalant allergy by parental-reported questionnaires and/or measurement of allergic sensitization by skin prick or allergen-specific Immunoglobulin E testing. Lung function measures were obtained by spirometry and converted into an age, sex, and ethnicity-adjusted obstructive lung function phenotype (FEV1/FVC < lower limited of normal). Statistical one-stage meta-analyses were performed through the shared federated R-based platform DataSHIELD. RESULTS Across cohorts, mean prevalences of eczema and wheezing were highest in infancy (<1y) or at preschool age (1-4y) after which they gradually declined into adolescence (≥12y)(21% to 5.2% and 23% to 16%, respectively), while those of inhalant allergy and asthma were reversely present (4.9% to 18% and 6.2% to 12%, respectively)(Figure 1). The prevalence of obstructive lung function remained consistent from school age (5-11y) through adolescence (5.5% to 5.9%). Compared to girls, boys had a higher prevalence of wheezing in infancy, at preschool age and at school age (27% vs. 19%; 26% vs. 21%; 19% vs. 16%, respectively), asthma in adolescence (13% vs. 10%), eczema at school age (14% vs. 13%), and inhalant allergy in adolescence (20% vs. 15%)(p-values <0.05 for meta-analyzed χ2 test for differences in prevalences). All atopic diseases from birth until adulthood were evenly present among children from Northern European/Western European/Australian and Southern European regions. Children with a family history of atopic diseases more often had wheezing in infancy and at preschool age, asthma in adolescence, eczema at school age and in adolescence, and inhalant allergy in adolescence than those without a family history of atopic diseases (p-values <0.05). CONCLUSION Prevalences of atopic diseases vary from birth through adolescence and are more commonly present among boys and children with a family history of atopic diseases. The novel developed collaborative library of individual-level participant data could be used as a resource for meta-analyses on the early origins of atopic diseases (https://data-catalogue.molgeniscloud.org/catalogue/ssr-catalogue/EUChildNetwork).

Whether greenspace affects lung function is unclear. We explored associations between the level of greenness or presence of urban green space near the home with lung function measures taken repeatedly during childhood and adolescence in five European birth cohorts. Lung function was measured by spirometry between six and 22 years (2-3 times), and 9,206 participants from BAMSE (Sweden), GINI/LISA South and GINI/LISA North (Germany), PIAMA (The Netherlands) and INMA (Spain) contributed at least one lung function measurement. The mean Normalized Difference Vegetation Index (NDVI) in a 300 m buffer and presence of urban green space within a 300 m buffer (yes/no) were estimated at the home address at the time of each spirometry measurement. Cohort-specific associations were assessed using adjusted linear mixed models and combined in a random-effects meta-analysis. Residential greenness was not associated with forced expiratory volume in one second (FEV1), forced vital capacity (FVC) or FEV1/FVC in the meta-analysis (2.3 ml [-3.2, 7.9], 6.2 ml [-3.4, 15.7] and -0.1 [-0.3, 0.1] per 0.1 increase in NDVI, respectively), nor was having a nearby urban green space (-8.6 ml [-22.3, 5.0], -7.6 ml [-24.7, 9.4] and 0.0 [-0.4, 0.3], respectively). Heterogeneity was low to moderate (I2 = 0 -39 %). Asthma, atopy, air pollution, sex, socioeconomic status and urbanization did not modify the null associations. Using repeated data from five large independent European birth cohorts, we did not find associations between vegetation levels around the home or the presence of an urban green space and lung function levels during childhood and adolescence.

Objectives To investigate the associations of physical activity (PA) and sedentary behaviour in early childhood with asthma and reduced lung function in later childhood within a large collaborative study.Design Pooling of longitudinal data from collaborating birth cohorts using meta-analysis of separate cohort-specific estimates and analysis of individual participant data of all cohorts combined.Setting Children aged 0-18 years from 26 European birth cohorts.Participants 136 071 individual children from 26 cohorts, with information on PA and/or sedentary behaviour in early childhood and asthma assessment in later childhood.Main outcome measure Questionnaire-based current asthma and lung function measured by spirometry (forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity) at age 6-18 years.Results Questionnaire-based and accelerometry-based PA and sedentary behaviour at age 3-5 years was not associated with asthma at age 6-18 years (PA in hours/day adjusted OR 1.01, 95% CI 0.98 to 1.04; sedentary behaviour in hours/day adjusted OR 1.03, 95% CI 0.99 to 1.07). PA was not associated with lung function at any age. Analyses of sedentary behaviour and lung function showed inconsistent results.Conclusions Reduced PA and increased sedentary behaviour before 6 years of age were not associated with the presence of asthma later in childhood.

