Publications by authors named "Sabrina Llop"

96 Publications

Prenatal arsenic exposure, arsenic methylation efficiency, and neuropsychological development among preschool children in a Spanish birth cohort.

Environ Res 2021 Oct 15:112208. Epub 2021 Oct 15.

Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain.

Background: Prenatal arsenic (As) exposure could negatively affect child neuropsychological development, but the current evidence is inconclusive.

Objectives: To explore the relationship between prenatal urinary total As (TAs) concentrations, the As species and the methylation efficiency, and child neuropsychological development in a Spanish birth cohort. We also studied the effect modification produced by sex and several nutrients and elements.

Materials And Methods: Study subjects were 807 mother-child pairs participating in the INMA (Childhood and Environment) Project. Urinary TAs and its metabolites, monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), inorganic As (iAs) and arsenobetaine were measured in the first trimester of pregnancy. Methylation efficiency was determined through the percentages of the metabolites and using principal component analysis. Children's neuropsychological development was assessed at the age of 4-5 years using the McCarthy Scales of Children's Abilities (MSCA). Multivariable linear regression models were built to assess the association between TAs, the As species and the maternal methylation efficiency, and the neuropsychological scores. We explored effect modification by sex, iron status, maternal nutrients status (serum manganese and selenium, and urinary zinc), and maternal vitamins intake (folate, and vitamins B and B).

Results: The geometric mean (95%CI) of ∑As (sum of DMA, MMA and iAs) was 7.78 (7.41, 8.17) μg/g creatinine. MMA concentrations were inversely associated with the scores for the general, verbal, quantitative, memory, executive function and working memory scales (i.e. β [CI95%] = -1.37 [-2.33, -0.41] for the general scale). An inverse association between %MMA and the memory scores was found. Children whose mothers had lower manganese, zinc and ferritin concentrations obtained lower scores on several MSCA scales with decreasing As methylation efficiency.

Discussion: An inverse association was observed between MMA concentrations and children's neuropsychological development. Maternal levels of manganese, zinc and ferritin affected the association between As methylation efficiency and MSCA scores.
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http://dx.doi.org/10.1016/j.envres.2021.112208DOI Listing
October 2021

Serum metal levels in a population of Spanish pregnant women.

Gac Sanit 2021 Oct 6. Epub 2021 Oct 6.

Biodonostia, Health Research Institute, Donostia, Gipuzkoa, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), Spain; Department of Health of the Basque Government, Public Health Division of Gipuzkoa, Donostia, Gipuzkoa, Spain.

Objective: To describe serum levels of calcium, copper, selenium, magnesium, iron and zinc and evaluate their relationship with maternal socio-demographic characteristics and dietary variables in women in the first trimester of pregnancy.

Method: Cross-sectional study with 1279 participants from the INMA cohorts.

Results: The concentrations of the elements analyzed were within the normal range. Associations with higher levels of these metals were found for calcium with white meat intake (p=0.026), for copper with excess body weight (p <0.01), low social class (p=0.03) and being multipara (p <0.01), for magnesium with being over 35 years old (p=0.001), high social class (p=0.044), primiparous status (p=0.002) and low daily intake of bread (p=0.009) and legumes (p=0.020); for zinc with university education (p=0.039) and residence in Gipuzkoa (p <0.01), and for selenium with residence in Valencia (p <0.01), university education (p=0.001), vitamin B supplementation (p=0.006), fish intake (> 71g/day) (p=0.014) and having been born in Spain (p=0.001). Further, lower iron levels were associated with being overweight (p=0.021) or obese (p <0.001) and vitamin B supplementation (p=0.006).

Conclusions: Our results suggest that trace elements in the analyzed cohorts are adequate for this stage of pregnancy. The variability in these elements is mainly linked to socio-demographic and anthropometric variables.
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http://dx.doi.org/10.1016/j.gaceta.2021.07.006DOI Listing
October 2021

DNA methylation changes associated with prenatal mercury exposure: A meta-analysis of prospective cohort studies from PACE consortium.

Environ Res 2021 Sep 22;204(Pt B):112093. Epub 2021 Sep 22.

Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain.

Mercury (Hg) is a ubiquitous heavy metal that originates from both natural and anthropogenic sources and is transformed in the environment to its most toxicant form, methylmercury (MeHg). Recent studies suggest that MeHg exposure can alter epigenetic modifications during embryogenesis. In this study, we examined associations between prenatal MeHg exposure and levels of cord blood DNA methylation (DNAm) by meta-analysis in up to seven independent studies (n = 1462) as well as persistence of those relationships in blood from 7 to 8 year-old children (n = 794). In cord blood, we found limited evidence of differential DNAm at cg24184221 in MED31 (β = 2.28 × 10, p-value = 5.87 × 10) in relation to prenatal MeHg exposure. In child blood, we identified differential DNAm at cg15288800 (β = 0.004, p-value = 4.97 × 10), also located in MED31. This repeated link to MED31, a gene involved in lipid metabolism and RNA Polymerase II transcription function, may suggest a DNAm perturbation related to MeHg exposure that persists into early childhood. Further, we found evidence for association between prenatal MeHg exposure and child blood DNAm levels at two additional CpGs: cg12204245 (β = 0.002, p-value = 4.81 × 10) in GRK1 and cg02212000 (β = -0.001, p-value = 8.13 × 10) in GGH. Prenatal MeHg exposure was associated with DNAm modifications that may influence health outcomes, such as cognitive or anthropometric development, in different populations.
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http://dx.doi.org/10.1016/j.envres.2021.112093DOI Listing
September 2021

Exposure to metals and metalloids among pregnant women from Spain: Levels and associated factors.

Chemosphere 2021 Aug 6;286(Pt 2):131809. Epub 2021 Aug 6.

Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain.

Background: Humans are regularly exposed to metals and metalloids present in air, water, food, soil and domestic materials. Most of them can cross the placental barrier and cause adverse impacts on the developing foetus.

Objectives: To describe the prenatal concentrations of metals and metalloids and to study the associated sociodemographic, environmental and dietary factors in pregnant Spanish women.

Methods: Subjects were 1346 pregnant women of the INMA Project, for whom the following metals arsenic (As), cadmium (Cd), cobalt (Co), copper (Cu), molybdenum (Mo), nickel (Ni), lead (Pb), antimony (Sb), selenium (Se), thallium (Tl) and zinc (Zn) were determined in urine, at both the first and the third trimesters of gestation. Sociodemographic, dietary and environmental information was collected through questionnaires during pregnancy. Multiple linear mixed models were built in order to study the association between each metal and metalloid concentrations and the sociodemographic, environmental and dietary factors.

