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Neurodevelopmental disorders are increasing globally, and metal exposure may play a significant role as an environmental factor. This cross-sectional study aimed to identify metal mixture patterns and assess their impact on children’s neurodevelopment. Data from 962 children (aged 4–5 years) participating in the Spanish INMA cohort study were analysed. Urinary metal concentrations (cobalt (Co), copper (Cu), molybdenum (Mo), selenium (Se), lead (Pb), zinc (Zn), and arsenic speciation) were used as exposure biomarkers. Principal component analysis (PCA) revealed four latent exposure variables representing uncorrelated metal mixture patterns. Linear regression analyses examined the associations between these variables and children’s neuropsychological functions assessed through the McCarthy Scales of Children’s Abilities. The first latent exposure variable (Cu, Se, Pb, Zn) and the second (inorganic arsenic, monomethylarsonic acid) showed negative associations with verbal executive function (ß = − 1.88, 95% confidence interval (CI) = − 3.17 to − 0.59) and gross motor function (ß = − 1.41, 95% CI = − 2.36 to − 0.46), respectively. Conversely, the third variable (Mo, Co) and the fourth (arsenobetaine) exhibited positive associations with visual and verbal span functions (ß = 1.14, 95% CI = 0.16 to 2.12) and fine motor function (ß = 1.01, 95% CI = 0.11 to 1.92), respectively. This study suggests that even relatively low levels of metal latent exposures, notably inorganic arsenic and a mixture of metals including Pb, adversely affect children’s neuropsychological development function scores, while exposure to arsenobetaine and a mixture of Co and Mo has a positive impact.

A balanced concentration of polyunsaturated fatty acids (PUFA) in the prenatal stage is essential for children¿s neurodevelopment. Also, animal studies showed that high levels of anti-inflammatory PUFA metabolites in the embryonic brain protect against genetic or environmental insults that would otherwise cause cognitive impairment. Here we used liquid chromatography - mass spectrometry to analyze oxylipins, the oxygenated metabolites of PUFA, in the placenta tissue (N=12) and cord blood plasma (N=39) of children from the INMA cohort (Valencia, Spain). Both tissues were characterized for total Hg levels as a reference for developmental neurotoxic MeHg exposure during pregnancy and distributed in low and high Hg groups. Deleterious effects of high Hg were confirmed in the placenta as decreased proteasome activity and inhibitory epigenetic changes. Children¿s neurodevelopment was assessed using the Bayley (14 months) and McCarthy (5 years) scales. Spearman correlation coefficients were calculated between scores and oxylipin levels. We also analyzed cortical brain tissue from wild type and transgenic Alzheimer's disease (5XFAD) mice dosed for 2 months with vehicle or a soluble epoxide hydrolase enzyme (sEH) inhibitor, UB-BJ-02 (5 mg/Kg, N=5/group). Inhibition of sEH increases levels of the potent anti-inflammatory epoxyeicosatrienoic acids (EETs) by inhibiting their hydrolysis to dihydro-EETs (DiHETs). We found that DiHETs were increased in the placenta of high Hg group. Furthermore, the mental and psychomotor development of 14-month-old children correlates positively with DiHETs levels in both placenta and cord blood tissues. Interestingly, cord blood DiEHTs positively correlate with working memory at 5 years. Thus we suggest that higher levels of DiHETs indicate higher synthesis of their anti-inflammatory EETs precursors. Accordingly, placenta levels of EETs correlate with mental development at 14 months of age. Other oxylipin changes also suggested an involvement of

