The impact of prenatal mercury on neurobehavioral functioning longitudinally assessed from a young age to pre-adolescence in a Spanish birth cohort.

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

Pro-vegetarian dietary patterns and essential and heavy metal exposure in children of 4-5-years from the INfancia y medio Ambiente cohort (INMA).

Dietary patterns provide a comprehensive assessment of food consumption, including essential nutrients and potential exposure to environmental contaminants. While pro-vegetarian (PVG) dietary patterns have shown health benefits in adults, their effects on children are less well studied. This study aims to explore the association between children's adherence to the most common PVG dietary patterns and their exposure to metals, assessed through urine concentration. In our study, we included a population of 723 children aged 4-5-years from the INfancia y Medio Ambiente (INMA) cohort in Spain. We calculated three predefined PVG dietary patterns, namely general (gPVG), healthful (hPVG), and unhealthful (uPVG), using dietary information collected through a validated Food Frequency Questionnaire. Urinary concentrations of various essential and heavy metals (Co, Cu, Zn, Se, Mo, Pb, and Cd) were measured using mass spectrometry. Additionally, urinary arsenic speciation, including arsenobetaine (AsB), dimethylarsinic acid (DMA), monomethylarsonic acid (MMA), and inorganic arsenic (iAs), was measured. The sum of urinary MMA and iAs was used to assess iAs exposure. We estimated primary (PMI) and secondary iAs methylation (SMI) indices. To explore the association between PVG dietary patterns in quintiles and metal exposure, we utilized multiple-adjusted linear regression models and the quantile g-computation approach. Compared with the lowest quintile, participants in the highest quintile of gPVG showed a 22.7% lower urinary Co (95% confidence interval (CI): -38.7; -1.98) and a 12.6% lower Se (95%CI: -22.9; -1.00) concentrations. Second quintile of adherence to hPVG was associated with a 51.7% lower urinary iAs + MMA concentrations (95%CI: -74.3; -8.61). Second quintile of adherence to an uPVG was associated with a 13.6% lower Se levels (95%CI: -22.9; -2.95) while the third quintile to this pattern was associated with 17.5% lower Mo concentrations (95%CI: -29.5; -2.95). The fourth quintile of adherence to gPVG was associated with a 68.5% higher PMI and a 53.7% lower SMI. Our study showed that adherence to a gPVG dietary pattern in childhood may modestly reduce the intakes of some essential metals such as Co and Se. Further investigations are warranted to explore any potential health implications.

[Niveles de mercurio en pescado en la Comunitat Valenciana: evolución temporal (2011-2017) y factores asociados.] / Mercury levels in fish in the Valencian Community: temporal evolution (2011-2017) and associated factors.

OBJECTIVE: Mercury (Hg) is a toxic metal, and dietary exposure is the main one in humans, especially fish consumption. In order to reduce Hg exposure, maximum levels in fish products have been established. We aimed to describe total mercury (THg) and methylmercury (MeHg) concentrations in fish species consumed in Comunitat Valenciana, as well as factors associated and their tendency during the period 2011-2017. METHODS: A retrospective descriptive study of Hg levels in fish meat samples in Comunitat Valenciana between 2011 and 2017 and their temporal trend was carried out, both in general and by fish groups. Data comes from Generalitat Valenciana's Health Surveillance of Food Program. We created multivariate linear regression models to evaluate the association between sampling year, fish group and origin and THg (n=560) / MeHg (n=206) concentrations. The average annual trend of THg and MeHg levels throughout the period was evaluated. RESULTS: The median was 0.20 mg/kg for THg and 0.14 mg/kg for MeHg. Swordfish, fresh tuna/albacore and canned tuna, in that order, showed the highest concentrations. Global tendency of THg levels was descending when adjusting by swordfish annual percentage. When we analized the tendency in swordfish, we observed a 7% decrease on average per year. CONCLUSIONS: Global temporal trend of THg levels in fish in Comunitat Valenciana during the period 2011-2017 is descending after adjusting by the relative weight of swordfish over the total number of samples by year. We observe a descending tendency when studied by species (swordfish).