Results: The most detected compounds were As, Co, Mo, Sb, Se and Zn at both trimesters. Zn was the element found in the highest concentrations at both trimesters and Tl was detected in the lowest concentrations. We observed significant associations between As, Cd, Cu, Sb, Tl and Zn concentrations and working situation, social class and age. Seafood, meat, fruits, nuts, vegetables and alcohol intake affected the levels of all the metals but Cd and Cu. Proximity to industrial areas, fields and air pollution were related to all metals except Cd, Sb and Se.

Conclusions: This is the first large prospective longitudinal study on the exposure to metals and metalloids during pregnancy and associated factors to include several cohorts in Spain. The present study shows that some modifiable lifestyles, food intakes and environmental factors could be associated with prenatal exposure to metal(loid)s, which may be considered in further studies to assess their relationship with neonatal health outcomes.
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http://dx.doi.org/10.1016/j.chemosphere.2021.131809DOI Listing
August 2021

Genetic association study of childhood aggression across raters, instruments, and age.

Transl Psychiatry 2021 07 30;11(1):413. Epub 2021 Jul 30.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGG) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGG. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (r) among rater-specific assessment of AGG ranged from r = 0.46 between self- and teacher-assessment to r = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
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http://dx.doi.org/10.1038/s41398-021-01480-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324785PMC
July 2021

Maternal Perfluoroalkyl Substances, Thyroid Hormones, and Genes: A Spanish Cross-sectional Study.

Environ Sci Technol 2021 Jul 27. Epub 2021 Jul 27.

Epidemiology and Environmental Health Joint Research Unit, FISABIO-University Jaume I-University of Valencia, 46019 Valencia, Spain.

Results of studies on perfluoroalkyl substances (PFASs) and thyroid hormones (THs) are heterogeneous, and the mechanisms underlying the action of PFASs to target THs have not been fully characterized. We examined the relation between first-trimester maternal PFAS and TH levels and the role played by polymorphisms in the iodothyronine deiodinase 1 (1) and 2 (2) genes in this association. Our sample comprised 919 pregnant Spanish women (recruitment = 2003-2008) with measurements of perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), thyroid-stimulating hormone (TSH), total triiodothyronine (TT3), and free thyroxine (FT4), and we genotyped for single-nucleotide polymorphisms in the 1 (rs2235544) and 2 (rs12885300) genes. We performed multivariate regression analyses between PFASs and THs and included the interaction term PFAS-genotypes in the models. PFHxS was associated with an increase in TSH (% change in outcome [95% CI] per 2-fold PFAS increase = 6.09 [-0.71, 13.4]), and PFOA and PFNA were associated with a decrease in TT3 (-7.17 [-13.5, -0.39] and -6.28 [-12.3, 0.12], respectively). We found stronger associations between PFOA, PFNA, and TT3 for 1-CC and 2-CT genotypes, although interaction -values were not significant. In conclusion, this study found evidence of an inverse association between PFOA and TT3 levels. No clear effect modification by enzyme genes was observed.
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http://dx.doi.org/10.1021/acs.est.1c01452DOI Listing
July 2021

Prenatal perfluoroalkyl substance exposure and neuropsychological development throughout childhood: The INMA Project.

J Hazard Mater 2021 08 20;416:125185. Epub 2021 Jan 20.

Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain; Faculty of Nursing and Chiropody, Universitat de València, Valencia, Spain. Electronic address:

Background: Perfluoroalkyl substances (PFASs) have been related to neurodevelopmental toxicity in animals. However, human studies are inconclusive.

Objectives: To evaluate the association between prenatal PFAS exposure and neuropsychological development during childhood.

Methods: 1240 mother-child pairs from the Spanish INMA Project were analyzed. Perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorononanoic acid (PFNA) were measured in first-trimester maternal plasma. Neuropsychological development was assessed at 14 months, 4-5 and 7 years covering four domains: general cognitive, general motor, attention, and working memory. Associations were studied by means of multivariable regression analyses.

Results: PFHxS, PFOA, PFOS, and PFNA medians were: 0.6, 2.4, 6.1, and 0.7 ng/mL. Higher PFAS prenatal exposure was associated with worse motor development at 14 months, especially in the case of PFHxS (β[95%CI]: -1.49[-2.73, -0.24]) and to a lesser extent PFOS (-1.25[-2.62, 0.12]). There was also a marginal positive association between general cognitive development at 4-5 years and PFOS (1.17[-0.10, 2.43]) and PFNA (0.99[-0.13, 2.12]). No clear associations for other neuropsychological outcomes or any sex differences were found.

Discussion: This study shows no clear-cut evidence of an association between prenatal PFAS exposure and adverse neuropsychological development in children up to the age of 7 years.
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http://dx.doi.org/10.1016/j.jhazmat.2021.125185DOI Listing
August 2021

Prenatal manganese serum levels and neurodevelopment at 4 years of age.

Environ Res 2021 06 12;197:111172. Epub 2021 Apr 12.

Biodonostia Health Research Institute, Group of Environmental Epidemiology and Child Development, Paseo Doctor Begiristain s/n, 20014, San Sebastian, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, C/Monforte de Lemos 3-5, 28029, Madrid, Spain; Department of Preventive Medicine and Public Health, Faculty of Medicine, University of the Basque Country (UPV/EHU), 48940, Leioa, Spain.

Background: The excess of manganese (Mn) causes severe deleterious effects in the central nervous system, and the developing brain is especially sensitive to Mn overload. However, results of prospective studies regarding Mn neurodevelopmental effects remain inconclusive. The present study aims at studying the association of prenatal Mn exposure and neurodevelopment at 4-5 years of age.

Methods: Mn serum concentration was measured in 1465 pregnant women from the INMA (INfancia y MedioAmbiente, Environment and Childhood) Project. Neurodevelopment was assessed using a standardized version of the McCarthy Scales of Children's Abilities (MSCA). Multivariate regression models were used for data analysis.

Results: No association was found between Mn levels in serum and any of the McCarthy scales. However, the stratification by sex showed a positive and beneficial association of prenatal Mn levels and the verbal, quantitative and general-cognitive scales in girls (β (95%CI): 4 (0.03, 7.96), 4.5 (0.43, 8.57) and 4.32 (0.6, 8.05), respectively).