Background: There are few studies that look at the intake of all types of omega-3 polyunsaturated fatty acids (n-3 PUFAs) during the different stages of pregnancy along with a long-term neuropsychological follow-up of the child. This study aims to explore the association between maternal n-3 PUFA intake during two periods of pregnancy and the child’s neuropsychological scores at different ages. Methods: Prospective data were obtained for 2644 pregnant women recruited between 2004 and 2008 in population-based birth cohorts in Spain. Maternal n-3 PUFA intake during the first and third trimester of pregnancy was estimated using validated food frequency questionnaires. Child neuropsychological functions were assessed using Bayley Scales of Infant Development version one (BSID) at 1 year old, the McCarthy Scale of Children’s Abilities (MSCA) at 4 years old, and the Attention Network Test (ANT) at 7 years old. Data were analysed using multivariate linear regression models and adjusted for potential covariates, such as maternal social class, education, cohort location, alcohol consumption, smoking, breastfeeding duration, and energy intake. Results: Compared to participants in the lowest quartile (<1.262 g/week) of n-3 PUFA consumption during the first trimester, those in the highest quartile (>1.657 g/week) had a 2.26 points (95% confidence interval (CI): 0.41, 4.11) higher MSCA general cognitive score, a 2.48 points (95% CI: 0.53, 4.43) higher MSCA verbal score, and a 2.06 points (95% CI: 0.166, 3.95) higher MSCA executive function score, and a 11.52 milliseconds (95% CI:-22.95,-0.09) lower ANT hit reaction time standard error. In the third pregnancy trimester, the associations were weaker. Conclusions: Positive associations between n-3 PUFA intake during early pregnancy and

Early life is an important window of opportunity to improve health across the full lifecycle. An accumulating body of evidence suggests that exposure to adverse stressors during early life leads to developmental adaptations, which subsequently affect disease risk in later life. Also, geographical, socio-economic, and ethnic differences are related to health inequalities from early life onwards. To address these important public health challenges, many European pregnancy and childhood cohorts have been established over the last 30 years. The enormous wealth of data of these cohorts has led to important new biological insights and important impact for health from early life onwards. The impact of these cohorts and their data could be further increased by combining data from different cohorts. Combining data will lead to the possibility of identifying smaller effect estimates, and the opportunity to better identify risk groups and risk factors leading to disease across the lifecycle across countries. Also, it enables research on better causal understanding and modelling of life course health trajectories. The EU Child Cohort Network, established by the Horizon2020-funded LifeCycle Project, brings together nineteen pregnancy and childhood cohorts, together including more than 250,000 children and their parents. A large set of variables has been harmonised and standardized across these cohorts. The harmonized data are kept within each institution and can be accessed by external researchers through a shared federated data analysis platform using the R-based platform

Contains fulltext : 215577.pdf (publisher's version ) (Open Access)

Early iron status plays an important role in prenatal neurodevelopment. Iron deficiency and high iron status have been related to alterations in child cognitive development; however, there are no data about iron intake during pregnancy with other environmental factors in relation to long term cognitive functioning of children. The aim of this study is to assess the relationship between maternal iron status and iron intake during pregnancy and child neuropsychological outcomes at 7 years of age. We used data from the INMA Cohort population-based study. Iron status during pregnancy was assessed according to serum ferritin levels, and iron intake was assessed with food frequency questionnaires. Working memory, attention, and executive function were assessed in children at 7 years old with the N-Back task, Attention Network Task, and the Trail Making Test, respectively. The results show that, after controlling for potential confounders, normal maternal serum ferritin levels (from 12 mg/L to 60 mg/L) and iron intake (from 14.5 mg/day to 30.0 mg/day), respectively, were related to better scores in working memory and executive functioning in offspring. Since these functions have been associated with better academic performance and adaptation to the environment

CONTEXT: Although the consequences of severe iodine deficiency are beyond doubt, the effects of mild to moderate iodine deficiency in pregnancy on child neurodevelopment are less well established. OBJECTIVE: To study the association between maternal iodine status during pregnancy and child IQ and identify vulnerable time windows of exposure to suboptimal iodine availability. DESIGN: Meta-analysis of individual participant data from three prospective population-based birth cohorts: Generation R (Netherlands), INMA (Spain), and ALSPAC (United Kingdom); pregnant women were enrolled between 2002 and 2006, 2003 and 2008, and 1990 and 1992, respectively. SETTING: General community. PARTICIPANTS: 6180 mother-child pairs with measures of urinary iodine and creatinine concentrations in pregnancy and child IQ. Exclusion criteria were multiple pregnancies, fertility treatment, medication affecting the thyroid, and preexisting thyroid disease. MAIN OUTCOME MEASURE: Child nonverbal and verbal IQ assessed at 1.5 to 8 years of age. RESULTS: There was a positive curvilinear association of urinary iodine/creatinine ratio (UI/Creat) with mean verbal IQ only. UI/Creat <150 µg/g was not associated with lower nonverbal IQ (-0.6 point; 95% CI: -1.7 to 0.4 points; P = 0.246) or lower verbal IQ (-0.6 point; 95% CI: -1.3 to 0.1 points; P = 0.082). Stratified analyses showed that the association of UI/Creat with verbal IQ was only present up to 14 weeks of gestation. CONCLUSIONS: Fetal brain development is vulnerable to mild to moderate iodine deficiency, particularly in the first trimester. Our results show that potential randomized controlled trials investigating the effect of iodine supplementation in women with mild to moderate iodine deficiency on child neurodevelopment should begin supplementation not later than the first trimester.