The objective is to investigate the relation between cord blood mercury concentrations and child neurobehavioural functioning assessed longitudinally during childhood until pre -adolescence. Methods: The study involves mothers and their offspring engaged in the Spanish INMA birth cohort (n = 1147). Total mercury (THg) was determined in cord blood. Behavioural problems were assessed several times during childhood using the ADHD-DSM-IV at age 4, SDQ at ages 7 and 11, CPRS-R:S and the CBCL at ages 7, 9 and 11. Covariates were obtained through questionnaires during the whole period. Multivariate generalised negative binomial (MGNB) models or mixed -effects MGNB (for those tests with information at one or more time points, respectively) were used to investigate the relation between cord blood THg and the children 's punctuations. Models were adjusted for prenatal fish intake. Effect modification by sex, prenatal and postnatal fish intake, prenatal fruit and vegetable intake, and maternal polychlorinated biphenyl concentrations (PCBs) was assessed by interaction terms. Results: The geometric mean +/- standard deviation of cord blood THg was 8.22 +/- 2.19 mu g/L. Despite adjusting for fish consumption, our results did not show any statistically significant relationship between prenatal Hg and the children 's performance on behavioural tests conducted between the ages of 4 and 11. Upon assessing the impact of various factors, we observed no statistically significant interaction. Conclusion: Despite elevated prenatal THg exposure, no association was found with children's behavioural functioning assessed from early childhood to pre -adolescence. The nutrients in fish could offset the potential neurotoxic impact of Hg. Further birth cohort studies with longitudinal data are warranted.

Air pollution is a global public health issue, with particulate matter (PM) being the pollutant with the greatest impact on health. The main objective of this article was to estimate the impact of mortality attributable to particulate pollution in the city of Valencia during the period 2015-2017.

OBJECTIVE:The existence of catch-up lung function growth and its predictors is uncertain. We aimed to identify lung function trajectories and their predictors in a population-based birth cohort. METHODS:We applied group-based trajectory modelling to z-scores of forced expiratory volume in 1 second (zFEV1) and z-scores of forced vital capacity (zFVC) from 1151 children assessed at around 4, 7, 9, 10, 11, 14 and 18 years. Multinomial logistic regression models were used to test whether potential prenatal and postnatal predictors were associated with lung function trajectories. RESULTS:We identified four lung function trajectories: a low (19% and 19% of the sample for zFEV1 and zFVC, respectively), normal (62% and 63%), and high trajectory (16% and 13%) running in parallel, and a catch-up trajectory (2% and 5%) with catch-up occurring between 4 and 10 years. Fewer child allergic diseases and higher body mass index z-score (zBMI) at 4 years were associated with the high and normal compared with the low trajectories, both for zFEV1 and zFVC. Increased children's physical activity during early childhood and higher zBMI at 4 years were associated with the catch-up compared with the low zFEV1 trajectory (relative risk ratios: 1.59 per physical activity category (1.03-2.46) and 1.47 per zBMI (0.97-2.23), respectively). No predictors were identified for zFVC catch-up growth. CONCLUSION:We found three parallel-running and one catch-up zFEV1 and zFVC trajectories, and identified physical activity and body mass at 4 years as predictors of zFEV1 but not zFVC catch-up growth.

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.

BACKGROUND:The purpose of this study was to assess the relationship between noise disturbance at home, sleep disturbance, and neurodevelopmental problems in 9-year-old children. MATERIAL AND METHODS:Noise exposure (frequency) perceived by 430 9-year-old children from the INMA cohort in Valencia, Spain, were reported by their mothers. The risk of developing attention deficit hyperactivity disorder, as well as internalizing and externalizing problems, were assessed using the Child Behaviour Checklist. RESULTS:The risk of internalizing (18%) and externalizing problems (11.7%) was higher compared to the risk of developing attention deficit hyperactivity disorder (1.4%) and were more prevalent in boys than in girls. The most common and bothersome noise exposures were generated at home (50.8-55.3%) and by neighbours (24.5%). The risk of neurodevelopmental problems was associated with sleep disturbances, particularly in relation with attention deficit hyperactivity disorder (16.1 vs 4%; p<0.001), with no differences observed between sex. Sleep disturbances were significantly more common in children exposed to noise from household or neighbours. High levels of noise exposure from street traffic and neighbours were linked to an increased risk of attention deficit hyperactivity disorder, while noise from other children at home was associated with a higher risk of internalizing and externalizing problems. These effects remained consistent even after adjusting for sleep disturbances. CONCLUSIONS:High levels of noise annoyance from various sources perceived at home are differently associated with the risks of different neurodevelopmental problems in 9-year-old boys and girls, with sleep disturbances not influencing this relationship.