Conclusions: A beneficial association was found for the first time between prenatal Mn levels measured in serum and neurodevelopment of female offspring at 4 years of age, which could have implications on public health policies, specifically on the establishment of policies promoting prenatal health related to dietary deficits of micronutrients such as Mn.
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http://dx.doi.org/10.1016/j.envres.2021.111172DOI Listing
June 2021

Pre and postnatal exposure to mercury and respiratory health in preschool children from the Spanish INMA Birth Cohort Study.

Sci Total Environ 2021 Aug 20;782:146654. Epub 2021 Mar 20.

Epidemiology and Environmental Health Joint Research Unit, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region, FISABIO-Public Health, FISABIO-Universitat Jaume I-Universitat de València, Av. Catalunya 21, 46020 Valencia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Av. Monforte de Lemos, 3-5. Pabellón 11, 28029 Madrid, Spain.

Effects of mercury on maturing immune system have been reported, however the association with respiratory and allergy problems during infancy remains unclear. The aim of this study is to evaluate the association between pre and postnatal mercury exposure and respiratory and allergy problems among preschool children and to examine the role of potential modifying factors. Study subjects were children participant in Spanish Childhood and Environment Project (INMA, 2003-2008). We measured total mercury levels in cord blood (n = 1868) and hair at 4 years of age (n = 1347). Respiratory outcomes (wheezing, severe wheezing, chestiness, persistent cough, eczema and otitis) were obtained by questionnaires administered to parents. Associations were investigated by logistic regression adjusted for socio-demographic and lifestyle-related variables in each cohort and subsequent meta-analysis. We tested effect modification by factors related to individual susceptibility, diet and co-exposure with other pollutants. The geometric mean of cord blood and hair total mercury was 8.20 μg/L and 0.97 μg/g, respectively. No statistically significant association between pre or postnatal mercury exposure and respiratory and allergy outcomes was found. Notwithstanding, lower maternal intake of fruits and vegetables increased the risk of some respiratory outcomes due to the prenatal exposure to mercury (p < 0.05). Moreover, an inverse association between prenatal mercury exposure and some respiratory outcomes was observed among children with higher maternal exposure to organocholorine compounds or smoking (p < 0.05). Also, sex and postnatal smoking exposure modulated mercury postnatal effects on persistent cough (p < 0.05). In conclusion, no association between pre and postnatal mercury exposure and respiratory and allergy problems among the whole population at study was found. However, diet and other toxicants could modulate this relation, especially during prenatal period. More research on this topic is warranted due to the limited evidence.
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http://dx.doi.org/10.1016/j.scitotenv.2021.146654DOI Listing
August 2021

Urinary arsenic species and methylation efficiency during pregnancy: Concentrations and associated factors in Spanish pregnant women.

Environ Res 2021 05 17;196:110889. Epub 2021 Feb 17.

Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain.

Background: Arsenic (As) is considered to be toxic for humans, the main routes of exposure being through drinking water and the diet. Once ingested, inorganic arsenic can be methylated sequentially to monomethyl and dimethyl arsenicals. Several factors can affect both As exposure and methylation efficiency.

Objectives: To describe the urinary concentrations of the different As species and evaluate the methylation efficiency during pregnancy, as well as their associated factors in a birth cohort of pregnant Spanish women.

Methods: Participants in this cross-sectional study were 1017 pregnant women from two areas of Spain who had taken part in the INMA (Environment and Childhood) project (2003-2008). Total As (organic and inorganic compounds) and its main metabolites (monomethylarsonic acid, [MMA], dimethylarsinic acid, [DMA], inorganic As [iAs]) and arsenobetaine [AB]) were measured in urine samples collected during the first trimester. Sociodemographic and dietary information was collected through questionnaires. Multivariate linear regression models were used to explore the association between As species concentrations and covariates. Arsenic methylation efficiency was determined through the percentages of the metabolites and using As methylation phenotypes, obtained from principal component analysis.

Results: Median urine concentrations were 33.0, 21.6, 6.5, 0.35 and 0.33 μg/g creatinine for total As, AB, DMA, MMA and iAs, respectively. Daily consumption of rice and seafood during the first trimester of pregnancy were positively associated with the concentration of As species (i.e., β [CI95%] = 0.36 [0.09, 0.64] for rice and iAs, and 1.06 [0.68, 1.44] for seafood and AB). TAs, AB and iAs concentrations, and DMA and MMA concentrations were associated with legume and vegetable consumption, respectively. The medians of the percentage of As metabolites were 89.7 for %DMA, 5.1 for %MMA and 4.7 for %iAs. Non-smoker women and those with higher body mass index presented a higher methylation efficiency (denoted by a higher %DMA and lower %MMA).

Discussion: Certain dietary, lifestyle, and environmental factors were observed to have an influence on both As species concentrations and methylation efficiency in our population. Further birth cohort studies in low exposure areas are necessary to improve knowledge about arsenic exposure, especially to inorganic forms, and its potential health impact during childhood.
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http://dx.doi.org/10.1016/j.envres.2021.110889DOI Listing
May 2021

Maternal Ferritin Levels during Pregnancy and ADHD Symptoms in 4-Year-Old Children: Results from the INMA-INfancia y Medio Ambiente (Environment and Childhood) Prospective Birth Cohort Study.

Int J Environ Res Public Health 2020 10 22;17(21). Epub 2020 Oct 22.

Haringey Child and Adolescent Mental Health Service, Barnet, Enfield and Haringey NHS Mental Health Trust, London N15 3TH, UK.

Ferritin status during prenatal brain development may influence the risk of attention deficit and hyperactivity disorder (ADHD) symptoms in childhood. We investigated the association of maternal ferritin in pregnancy and ADHD-like symptoms in offspring. A total of 1095 mother-child pairs from three birth cohorts of the INMA Project (Spain) were studied. Maternal plasma ferritin in pregnancy was measured at 11.57 weeks of gestation. Children's ADHD-like symptoms at ages 4-5 years were assessed using the ADHD Rating Scale-IV. The count model of the zero-inflated Poisson regression model showed a significant inverse association between ferritin (continuous variable) and inattention, β = -0.19 (-0.32, -0.07), for boys. Comparing ferritin level by tertiles, significant differences were observed between the first tertile ([1.98, 20.92]) and the second ([20.92, 38.79]) and third tertiles ([38.79, 216.5]) (mg/L).The number of symptoms was lower for those in the third tertile, β = -0.3 (-0.55, -0.5), and for those in the second one, β = -0.37 (-0.6, -0.14). The model stratification by sex also showed this inverse association for boys only, β = -0.21 (-0.34, -0.08). No associations were found between ferritin level and hyperactivity or total ADHD symptoms. High ferritin levels during pregnancy show a protective association with child inattentive-type ADHD symptoms.
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http://dx.doi.org/10.3390/ijerph17217704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659477PMC
October 2020

Exposure to mercury among 9-year-old children and neurobehavioural function.