Contains fulltext : 215577.pdf (publisher's version ) (Open Access)

Contains fulltext : 215577.pdf (publisher's version ) (Open Access)

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Early iron status plays an important role in prenatal neurodevelopment. Iron deficiency and high iron status have been related to alterations in child cognitive development; however, there are no data about iron intake during pregnancy with other environmental factors in relation to long term cognitive functioning of children. The aim of this study is to assess the relationship between maternal iron status and iron intake during pregnancy and child neuropsychological outcomes at 7 years of age. We used data from the INMA Cohort population-based study. Iron status during pregnancy was assessed according to serum ferritin levels, and iron intake was assessed with food frequency questionnaires. Working memory, attention, and executive function were assessed in children at 7 years old with the N-Back task, Attention Network Task, and the Trail Making Test, respectively. The results show that, after controlling for potential confounders, normal maternal serum ferritin levels (from 12 mg/L to 60 mg/L) and iron intake (from 14.5 mg/day to 30.0 mg/day), respectively, were related to better scores in working memory and executive functioning in offspring. Since these functions have been associated with better academic performance and adaptation to the environment, maintaining a good state of maternal iron from the beginning of pregnancy could be a valuable strategy for the community.

Contains fulltext : 193339.pdf (publisher's version ) (Closed access), BACKGROUND: DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma. METHODS: We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4-5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4-16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2-56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1-79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting. FINDINGS: 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p<1.14 x 10(-7)) after meta-analysis. Consistently lower methylation le

Contains fulltext : 193339.pdf (publisher's version ) (Closed access), BACKGROUND: DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma. METHODS: We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4-5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4-16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2-56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1-79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting. FINDINGS: 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p<1.14 x 10(-7)) after meta-analysis. Consistently lower methylation le

Contains fulltext : 193339.pdf (publisher's version ) (Closed access), BACKGROUND: DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma. METHODS: We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4-5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4-16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2-56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1-79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting. FINDINGS: 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p<1.14 x 10(-7)) after meta-analysis. Consistently lower methylation le

BACKGROUND: Natural environments, including green spaces, may have beneficial impacts on brain development. However, longitudinal evidence of an association between long-term exposure to green spaces and cognitive development (including attention) in children is limited. OBJECTIVES: We evaluated the association between lifelong residential exposure to green space and attention during preschool and early primary school years. METHODS: This longitudinal study was based on data from two well-established population-based birth cohorts in Spain. We assessed lifelong exposure to residential surrounding greenness and tree cover as the average of satellite-based normalized difference vegetation index and vegetation continuous fields, respectively, surrounding the child's residential addresses at birth, 4-5 y, and 7 y. Attention was characterized using two computer-based tests: Conners' Kiddie Continuous Performance Test (K-CPT) at 4-5 y (n=888) and Attentional Network Task (ANT) at 7 y (n=987). We used adjusted mixed effects models with cohort random effects to estimate associations between exposure to greenness and attention at ages 4-5 and 7 y. RESULTS: Higher lifelong residential surrounding greenness was associated with fewer K-CPT omission errors and lower K-CPT hit reaction time-standard error (HRT-SE) at 4-5 y and lower ANT HRT-SE at 7 y, consistent with better attention. This exposure was not associated with K-CPT commission errors or with ANT omission or commission errors. Associations with residential surrounding tree cover also were close to the null, or were negative (for ANT HRT-SE) but not statistically significant. CONCLUSION: Exposure to residential surrounding greenness was associated with better scores on tests of attention at 4-5 y and 7 y of age in our longitudinal cohort. https://doi.org/10.1289/EHP694.