OBJETIVO: El mercurio (Hg) es un metal tóxico cuya principal fuente de exposición en humanos es la dieta, principalmente el consumo de pescado. Para reducir la exposición al Hg se han establecido unos niveles máximos permitidos en productos de pesca. El objetivo del presente trabajo fue describir las concentraciones de mercurio total (THg) y metilmercurio (MeHg) en las especies de pescado dispuestas para el consumo en la Comunitat Valenciana, así como los factores asociados a dichas concentraciones y su evolución en el período 2011-2017. METODOS: Se realizó un estudio descriptivo, retrospectivo, de los niveles de Hg en muestras de pescado y de su evolución temporal, tanto en general como por grupos de pescado. Los datos proceden del Programa de Vigilancia Sanitaria de Alimentos de la Generalitat Valenciana. Se construyeron modelos de regresión lineal multivariantes para evaluar la asociación del año de muestreo, el grupo de pescado y el origen del mismo con las concentraciones de THg (n=560) y MeHg (n=206). Se evaluó la tendencia anual media de los niveles de THg y MeHg a lo largo del período. RESULTADOS: La mediana para THg fue de 0,20 mg/kg, y de 0,14 mg/kg para MeHg. El pez espada/emperador fue el grupo de pescado que presentó niveles más altos, seguido del atún/bonito frescos y del atún en lata. La tendencia global de los niveles de THg fue descendente ajustando por el peso anual de las muestras de pez espada/emperador. Al analizar la tendencia en pez espada/emperador se observó una disminución del 7% en promedio por año. CONCLUSIONES: La evolución temporal de los niveles de THg en pescado en la Comunitat Valenciana en el período 2011-2017 presenta una tendencia global descendente cuando se ajusta por el peso relativo de pez/espada emperador sobre el total de muestras para cada año. Además, al estudiar los niveles de THg en este grupo se observa una tendencia decreciente.

Genetic Susceptibility to Neurotoxicity Related to Prenatal Inorganic Arsenic Exposure in Young Spanish Children.

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

Niveles de mercurio en pescado en la Comunitat Valenciana: evolución temporal (2011-2017) y factores asociados / Mercury levels in fish in the Valencian Community: temporal evolution (2011-2017) and associated factors

Fundamentos: El mercurio (Hg) es un metal tóxico cuya principal fuente de exposición en humanos es la dieta, principalmenteel consumo de pescado. Para reducir la exposición al Hg se han establecido unos niveles máximos permitidos en productos de pesca. El objetivo del presente trabajo fue describir las concentraciones de mercurio total (THg) y metilmercurio (MeHg) en las especiesde pescado dispuestas para el consumo en la Comunitat Valenciana, así como los factores asociados a dichas concentraciones y suevolución en el período 2011-2017. Métodos: Se realizó un estudio descriptivo, retrospectivo, de los niveles de Hg en muestras de pescado y de su evolucióntemporal, tanto en general como por grupos de pescado. Los datos proceden delPrograma de Vigilancia Sanitaria de Alimentos de laGeneralitat Valenciana. Se construyeron modelos de regresión lineal multivariantes para evaluar la asociación del año de muestreo,el grupo de pescado y el origen del mismo con las concentraciones de THg (n=560) y MeHg (n=206). Se evaluó la tendencia anualmedia de los niveles de THg y MeHg a lo largo del período.Resultados: La mediana para THg fue de 0,20 mg/kg, y de 0,14 mg/kg para MeHg. El pez espada/emperador fue el grupo depescado que presentó niveles más altos, seguido del atún/bonito frescos y del atún en lata. La tendencia global de los niveles deTHg fue descendente ajustando por el peso anual de las muestras de pez espada/emperador. Al analizar la tendencia en pez espada/emperador se observó una disminución del 7% en promedio por año. Conclusiones: La evolución temporal de los niveles de THg en pescado en la Comunitat Valenciana en el período 2011-2017 presenta una tendencia global descendente cuando se ajusta por el peso relativo de pez/espada emperador sobre el total de muestraspara cada año. Además, al estudiar los niveles de THg en este grupo se observa una tendencia decreciente.(AU)