Environ Int 2021 01 20;146:106173. Epub 2020 Oct 20.

Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain.

Mercury (Hg) is an environmental neurotoxicant whose main route of exposure in humans is the consumption of seafood. The aim of this study was to explore the relationship between Hg exposure at 9 years old and behaviour assessed at 9 and 11 years old. Study subjects were mother-child pairs participating in the INMA (Environment and Childhood) Project in Valencia (Spain). Total Hg (THg) was measured in hair samples from the children at 9 years old. Behaviour and emotions were assessed at 9 (n = 472) years and 11 (n = 385) years of age using the Child Behaviour Checklist test (CBCL) and the Conners Parents Rating Scale-Revised: Short Form (CPRS-R:S). Furthermore, the attention function was assessed by the Attention Network Test at 11 years old. Socio-demographic, lifestyle and dietary information was collected through questionnaires during pregnancy and childhood. Polymorphism in BDNF, APOE and GSTP1 were genotyped in cord blood DNA. Multivariable negative binomial regression models were built in order to study the association between THg concentrations and the scores obtained by the children at 9 and 11 years old. Effect modification by sex and genetic polymorphisms was assessed. The association between Hg levels and CBCL scores was positive (worse neurobehavioural development) for the CBCL internalizing and total problem scales (Incidence Rate Ratio [95% confidence interval] = 1.07 [1.01, 1.13] and 1.05 [0.99, 1.11], respectively). The association between Hg and the externalizing and total problems CBCL scales and the Attention Deficit Hyperactivity Disorder (ADHD) index of the CPRS-R:S was different according to sex, with boys obtaining worse scores with increasing Hg, compared to girls. Statistically significant interactions were also observed for genetic polymorphisms affecting the association between early exposure to Hg and both CBCL and CPRS-R:S scores. In conclusion, postnatal Hg exposure is associated with poorer neurobehavioural development in 9- and 11-year-old children. Sex and the presence of certain genetic polymorphisms modified this association.
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http://dx.doi.org/10.1016/j.envint.2020.106173DOI Listing
January 2021

Maternal Iodine Status During Pregnancy Is Not Consistently Associated with Attention-Deficit Hyperactivity Disorder or Autistic Traits in Children.

J Nutr 2020 06;150(6):1516-1528

Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, Netherlands.

Background: Severe iodine deficiency during pregnancy can cause intellectual disability, presumably through inadequate placental transfer of maternal thyroid hormone to the fetus. The association between mild-to-moderate iodine deficiency and child neurodevelopmental problems is not well understood.

Objectives: We investigated the association of maternal iodine status during pregnancy with child attention-deficit hyperactivity disorder (ADHD) and autistic traits.

Methods: This was a collaborative study of 3 population-based birth cohorts: Generation R (n = 1634), INfancia y Medio Ambiente (n = 1293), and the Avon Longitudinal Study of Parents and Children (n = 2619). Exclusion criteria were multiple fetuses, fertility treatment, thyroid-interfering medication use, and pre-existing thyroid disease. The mean age of assessment in the cohorts was between 4.4 and 7.7 y for ADHD symptoms and 4.5 and 7.6 y for autistic traits. We studied the association of the urinary iodine-to-creatinine ratio (UI/Creat) <150 μg/g-in all mother-child pairs, and in those with a urinary-iodine measurement at ≤18 weeks and ≤14 weeks of gestation-with the risk of ADHD or a high autistic-trait score (≥93rd percentile cutoff), using logistic regression. The cohort-specific effect estimates were combined by random-effects meta-analyses. We also investigated whether UI/Creat modified the associations of maternal free thyroxine (FT4) or thyroid-stimulating hormone concentrations with ADHD or autistic traits.

Results: UI/Creat <150 μg/g was not associated with ADHD (OR: 1.2; 95% CI: 0.7, 2.2; P = 0.56) or with a high autistic-trait score (OR: 0.8; 95% CI: 0.6, 1.1; P = 0.22). UI/Creat <150 μg/g in early pregnancy (i.e., ≤18 weeks or ≤14 weeks of gestation) was not associated with a higher risk of behavioral problems. The association between a higher FT4 and a greater risk of ADHD (OR: 1.3; 95% CI: 1.0, 1.6; P = 0.017) was not modified by iodine status.

Conclusions: There is no consistent evidence to support an association of mild-to-moderate iodine deficiency during pregnancy with child ADHD or autistic traits.
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http://dx.doi.org/10.1093/jn/nxaa051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269752PMC
June 2020

Postnatal exposure to mercury and neuropsychological development among preschooler children.

Eur J Epidemiol 2020 Mar 13;35(3):259-271. Epub 2020 Mar 13.

Epidemiology and Environmental Health Joint Research Unit, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region, FISABIO-Public Health, FISABIO-Universitat Jaume I-Universitat de València, Av. Catalunya 21, 46020, Valencia, Spain.

The objective of this study was to describe the postnatal exposure to Hg and to evaluate its association with neuropsychological development among preschool children. The study population are 4-5 years old children (n = 1252) participant in the Spanish INMA Project. Total Hg was measured in cord blood and in hair samples taken at 4 years of age (2008-2012). Neuropsychological development was assessed using the McCarthy Scales of Children's Abilities (MSCA). Information on covariates and possible confounders was obtained by questionnaires during pregnancy and childhood. Generalized additive and linear regression models were built in order to assess the relationship between MSCA scores and Hg exposure. We also evaluated the magnitude of the possible bias generated from measurement error in seafood intake estimate from questionnaire and Hg determination. The geometric mean of hair Hg was 0.98 µg/g [95% confidence interval (CI) 0.94, 1.03]. In the regression analysis, the association between Hg and the MSCA scores was positive for all the scales and statistically significant for the verbal (β = 0.89; 95%CI 0.38, 1.39), memory (β = 0.42; 95%CI 0.09, 0.76) and general cognitive scales (β = 1.35; 95%CI 0.45, 2.25). However, these associations were clearly attenuated when we adjusted by the children's fish intake variables or when took into account theoretical scenarios of low precision in fish intake and Hg measurements. Hg levels in this Spanish population were high in comparison with other European countries; however, we did not observe adverse effects on child neuropsychological development associated with this postnatal exposure to Hg.
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http://dx.doi.org/10.1007/s10654-020-00620-9DOI Listing
March 2020

Prenatal manganese exposure and neuropsychological development in early childhood in the INMA cohort.