The chromosome bands 15q24.1-15q24.3 contain a complex region with numerous segmental duplications that predispose to regional microduplications and microdeletions, both of which have been linked to intellectual disability, speech delay and autistic features. The region may also harbour common inversion polymorphisms whose functional and phenotypic manifestations are unknown. Using single nucleotide polymorphism (SNP) data, we detected four large contiguous haplotype-genotypes at 15q24 with Mendelian inheritance in 2,562 trios, African origin, high population stratification and reduced recombination rates. Although the haplotype-genotypes have been most likely generated by decreased or absent recombination among them, we could not confirm that they were the product of inversion polymorphisms in the region. One of the blocks was composed of three haplotype-genotypes (N1a, N1b and N2), which significantly correlated with intelligence quotient (IQ) in 2,735 children of European ancestry from three independent population cohorts. Homozygosity for N2 was associated with lower verbal IQ (2.4-point loss, p-value = 0.01), while homozygosity for N1b was associated with 3.2-point loss in non-verbal IQ ( p-value = 0.0006). The three alleles strongly correlated with expression levels of MAN2C1 and SNUPN in blood and brain. Homozygosity for N2 correlated with over-expression of MAN2C1 over many brain areas but the occipital cortex where N1b homozygous highly under-expressed. Our population-based analyses suggest that MAN2C1 may contribute to the verbal difficulties observed in microduplications and to the intellectual disability of microdeletion syndromes, whose characteristic dosage increment and removal may affect different brain areas.

Seafood consumption during pregnancy is thought to be beneficial for child neuropsychological development, but to our knowledge no large cohort studies with high fatty fish consumption have analyzed the association by seafood subtype. We evaluated 1,892 and 1,589 mother-child pairs at the ages of 14 months and 5 years, respectively, in a population-based Spanish birth cohort established during 2004-2008. Bayley and McCarthy scales and the Childhood Asperger Syndrome Test were used to assess neuropsychological development. Results from multivariate linear regression models were adjusted for sociodemographic characteristics and further adjusted for umbilical cord blood mercury or long-chain polyunsaturated fatty acid concentrations. Overall, consumption of seafood above the recommended limit of 340 g/week was associated with 10-g/week increments in neuropsychological scores. By subtype, in addition to lean fish, consumption of large fatty fish showed a positive association; offspring of persons within the highest quantile (>238 g/week) had an adjusted increase of 2.29 points in McCarthy general cognitive score (95% confidence interval: 0.42, 4.16). Similar findings were observed for the Childhood Asperger Syndrome Test. Beta coefficients diminished 15%-30% after adjustment for mercury or long-chain polyunsaturated fatty acid concentrations. Consumption of large fatty fish during pregnancy presents moderate child neuropsychological benefits, including improvements in cognitive functioning and some protection from autism-spectrum traits.

This article aims to analyze the impact of the economic and financial crisis on environmental determinants of health. The World Health Organization estimates that between 13% and 27% of the disease burden in countries could be prevented by improving the environment. These effects are larger in vulnerable populations, especially among the poorest. In the last decade, outdoor air pollution (the most significant environmental health risk in most European countries) has declined, mostly due to the European policy of reducing emissions and to the decrease in activity following the economic crisis. During the last few years, this improvement in air quality has occurred simultaneously with a reduction in investment in environmental protection and could therefore be offset in the medium-term. The economic crisis has not reduced the trend for higher temperatures in Spain and Europe because climate change is a global phenomenon that is not directly related to local emissions. To reduce the risk of an increase in the health impact of environmental factors, certain key aspects should be considered, such as the need to maintain or develop adequate monitoring and control systems and the opportunity to implement policies that help improve the quality of the environment and reduce the vulnerability of different population groups in a cross-disciplinary framework of transparency and citizen participation. © 2014 SESPAS.