Background: Mercury (Hg) is a toxic metal, and dietary exposure is the main one in humans, especially fish consumption. Inorder to reduce Hg exposure, maximum levels in fish products have been established. We aimed to describe total mercury (THg) andmethylmercury (MeHg) concentrations in fish species consumed in Comunitat Valenciana, as well as factors associated and theirtendency during the period 2011-2017. Methods: A retrospective descriptive study of Hg levels in fish meat samples in Comunitat Valenciana between 2011 and 2017 andtheir temporal trend was carried out, both in general and by fish groups. Data comes from Generalitat Valenciana’sHealth Surveillance ofFood Program. We created multivariate linear regression models to evaluate the association between sampling year, fish group and originand THg (n=560) / MeHg (n=206) concentrations. The average annual trend of THg and MeHg levels throughout the period was evaluated. Results: The median was 0.20 mg/kg for THg and 0.14 mg/kg for MeHg. Swordfish, fresh tuna/albacore and canned tuna, in thatorder, showed the highest concentrations. Global tendency of THg levels was descending when adjusting by swordfish annual percentage. When we analized the tendency in swordfish, we observed a 7% decrease on average per year. Conclusions: Global temporal trend of THg levels in fish in Comunitat Valenciana during the period 2011-2017 is descending afteradjusting by the relative weight of swordfish over the total number of samples by year. We observe a descending tendency whenstudied by species (swordfish).(AU)

Influence of genetic polymorphisms on arsenic methylation efficiency during pregnancy: Evidence from a Spanish birth cohort.

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

Exposure to mercury among Spanish adolescents: Eleven years of follow-up.

The toxic effects of mercury exposure on human health are a public health concern. The most important source of this exposure is the consumption of fish and marine mammals. This study aims to describe hair mercury concentrations and their evolution from birth until eleven years of age in adolescents from the INMA (Environment and Childhood) birth cohort study, and to assess the association of hair mercury concentrations at eleven years of age with sociodemographic and dietary factors. The sample comprised 338 adolescents from the sub-cohort of Valencia (in eastern Spain). Total mercury (THg) was measured in hair samples collected at 4, 9 and 11 years old and in cord blood at birth. The equivalent of hair for cord-blood THg concentrations was calculated. Fish consumption and other characteristics at 11 years old were collected through questionnaires. Multivariate linear regression models were conducted to explore the association between THg concentrations, fish consumption and covariates. The geometric mean of hair THg concentrations at 11 years of age was 0.86 µg/g (95%CI: 0.78-0.94) and 45.2% of the participants presented concentrations above the equivalent RfD proposed by the US EPA (1 µg/g). Consumption of fish such as swordfish, canned tuna and other large oily fish was associated with higher levels of hair mercury at 11 years of age. Swordfish had the highest effect with an increase of 125% in hair mercury (95%CI: 61.2-214.9%) given a 100 g/week increase in its consumption, and, taking into account the frequency of consumption, canned tuna was the main contributor to Hg exposure among our population. The hair THg concentrations at 11 years of age represented a reduction of around 69% with respect to that estimated at childbirth. Even though THg exposure shows a sustained decreasing trend, it can still be considered elevated. INMA birth cohort studies provide a longitudinal assessment of mercury exposure in a vulnerable population, its associated factors and temporal trends, and this information could be used to adjust recommendations about this issue.

Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders.