Int J Hyg Environ Health 2020 03 7;224:113443. Epub 2020 Jan 7.

Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain. Electronic address:

Introduction: Manganese (Mn) is an essential element, diet being its main source. Some epidemiological studies have found that a prenatal excess of Mn could negatively affect neuropsychological development during infancy, but the evidence is inconclusive. The aim of this study was to explore the relationship between maternal serum Mn concentrations and child neuropsychological development assessed at 1 year of age.

Methods: study subjects were 1179 mother-child pairs from two Spanish cohorts (Valencia and Gipuzkoa) of the INMA (Environment and Childhood) Project. Mn was measured in serum samples collected during the first trimester of pregnancy. Child neuropsychological development was assessed using the Bayley Scales of Infant Development, composed of both mental and psychomotor scales. Sociodemographic, lifestyle and dietary information was collected through questionnaires during pregnancy and during the child's first year of life. Serum Mn was log-2 transformed. Multivariable linear regression models were built. Generalized additive models were used to assess the shape of the relation between prenatal exposure to Mn and the neuropsychological test scores.

Results: geometric mean and 95% confidence interval (95% CI) of maternal serum Mn was 1.50 (1.48-1.53) μg/L. Levels of Mn were higher among non-working mothers and in those with a higher consumption of nuts. The association between maternal Mn levels and child neuropsychological development was negative in the multivariable models for the mental (β [95% CI] = -0.39 [-2.73, 1.95]) and psychomotor scales (β [95% CI] = -0.92 [-3.48, 1.65]), although the coefficients were not statistically significant. The best shape describing the relationship between Mn and the Bayley scales was linear in both cases.

Conclusion: This study shows a null association between maternal prenatal levels of Mn and neuropsychological development at one year after birth in two cohorts within the INMA study.
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http://dx.doi.org/10.1016/j.ijheh.2019.113443DOI Listing
March 2020

Association of Iron Status and Intake During Pregnancy with Neuropsychological Outcomes in Children Aged 7 Years: The Prospective Birth Cohort Infancia y Medio Ambiente (INMA) Study.

Nutrients 2019 Dec 7;11(12). Epub 2019 Dec 7.

Pere Virgili Institute for Health Research (IISPV), Universitat Rovira i Virgili, 43003 Tarragona, Spain.

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.
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http://dx.doi.org/10.3390/nu11122999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949977PMC
December 2019

Prenatal Se concentrations and anthropometry at birth in the INMA study (Spain).

Environ Res 2020 02 19;181:108943. Epub 2019 Nov 19.

Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain. Electronic address:

We assessed whether prenatal selenium (Se) exposure is associated with anthropometry at birth, placental weight and gestational age. Study subjects were 1249 mother-child pairs from the Valencia and Gipuzkoa cohorts of the Spanish Childhood and Environment Project (INMA, 2003-2008). Se was determined in serum samples taken at the first trimester of pregnancy. Socio-demographic and dietary characteristics were also collected by questionnaires. Mean (SD) serum Se concentration was 79.57 (9.64) μg/L. Se showed weak associations with both head circumference and gestational age. The association between serum Se concentration and birth weight and length was negative, and direct for placental weight and probability of preterm birth, although the coefficients did not reach statistical significance. Individuals with total mercury (THg) levels >15 μg/L reversed the serum Se concentration effect on head circumference. Significant interactions were found between sex and both gestational age and prematurity. Spontaneous birth gestational ages were estimated to be lower for males and their probability of prematurity was higher. In conclusion, prenatal Se exposure may be associated with lower head circumference and lower gestational ages at spontaneous birth. Interactions with THg exposure and gender should be considered when assessing these relationships.
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http://dx.doi.org/10.1016/j.envres.2019.108943DOI Listing
February 2020

Maternal circulating Vitamin D levels during pregnancy and behaviour across childhood.

Sci Rep 2019 10 15;9(1):14792. Epub 2019 Oct 15.

ISGlobal, Barcelona, Spain.

Vitamin D deficiency during critical periods of development could lead to persistent brain alterations. We aimed to assess the association between maternal vitamin D, the major circulatory form of vitamin D, at pregnancy and neurodevelopmental outcomes during childhood, namely: behavioural problems, Attention Deficit and Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) symptoms, and social competence. This study included 2,107 mother-child pairs of a Spanish population-based birth cohort. Maternal plasma vitamin D was measured in pregnancy. The outcomes were measured through questionnaires at 5, 8, 14, and 18 years old. We ran multivariate regression models adjusted for potential confounding variables. We found that per each 10 ng/mL increment of maternal vitamin D, children obtained higher social competence scores (coefficient = 0.77; 95% CI = 0.19, 1.35) at 5 years old. However, we observed null associations between maternal vitamin D and total behavioural problems and ADHD and ASD symptoms in children from 5 to 18 years old. Further studies carried out in countries where the population is exposed to lower vitamin D levels are needed.
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http://dx.doi.org/10.1038/s41598-019-51325-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794315PMC
October 2019

Maternal seafood consumption during pregnancy and child attention outcomes: a cohort study with gene effect modification by PUFA-related genes.

Int J Epidemiol 2020 04;49(2):559-571

Barcelona Institute for Global Health (ISGlobal), Barcelona, Catalonia, Spain.

Background: There is a need to test the fetal programming theoretical framework in nutritional epidemiology. We evaluated whether maternal seafood intake during pregnancy was associated with 8-year-old attention outcomes after adjusting for previous child seafood intake and cognitive function. We also explored effect modification by several single nucleotide polymorphisms (SNPs) related with polyunsaturated fatty acid (PUFA) metabolism.