INTRODUCTION:Ambient air temperature may affect birth outcomes adversely, but little is known about their impact on foetal growth throughout pregnancy. We evaluated the association between temperature exposure during pregnancy and foetal size and growth in three European birth cohorts. METHODS:We studied 23,408 pregnant women from the English Born in Bradford cohort, Dutch Generation R Study, and Spanish INMA Project. Using the UrbClimTM model, weekly ambient air temperature exposure at 100x100m resolution at the mothers' residences during pregnancy was calculated. Estimated foetal weight, head circumference, and femur length at mid and late pregnancy and weight, head circumference, and length at birth were converted into standard deviation scores (SDS). Foetal growth from mid to late pregnancy was calculated (grams or centimetres/week). Cohort/region-specific distributed lag non-linear models were combined using a random-effects meta-analysis and results presented in reference to the median percentile of temperature (14 °C). RESULTS:Weekly temperatures ranged from -5.6 (Bradford) to 30.3 °C (INMA-Sabadell). Cold and heat exposure during weeks 1-28 were associated with a smaller and larger head circumference in late pregnancy, respectively (e.g., for 9.5 °C: -1.6 SDS [95 %CI -2.0; -0.4] and for 20.0 °C: 1.8 SDS [0.7; 2.9]). A susceptibility period from weeks 1-7 was identified for cold exposure and a smaller head circumference at late pregnancy. Cold exposure was associated with a slower head circumference growth from mid to late pregnancy (for 5.5 °C: -0.1 cm/week [-0.2; -0.04]), with a susceptibility period from weeks 4-12. No associations that survived multiple testing correction were found for other foetal or any birth outcomes. CONCLUSIONS:Cumulative exposure to cold and heat during pregnancy was associated with changes in foetal head circumference throughout gestation, with susceptibility periods for cold during the first pregnancy trimester. No associations were found at birth, suggesting potential recovery. Future research should replicate this study across different climatic regions including varying temperature profiles.

BACKGROUND // Air pollution is a global public health issue, with particulate matter (PM) being the pollutant with the greatest impact on health. The main objective of this article was to estimate the impact of mortality attributable to particulate pollution in the city of Valencia during the period 2015-2017. METHODS //The The Health Impact Assessment (HIA) methodology from the Aphekom project was used. Scenarios of a 5 N g/m 3 reduction in the annual mean concentration of PM10 10 and PM 2.5 were employed, along with the assumption of meeting the World Health Organization (WHO) recommendations in effect during the study period, to estimate both short- and long-term impacts. RESULTS // The estimated average concentrations for 2015-2017 were 18.4 N g/m 3 for PM10 10 and 12.3 N g/m 3 for PM2.5. 2.5 . The short-term HIA, assuming a reduction of 5 N g/m 3 in the averages, resulted in a total of 65.4 premature deaths that could be postponed during that period (21.8 annually), corresponding to a rate of 2.8 deaths per 100,000 inhabitants. In the long term, if PM 2.5 concentrations had been reduced by 5 N g/m 3 , 124 premature deaths could have been postponed annually. CONCLUSIONS //The The annual average concentrations of these pollutants meet the limits set by European regulations. However, compared to WHO recommendations, PM 2.5 levels are higher by 2.3 N g/m 3 . An air quality scenario in line with WHO recommendations would have resulted in a reduction of 122 premature deaths annually.