Increasing evidence supports the role of placenta in neurodevelopment and potentially, in the later onset of neuropsychiatric disorders. Recently, methylation quantitative trait loci (mQTL) and interaction QTL (iQTL) maps have proven useful to understand SNP-genome wide association study (GWAS) relationships, otherwise missed by conventional expression QTLs. In this context, we propose that part of the genetic predisposition to complex neuropsychiatric disorders acts through placental DNA methylation (DNAm). We constructed the first public placental cis-mQTL database including nearly eight million mQTLs calculated in 368 fetal placenta DNA samples from the INMA project, ran cell type- and gestational age-imQTL models and combined those data with the summary statistics of the largest GWAS on 10 neuropsychiatric disorders using Summary-based Mendelian Randomization (SMR) and colocalization. Finally, we evaluated the influence of the DNAm sites identified on placental gene expression in the RICHS cohort. We found that placental cis-mQTLs are highly enriched in placenta-specific active chromatin regions, and useful to map the etiology of neuropsychiatric disorders at prenatal stages. Specifically, part of the genetic burden for schizophrenia, bipolar disorder and major depressive disorder confers risk through placental DNAm. The potential causality of several of the observed associations is reinforced by secondary association signals identified in conditional analyses, regional pleiotropic methylation signals associated to the same disorder, and cell type-imQTLs, additionally associated to the expression levels of relevant immune genes in placenta. In conclusion, the genetic risk of several neuropsychiatric disorders could operate, at least in part, through DNAm and associated gene expression in placenta.

Arsenic exposure and respiratory outcomes during childhood in the INMA study.

Ingested inorganic arsenic (iAs) is a human carcinogen that is also linked to other adverse health effects, such as respiratory outcomes. Yet, among populations consuming low-arsenic drinking water, the impact of iAs exposure on childhood respiratory health is still uncertain. For a Spanish child study cohort (INfancia y Medio Ambiente-INMA), low-arsenic drinking water is usually available and ingestion of iAs from food is considered the major source of exposure. Here, we explored the association between iAs exposure and children's respiratory outcomes assessed at 4 and 7 years of age (n = 400). The summation of 4-year-old children's urinary iAs, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) was used as a biomarker of iAs exposure (∑As) (median of 4.92 µg/L). Children's occurrence of asthma, eczema, sneeze, wheeze, and medication for asthma and wheeze at each assessment time point (i.e., 4- and 7-year) was assessed with maternal interviewer-led questionnaires. Crude and adjusted Poisson regression models using Generalized Estimating Equation (GEE) were performed to account for the association between natural logarithm transformed (ln) urinary ∑As in µg/L at 4 years and repeated assessments of respiratory symptoms at 4 and 7 years of age. The covariates included in the models were child sex, maternal smoking status, maternal level of education, sub-cohort, and children's consumption of vegetables, fruits, and fish/seafood. The GEE-splines function using Poisson regression showed an increased trend of the overall expected counts of respiratory symptoms with high urinary ∑As. The adjusted expected counts (95% confidence intervals) at ln-transformed urinary ∑As 1.57 (average concentration) and 4.00 (99th percentile concentration) were 0.63 (0.36, 1.10) and 1.33 (0.61, 2.89), respectively. These exploratory findings suggest that even relatively low-iAs exposure levels, relevant to the Spanish and other populations, may relate to an increased number of respiratory symptoms during childhood.

Gestational phthalate exposure and lung function during childhood: A prospective population-based study.