Methods: Our final analyses included 1644 mother-child pairs from the prospective INMA (INfancia y Medio Ambiente) cohort study (Spain, recruitment between 2003 and 2008). We used food frequency questionnaires to assess prenatal and postnatal seafood consumption of the mother-child pairs. We evaluated attention function of the children through the computer-based Attention Network Test (ANT) and we used the number of omission errors and the hit reaction time standard error (HRT-SE). Parents reported child attention deficit hyperactivity disorder (ADHD) symptoms using the Revised Conners' Parent Rating Scale Short Form (CPRS-R: S). We measured seven candidate SNPs in a subsample of 845 children. We estimated associations using regression models, adjusting for family characteristics, child seafood intake and cognitive functions at early ages, and to explore SNP effect modifications.

Results: Higher total seafood intake during early pregnancy was associated with a reduction of child ANT omission errors, 5th quintile (median = 854 g/week) vs 1st quintile (median = 195 g/week), incidence risk ratio (IRR) 0.76; 95% CI = 0.61, 0.94. Similar results were observed after adjusting the models for child seafood intake and previous cognitive status. Lean, large and small fatty fish showed similar results, and generally similar but less robust associations were observed with the other attention outcomes. Shellfish and canned tuna showed weaker associations. The association patterns were weaker in late pregnancy and null in child seafood consumption. Child rs1260326 (glucokinase regulator, GCKR) and child/maternal rs2281591 (fatty acid elongase 2, ELOVL2) polymorphisms showed nominal P-value for interactions <0.10 between total seafood intake and ANT outcomes.

Conclusions: After adjusting for previous child cognitive functions and child seafood intake, high pregnancy consumption (total, lean, small and large fatty fish) was independently associated with improvements of some 8-year-old attention outcomes. Genetic effect modification analyses suggest PUFA intake from seafood as a potential biological mechanism of such association.
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http://dx.doi.org/10.1093/ije/dyz197DOI Listing
April 2020

Exposure to mercury among 9-year-old Spanish children: Associated factors and trend throughout childhood.

Environ Int 2019 09 19;130:104835. Epub 2019 Jun 19.

Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain. Electronic address:

Mercury is considered a neurotoxicant and human exposure occurs mainly from the consumption of marine species. We aimed to describe total mercury concentrations (THg) and associated factors in 9-year old children, as well as to explore the trend in THg from 4 to 9 years of age. The study population consisted of 9-year-old children participating in the INMA (Environment and Childhood) birth cohort study in Valencia, Spain (n = 405, 2013-2014). THg in hair samples was measured by atomic absorption spectrometry at the age of 4 and 9 years. Sociodemographic and dietary data was obtained through questionnaires. Multiple linear regression was used to explore the association between THg and covariates. The geometric mean (95% confidence interval) of hair THg at 9 years old was 0.89 μg/g (0.81, 0.98). Thirteen percent of children had THg above the equivalent to the Provisional Tolerable Weekly Intake proposed by the World Health Organization. THg were higher among children whose mothers had a healthy body mass index before pregnancy. Children with non-smoker mothers and worker fathers had also higher THg. Children's fish intake at 9 years-old was positively associated with THg, being swordfish, canned tuna and lean fish (i.e. hake, sea bream and sole) the most associated categories. Levels decreased by around 22% between 4 and 9 years old. Birth cohort studies, such as the INMA Project, allow the longitudinal evaluation of Hg exposure and the possible effects on children's health. This information can be used to formulate diet recommendations in vulnerable populations.
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http://dx.doi.org/10.1016/j.envint.2019.05.029DOI Listing
September 2019

Inorganic arsenic exposure and neuropsychological development of children of 4-5 years of age living in Spain.

Environ Res 2019 07 29;174:135-142. Epub 2019 Apr 29.

Institute for Global Food Security, Queen's University Belfast, David Keir Building, Malone Road, Belfast BT9 5BN, Northern Ireland, UK.

Early-life exposure to inorganic arsenic (iAs) may adversely impact health later in life. To date, evidence of iAs adverse effects on children's neurodevelopment comes mainly from populations highly exposed to contaminated water with conflicting results. Little is known about those effects among populations with low iAs exposure from food intake. We investigated the cross-sectional association between exposure to iAs and neurodevelopment scores among children living in Spain whose main route of exposure was diet. Arsenic species concentrations in urine from 400 children was determined, and the sum of urinary iAs, dimethylarsinic acid, and monomethylarsonic acid was used to estimate iAs exposure. The McCarthy Scales of Children's Abilities was used to assess children's neuropsychological development at about 4-5 years of age. The median (interquartile range) of children's sum of urinary iAs, MMA, and DMA was 4.85 (2.74-7.54) μg/L, and in adjusted linear regression analyses the natural logarithm transformed concentrations showed an inverse association with children's motor functions (β, [95% confidence interval]; global scores (-2.29, [-3.95, -0.63])), gross scores (-1.92, [-3.52, -0.31]) and fine scores (-1.54, [-3.06, -0.03]). In stratified analyses by sex, negative associations were observed with the scores in the quantitative index (-2.59, [-5.36, 0.17]) and working memory function (-2.56, [-5.36, 0.24]) only in boys. Our study suggests that relatively low iAs exposure may impair children's neuropsychological development and that sex-related differences may be present in susceptibility to iAs related effects; however, our findings should be interpreted with caution given the possibility of residual confounding.
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http://dx.doi.org/10.1016/j.envres.2019.04.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541502PMC
July 2019

Association of Maternal Iodine Status With Child IQ: A Meta-Analysis of Individual Participant Data.

J Clin Endocrinol Metab 2019 12;104(12):5957-5967

Department of Internal Medicine, Academic Center For Thyroid Diseases, Erasmus University Medical Centre, CA Rotterdam, Netherlands.

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.
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http://dx.doi.org/10.1210/jc.2018-02559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804415PMC
December 2019

Maternal copper status and neuropsychological development in infants and preschool children.

Int J Hyg Environ Health 2019 04 1;222(3):503-512. Epub 2019 Feb 1.

Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Av. Catalunya 21, 46020 Valencia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Av. Monforte de Lemos, 3-5. Pabellón 11, 28029 Madrid, Spain. Electronic address:

Introduction: Copper (Cu) is an essential element involved in biological processes; however, excessive Cu could be harmful because of its reactive nature. Very few studies have evaluated its potential neurotoxic effects. We aimed to evaluate the association between maternal Cu levels and children's neuropsychological development.