Telomere length (TL) is a biomarker linked to age-related diseases based on its sensitivity to oxidative DNA damage and inflammation. Methylmercury (MeHg) is a common pollutant in fish. It may induce oxidative stress leading to shorter TL. However, previous research showed contradictory results and dose-concentration dependencies and non-linear relationships have been suggested. This study was carried out in the INMA multi-center birth cohort prospective study comprising mother–child pairs belonging to four different Spanish cohorts from 2004. We set out to assess the association between prenatal and 4-year-old children's exposure to MeHg with TL at the ages of 4 and 7–9 years (n = 1083). Sociodemographic and lifestyle covariates, as well as fish consumption and estimated polyunsaturated fatty acid content, were also considered in the analyses. A mixed regression model and interaction models based on sex and fish consumption were performed. Sensitivity analyses to assess confounding effects were also built by adding to the main model other pollutants present in fish, such as other metals, polychlorinated biphenyls, and dichlorodiphenyldichloroethylene, as well as single nucleotide polymorphisms in the TERT and CLPTM1L genes. Longer TL was associated with higher paternal age and female sex in children. MeHg concentrations were related to higher maternal age, being primiparous, working during pregnancy, higher education, and higher fish consumption. No significant associations between prenatal or postnatal MeHg concentrations and TL were found. Sensitivity analyses showed no MeHg modification effect on TL. Further research is needed to elucidate the TL modifications found by previous studies associated with MeHg and fish consumption.

OBJECTIVE:Air pollution is a global public health issue, with particulate matter (PM) being the pollutant with the greatest impact on health. The main objective of this article was to estimate the impact of mortality attributable to particulate pollution in the city of Valencia during the period 2015-2017. METHODS:The Health Impact Assessment (HIA) methodology from the Aphekom project was used. Scenarios of a 5 µg/m3 reduction in the annual mean concentration of PM10 and PM2.5 were employed, along with the assumption of meeting the World Health Organization (WHO) recommendations in effect during the study period, to estimate both short- and long-term impacts. RESULTS:The estimated average concentrations for 2015-2017 were 18.4 µg/m3 for PM10 and 12.3 µg/m3 for PM2.5. The short-term HIA, assuming a reduction of 5 µg/m3 in the averages, resulted in a total of 65.4 premature deaths that could be postponed during that period (21.8 annually), corresponding to a rate of 2.8 deaths per 100,000 inhabitants. In the long term, if PM2.5 concentrations had been reduced by 5 µg/m3, 124 premature deaths could have been postponed annually. CONCLUSIONS:The annual average concentrations of these pollutants meet the limits set by European regulations. However, compared to WHO recommendations, PM2.5 levels are higher by 2.3 µg/m3. An air quality scenario in line with WHO recommendations would have resulted in a reduction of 122 premature deaths annually.

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.

Rationale: The identification of novel molecules associated with asthma may provide insights into the mechanisms of disease and their potential clinical implications. Objectives: To conduct a screening of circulating proteins in childhood asthma and to study proteins that emerged from human studies in a mouse model of asthma. Methods: We included 2,264 children from eight birth cohorts from the Mechanisms of the Development of ALLergy project and the Tucson Children's Respiratory Study. In cross-sectional analyses, we tested 46 circulating proteins for association with asthma in the selection stage and carried significant signals forward to a validation and replication stage. As CK (creatine kinase) was the only protein consistently associated with asthma, we also compared whole blood CK gene expression between subjects with and without asthma (n = 249) and used a house dust mite (HDM)-challenged mouse model to gain insights into CK lung expression and its role in the resolution of asthma phenotypes. Measurements and Main Results: As compared with the lowest CK tertile, children in the highest tertile had significantly lower odds for asthma in selection (adjusted odds ratio, 95% confidence interval: 0.31; 0.15-0.65; P = 0.002), validation (0.63; 0.42-0.95; P = 0.03), and replication (0.40; 0.16-0.97; P = 0.04) stages. Both cytosolic CK forms (CKM and CKB) were underexpressed in blood from asthmatics compared with control subjects (P = 0.01 and 0.006, respectively). In the lungs of HDM-challenged mice, Ckb expression was reduced, and after the HDM challenge, a CKB inhibitor blocked the resolution of airway hyperresponsiveness and reduction of airway mucin. Conclusions: Circulating concentrations and gene expression of CK are inversely associated with childhood asthma. Mouse models support a possible direct involvement of CK in asthma protection via inhibition of airway hyperresponsiveness and reduction of airway mucin.