The potential effect of gestational exposure to phthalates on the lung function levels during childhood is unclear. Therefore, we examined this association at different ages (from 4 to 11 years) and over the whole childhood. Specifically, we measured 9 phthalate metabolites (MEP, MiBP, MnBP, MCMHP, MBzP, MEHHP, MEOHP, MECPP, MEHP) in the urine of 641 gestating women from the INMA study (Spain) and the forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and FEV1/FVC in their offspring at ages 4, 7, 9 and 11. We used linear regression and mixed linear regression with a random intercept for subject to assess the association between phthalates and lung function at each study visit and for the overall childhood, respectively. We also assessed the phthalate metabolites mixture effect on lung function using a Weighted Quantile Sum (WQS) regression. We observed that the phthalate metabolites gestational levels were consistently associated with lower FVC and FEV1 at all ages, both when assessed individually and jointly as a mixture, although most associations were not statistically significant. Of note, a 10% increase in MiBP was related to lower FVC (-0.02 (-0.04, 0)) and FEV1 z-scores (-0.02 (-0.04, -0.01) at age 4. Similar significant reductions in FVC were observed at ages 4 and 7 associated with an increase in MEP and MnBP, respectively, and for FEV1 at age 4 associated with an increase in MBzP. WQS regression consistently identified MBzP as an important contributor to the phthalate mixture effect. We can conclude that the gestational exposure to phthalates was associated with children's lower FVC and FEV1, especially in early childhood, and in a statistically significant manner for MEP, MiBP, MBzP and MnBP. Given the ubiquity of phthalate exposure and its established endocrine disrupting effects in children, our findings support current regulations that limit phthalate exposure.

Pre and postnatal exposure to mercury and sexual development in 9-year-old children in Spain: The role of brain-derived neurotrophic factor.

Early exposure to mercury has been related to endocrine disruption. Steroid hormones play a crucial role in neural cell migration, differentiation, etc., as well as protecting against several neurotoxic compounds. We investigate the relation between mercury exposure and children's sexual development, and we evaluate the possible influence of different brain-derived neurotrophic factor (BDNF) polymorphisms on this association. Our study sample comprised 412 9-year-old children participating in the INMA cohort (2004-2015). Mercury concentrations were measured at birth (cord blood) and at 4 and 9 years of age (hair). Sexual development was assessed by levels of sex steroid hormones (estradiol and testosterone) in saliva and the Tanner stages of sex development at 9 years (categorized as 1: prepuberty and >1: pubertal onset). Covariates and confounders were collected through questionnaires during pregnancy and childhood. Polymorphisms in the BDNF gene were genotyped in cord blood DNA. Multivariate linear regression analyses were performed between mercury levels and children's sexual development by sex. Effect modification by genetic polymorphisms and fish intake was assessed. We found marginally significant inverse associations between postnatal exposure to mercury (at 9 years) and testosterone levels (ß[95%CI] = -0.16[-0.33,0.001], and -0.20[-0.42,0.03], for boys and girls, respectively). Additionally, we found that prenatal mercury was negatively associated with Tanner stage >1 in boys. Finally, we found significant genetic interactions for some single nucleotide polymorphisms in the BDNF gene. In conclusion, pre and postnatal exposure to mercury seems to affect children's sexual development and BDNF may play a role in this association, but further research would be needed.

Omega-3 Fatty Acid Intake during Pregnancy and Child Neuropsychological Development: A Multi-Centre Population-Based Birth Cohort Study in Spain.

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/day) of n-3 PUFA consumption during the first trimester, those in the highest quartile (>1.657 g/day) 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 child neuropsychological functions at 4 and 7 years of age were found, and further clinical research is needed to confirm these findings.

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

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 B12 and B6). 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. ß [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.

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

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

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

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.

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

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 (ß = 2.28 × 10-4, p-value = 5.87 × 10-5) in relation to prenatal MeHg exposure. In child blood, we identified differential DNAm at cg15288800 (ß = 0.004, p-value = 4.97 × 10-5), 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 (ß = 0.002, p-value = 4.81 × 10-7) in GRK1 and cg02212000 (ß = -0.001, p-value = 8.13 × 10-7) in GGH. Prenatal MeHg exposure was associated with DNAm modifications that may influence health outcomes, such as cognitive or anthropometric development, in different populations.

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

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 (ß (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.

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

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., ß [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.

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

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.

Postnatal exposure to mercury and neuropsychological development among preschooler children.

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 (ß = 0.89; 95%CI 0.38, 1.39), memory (ß = 0.42; 95%CI 0.09, 0.76) and general cognitive scales (ß = 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.