Methods: Study subjects were mother-child pairs from the Spanish INMA (i.e. Childhood and Environment) Project. Cu was measured by inductively coupled plasma mass spectrometry in serum samples taken at the first trimester of pregnancy (2003-2005). Neuropsychological development was assessed using the Bayley Scales of Infant Development (BSID) at 12 months (n = 651) and the McCarthy Scales of Children's Abilities (MSCA) at 5 years of age (n = 490). Covariates were obtained by questionnaires during pregnancy and childhood. Multivariate linear and non-linear models were built in order to study the association between maternal Cu and child neuropsychological development.

Results: The mean ± standard deviation of maternal Cu concentrations was 1606 ± 272 μg/L. In the multivariate analysis, a negative linear association was found between maternal Cu concentrations and both the BSID mental scale (beta = -0.051; 95% confidence intervals [CI]: -0.102, -0.001) and the MSCA verbal scale (beta = -0.044; 95%CI:-0.094, 0.006). Boys obtained poorer scores than girls, with increasing Cu at 12 months (interaction p-value = 0.040 for the mental scale and 0.074 for the psychomotor scale). This effect modification disappeared at 5 years of age. The association between Cu and the MSCA scores (verbal, perceptive performance, global memory and motor, general cognitive, and executive function scales) was negative for those children with lowest maternal iron concentrations (<938μg/L).

Conclusion: The Cu concentrations observed in our study were within the reference range established for healthy pregnant women in previous studies. The results of this study contribute to the body of scientific knowledge with important information on the possible neurotoxic capability of Cu during pregnancy.
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http://dx.doi.org/10.1016/j.ijheh.2019.01.007DOI Listing
April 2019

Placental metal concentrations and birth outcomes: The Environment and Childhood (INMA) project.

Int J Hyg Environ Health 2019 04 10;222(3):468-478. Epub 2019 Jan 10.

Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012, Granada, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), Spain; Department of Radiology, School of Medicine, and Center for Biomedical Research, University of Granada, 18071, Granada, Spain.

Objective: To examine the association of placental levels of arsenic (As), cadmium (Cd), mercury (Hg), lead (Pb), manganese (Mn), and chromium (Cr) with birth outcomes (birth weight, length, and head circumference, low birth weight [LBW], gestational age, preterm delivery, and small for gestational age [SGA]) in mother-child pairs from the Environment and Childhood (INMA) Project in Spain.

Methods: Metal concentrations were measured in placenta tissue samples randomly selected from five INMA cohorts. Data on birth outcomes were obtained from medical records. Associations were assessed in a sub-sample of 327 mother-infant pairs by regression models adjusted for confounding factors and for all metals simultaneously. Effect modification by sex was also evaluated.

Results: Elevated placental Cd levels (>5.79 vs. <3.30 ng/g) were associated with reduced birth weight (-111.8 g, 95%CI = -215.6; -8.06, p-trend = 0.01) and length (-0.62 cm, 95%CI = -1.20; -0.04, p-trend = 0.02), while a 10% increase in Cd was associated with 1.21-fold increased odds (95%CI = 1.01; 1.43) of LBW in the global sample but with 14% lower odds (95%CI = 0.78; 0.96) of preterm delivery in males (P = 0.10). Detected (vs. undetected) Hg was associated with reduced head circumference (-0.49 cm, 95%CI = -1.00; 0.03) in females (P = 0.03). A 10% increase in placental Mn was associated with slight increases in gestational age (0.04 weeks, 95%CI = 0.01; 0.07) in the global sample and in head circumference (0.05 cm, 95%CI = -0.01; 0.10) in females (P = 0.03). Elevated Cr levels (>99.6 vs. <56.1 ng/g) were associated with reduced birth length (-0.68 cm, 95%CI = -1.33; -0.04, p-trend = 0.02) and slightly increased gestational age (0.35 weeks, 95%CI = -0.07; 0.77, p-trend = 0.08) in the global sample. As and Pb were detected in few placentas (27% and 13%, respectively) and were not associated with any studied birth outcome.

Conclusions: Data suggest that in utero exposure to Cd, Hg, and Cr could adversely affect fetal growth, whereas Mn and Cr appear to have a positive effect on gestational age. Given the relatively small number of subjects, sex-specific associations should be interpreted with caution.
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http://dx.doi.org/10.1016/j.ijheh.2018.12.014DOI Listing
April 2019

Chronic mercury exposure and blood pressure in children and adolescents: a systematic review.

Environ Sci Pollut Res Int 2019 Jan 6;26(3):2238-2252. Epub 2018 Dec 6.

FISABIO-UJI-Universitat de València Joint Research Unit in Epidemiology and Environmental Health, Valencia, Spain.

The aim of this paper is to systematically review the scientific literature on the possible relation of chronic mercury exposure and blood pressure among children and adolescents. We searched for observational studies in 6 electronic databases and grey literature for English, French or Spanish language studies published up to 30 November 2017. We performed a quality assessment of primary studies. We identified 8 articles involving 5 cohorts, 1 cross-sectional study and 1 case-control study. The participants had mean ages of between 3 and 17 years. Mercury was analysed in different matrices and periods of exposure. Four articles evaluated prenatal exposure, 2 evaluated both prenatal and postnatal exposures and 2 postnatal exposure. Blood pressure was measured according to different protocols. The association between mercury and blood pressure was adjusted by different covariates in each study. Four articles found a positive significant association between chronic mercury exposure and blood pressure in children or adolescents. Among these 4 articles, three of them evaluated prenatal exposure. There are still few studies assessing chronic mercury exposure and blood pressure in children and adolescents with inconsistency in results. Designs are very heterogeneous, which hampers their comparability. Evidence of this association is scarce and further research is needed.
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http://dx.doi.org/10.1007/s11356-018-3796-yDOI Listing
January 2019

Maternal selenium status and neuropsychological development in Spanish preschool children.

Environ Res 2018 10 8;166:215-222. Epub 2018 Jun 8.

Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Av. Monforte de Lemos, 3-5. Pabellón 11, 28029 Madrid, Spain; Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Av. Catalunya 21, 46020 Valencia, Spain. Electronic address:

Background: The relationship between maternal selenium (Se) status and child neurodevelopment has been scarcely assessed. In a previous study we observed an inverse U-shaped association between maternal Se concentrations and infant neurodevelopment at 12 months of age. In this study, this non-linear association was explored at preschool age. The effect modification by breastfeeding, child's sex and cord blood mercury was also evaluated.