We explored the influence of child and maternal single nucleotide polymorphisms (SNPs) in genes related to neurological function and arsenic metabolism (i.e., ABCA1, ABCB1, PON1, CYP3A, BDNF, GSTP1, MT2A, and APOE as well as AS3MT) on the association between prenatal arsenic (As) exposure and methylation efficiency and neuropsychological development in 4-5-year-old children. Participants were 549 mother-child pairs from the INMA (Environment and Childhood) Spanish Project. We measured inorganic arsenic (iAs) and the metabolites monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in urine samples collected during pregnancy. Neuropsychological development was assessed at the age of 4-5 years using the McCarthy Scales of Children's Abilities (MSCA). Several SNPs were determined in maternal and child DNA; AS3MT and APOE haplotypes were inferred. The median ∑As (sum of iAs, DMA, and MMA) was 7.08 μg/g creatinine. Statistically significant interactions for children's APOE haplotype were observed. Specifically, ε4-carrier children had consistently lower MSCA scores in several scales with increasing ∑As and MMA concentrations. These results provide evidence regarding the neurotoxic effects of early life exposure to As, observing that the APOE ε4 allele could make children more vulnerable to this exposure.

Background: Inorganic arsenic (iAs) is a widespread toxic metalloid. It is well-known that iAs metabolism and its toxicity are mediated by polymorphisms in AS3MT and other genes. However, studies during pregnancy are scarce. We aimed to examine the role of genetic polymorphisms in AS3MT, GSTO2, N6AMT1, MTHFR, MTR, FTCD, CBS, and FOLH1 in iAs methylation efficiency during pregnancy.Methods: The study included 541 pregnant participants from the INMA (Environment and Childhood) Spanish cohort. Using high-performance liquid chromatography coupled to inductively coupled plasma-tandem mass, we measured arsenic (iAs and the metabolites monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)) in urine samples collected during the first trimester. iAs methylation efficiency was determined based on relative concentrations of the As metabolites in urine (%MMA, %DMA, and %iAs). Thirty-two single nucleotide poly-morphisms (SNPs) in nine genes were determined in maternal DNA; AS3MT haplotypes were inferred. We assessed the association between genotypes/haplotypes and maternal As methylation efficiency using multi-variate linear regression models. Results: The median %MMA and %DMA were 5.3 %, and 89 %, respectively. Ancestral alleles of AS3MT SNPs (rs3740393, rs3740390, rs11191453, and rs11191454) were significantly associated with higher %MMA, %iAs, and lower %DMA. Pregnant participants with zero copies of the GGCTTCAC AS3MT haplotype presented a higher%MMA. Statistically significant associations were also found for the FOLH1 SNP rs202676 (& beta; 0.89 95%CI: 0.24, 1.55 for carriers of the G allele vs. the A allele).Conclusions: Our study shows that ancestral alleles in AS3MT polymorphisms were associated with lower As methylation efficiency in early pregnancy and suggests that FOLH1 also plays a role in As methylation efficiency. These results support the hypothesis that As metabolism is multigenic, being a key element for identifying susceptible populations.

Emotional and behavioral problems during childhood raise the risk of subsequent developmental of mental disorders. Our aim was to study the association between maternal metal and trace element concentrations during gestation and these problems in 9 year-old children. The study sample comprised Spanish mother-child pairs in the INMA project (n = 1003). Metals and trace elements (As, Cd, Co, Cu, Mo, Ni, Pb, Sb, Se, Tl and Zn) were measured in urine samples collected during pregnancy. Inorganic As metabolites were speciated in a subsample (n = 729). Emotional and behavioral problems were assessed using the Child Behavior Checklist (CBCL) composed of three scales: internalizing, externalizing and total problems. Sociodemographic, dietary and exposure to other environmental pollutants were obtained through questionnaires. Single nucleotide polymorphisms in brain- and metabolism-related genes APOE , BDNF , GSTP1 , and PON1 were determined in cord blood. Multivariate negative binomial models were used. The interaction with sex and genotypes was evaluated including interaction terms. A multi-element analysis was carried out by a principal component analysis. Higher concentrations of Cu, monomethylarsonic acid, and Pb during pregnancy were associated with an increased incidence ratio risk (IRR) between 4.6 and 7.5% for internalizing and externalizing problems for all three CBCL scales in the children. Increasing Mo, Ni and Co concentrations were associated with higher IRR for internalizing problems (up to 8%), and Cd for externalizing problems (6.7%). Modifications by sex and genotypes were found for several associations. Multi-element analysis associated multiple metals and trace elements (Ni, Cu, Se, Cd and Pb) with higher internalizing problems.