Methods: Study subjects were 490 mother-child pairs from the Spanish Childhood and Environment Project (INMA, 2003-2012). Child neuropsychological development was assessed at around 5 years of age by the McCarthy Scales of Children's Abilities (MSCA). Sociodemographic and dietary characteristics were collected by questionnaire at the first and third trimester of gestation and at 5 years of age. Se was measured in serum samples by ICP-MS at the end of the first trimester of pregnancy (mean ± standard deviation (SD) = 12.4 ± 0.6 weeks of gestation).

Results: The mean ± SD of maternal serum Se concentrations was 79.9 ± 8.1 µg/L. In multivariate analysis, no linear association was found between Se concentrations and the nine MSCA scales. Generalized additive models indicated inverted U-shaped relationships between Se concentrations and the verbal and global memory scales. When assessing the influence of effect modifiers, breastfeeding played a role: the association between Se and neuropsychological development was inverted U-shaped for the quantitative, general cognitive, working memory, fine motor, global motor and executive function scales only for non-breastfed children.

Conclusion: Low and high maternal Se concentrations seem to be harmful for child neuropsychological development, however further studies should explore this non-linear relationship.
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http://dx.doi.org/10.1016/j.envres.2018.06.002DOI Listing
October 2018

DNA methylation in childhood asthma: an epigenome-wide meta-analysis.

Lancet Respir Med 2018 05 26;6(5):379-388. Epub 2018 Feb 26.

ISGlobal, Centre for Research in Environmental Epidemiology, the Barcelona Institute of Science and Technology, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.

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 × 10) after meta-analysis. Consistently lower methylation levels were observed at all associated loci across childhood from age 4 to 16 years in participants with asthma, but not in cord blood at birth. All 14 CpG sites were significantly associated with asthma in the second replication study using whole-blood DNA, and were strongly associated with asthma in purified eosinophils. Whole-blood transcriptional signatures associated with these CpG sites indicated increased activation of eosinophils, effector and memory CD8 T cells and natural killer cells, and reduced number of naive T cells. Five of the 14 CpG sites were associated with asthma in respiratory epithelial cells, indicating cross-tissue epigenetic effects.

Interpretation: Reduced whole-blood DNA methylation at 14 CpG sites acquired after birth was strongly associated with childhood asthma. These CpG sites and their associated transcriptional profiles indicate activation of eosinophils and cytotoxic T cells in childhood asthma. Our findings merit further investigations of the role of epigenetics in a clinical context.

Funding: EU and the Seventh Framework Programme (the MeDALL project).
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http://dx.doi.org/10.1016/S2213-2600(18)30052-3DOI Listing
May 2018

Iodine intake from supplements and diet during pregnancy and child cognitive and motor development: the INMA Mother and Child Cohort Study.

J Epidemiol Community Health 2018 03 26;72(3):216-222. Epub 2017 Dec 26.

CIBER Epidemiología y Salud Pública (CIBERESP), Spain.

Background: The effect of mild-to-moderate maternal iodine deficiency on the neuropsychological development of their offspring is uncertain. We aimed to assess the association between iodine status during pregnancy and the cognitive and motor development of children at 4-5 years.

Methods: We conducted a prospective cohort study in four Spanish regions with recruitment of pregnant women between 2003 and 2008 and follow-up of their children up to 4-5 years (mean (SD)=4.8 (0.6)). Cognitive and motor function was assessed in 1803 children using the McCarthy Scales of Children's Abilities. Dietary iodine and supplementation were measured through questionnaires twice during pregnancy. Urinary iodine concentration (UIC) was measured in spot samples. The residuals of a regression of UIC against creatinine were used to define a variable corrected for creatinine (UIC~Cr).

Results: Neither iodine supplements nor iodised salt consumption or maternal UIC were associated with cognitive or motor function. After adjusting for creatinine, children of women with UIC~Cr <100 µg/L had 3.93 (95% CI -6.18 to -1.69) general cognitive scores lower than the reference (150-249 µg/L). Dietary iodine was inversely associated with motor scores and milk but not other dairy products or seafood consumption accounted for this association (beta: -1.36; 95% CI -2.12 to -0.61; per one daily milk serving).

Conclusions: We found an association between low maternal urinary iodine and lower cognitive scores in childhood, although only when corrected for creatinine, adding to the evidence that iodine deficiency may have potential harmful effects on neurodevelopment. Iodine supplementation does not appear to improve child's neurodevelopment at 4-5 years.
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http://dx.doi.org/10.1136/jech-2017-209830DOI Listing
March 2018

Prenatal co-exposure to neurotoxic metals and neurodevelopment in preschool children: The Environment and Childhood (INMA) Project.

Sci Total Environ 2018 Apr 27;621:340-351. Epub 2017 Nov 27.

Health Research Institute of Granada (ibs.GRANADA), 18012 Granada, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Spain; Department of Radiology, School of Medicine, and Centre for Biomedical Research, University of Granada, 18071 Granada, Spain.

We sought to determine whether prenatal co-exposure to As, Cd, Hg, Mn, and Pb was associated with impaired neurodevelopment in preschool children from the Spanish Environment and Childhood (INMA) Project, using the placenta as exposure matrix. We measured metal levels in placenta tissue samples randomly selected from five of the seven population-based birth cohorts participating in the INMA Project, collected between 2000 and 2008. Neuropsychological assessment of cognitive and motor function was carried through the use of the McCarthy Scales of Children's Abilities (MSCA) at the age of 4-5years. Data on placental metal levels, MSCA scores, and relevant covariates was available for 302 children. Mn was detected in all placental samples, Cd in nearly all placentas (99%) and As, Hg, and Pb in 22%, 58%, and 17% of the placentas, respectively. After adjusting for potential confounders, detectable As levels were associated with decrements in global and verbal executive functions and quantitative abilities; detectable Hg was associated with lower scores on the verbal function of posterior cortex in a dose-response manner, and non-linearly related to poorer motor function and gross motor skills; and Mn levels were associated with decrement in perceptual-performance skills in a dose-response manner but with better memory span and quantitative skills. A synergistic interactive effect was found between As and Pb with respect to the general cognitive score, whereas an antagonistic interaction was found between Mn and Hg. Prenatal exposure to As and Hg may be a risk factor for cognitive and motor impairment in children, while the effects of Cd and Mn on neurodevelopment are less clear. Future studies should examine combined and interactive effects of exposure to multiple metals during vulnerable periods of brain development prospectively.
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http://dx.doi.org/10.1016/j.scitotenv.2017.11.273DOI Listing
April 2018
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