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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 and1: 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 (β[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 stage1 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.

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 × 10-4, p-value = 5.87 × 10-5) in relation to prenatal MeHg exposure. In child blood, we identified differential DNAm at cg15288800 (β = 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 (β = 0.002, p-value = 4.81 × 10-7) in GRK1 and cg02212000 (β = -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. INMA: Main funding of the epigenetic studies in INMA were grants from Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041), Spanish Ministry of Health (FIS-PI04/1436, FIS-PI08/1151 including FEDER funds, FIS-PI11/00610, FIS-FEDER-PI06/0867, FIS-FEDER-PI03–1615, FIS-FEDER PI16/1288, FIS-FEDER PI19/1338; Miguel Servet FEDER 15/0025 and 20/0006; FIS-FSE: 17/00260), Generalitat de Catalunya-CIRIT 1999SGR 00241, Generalitat Valenciana BEST/2020/059, Fundacio ́ La Marato ́ de TV3 (090,430), EU Commission (261357-MeDALL: Mechanisms of the Development of ALLergy), and European Research Council (268479-BREATHE: Brain dEvelopment and Air polluTion ultrafine particles in school childrEn). Korean exposome study: This study was supported by the Korean Environment Industry & Technology Institute (KEITI) through “the Environmental Health Action Program”, funded by Korea Ministry of Environment (2017001360005). MoBa: The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no N01-ES-75558), NIH/NINDS (grant no.1 UO1 NS 047537–01 and grant no.2 UO1 NS 047537–06A1). MoBa1 and MoBa 2 are supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and Norwegian Research Council/BIOBANK (grant no 221097). The work in MoBa3 was supported in part by a Postdoctoral Fellowship grant from the Ulleval Hospitals Research Council (now under Oslo University Hospital) and travel grants from the Unger-Vetlesens foundation and the Norwegian American Womens Club, all to M.C.M.K. MoBa3 epigenomics data analyses were funded by INCA/Plan Cancer-EVA-INSERM, France, and the International Childhood Cancer Cohort Consortium (I4C), and performed by the Epigenetics Group at the International Agency for Research on Cancer (IARC, Lyon, France), A.G. was supported by the grant from INCA/Plan Cancer-EVA-INSERM (France, 2015) to Z.H. and also by the IARC Postdoctoral Fellowship, partially supported by the EC FP7 Marie Curie Actions-People-Co-funding of regional, national and international programmes (COFUND). Project Viva: The Project Viva cohort is funded by NIH grants R01HL111108, R01NR013945, and R37 HD034568. RHEA: The Rhea project was financially supported by European projects, and the Greek Ministry of Health (Program of Prevention of Obesity and Neurodevelopmental Disorders in Preschool Children, in Heraklion district, Crete, Greece: 2011–2014; ‘Rhea Plus': Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012–2015). The work was also supported by MICINN (MTM2015-68140-R), Centro Nacional de Genotipado-CEGEN-PRB2-ISCIII, the H2020-EU.3.1.2. - Preventing Disease Programme (grant agreement no 874583) (ATHLETE project), and from the European Union's Horizon 2020 research and innovation programme (grant Agreement number: 733206) (Early Life stressors and Lifecycle Health (LIFECYCLE)).

This study has been funded by Instituto de Salud Carlos III through the projects “CP14/00108, PI16/00261 and PI21/00266” (co-funded by European Regional Development Fund “A way to make Europe”). This study was also funded bygrants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151incl. FEDER funds), CIBERESP, EU Commission (261357). We acknowledge support from the Spanish Ministry of Science and Innovation and the State Research Agency through the “Centro de Excelencia Severo Ochoa 2019–2023” program (CEX2018-000806-S). This study was also funded by Grants from UE (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), Spain: ISCIII (Red INMA G03/176, CB06/02/0041; FIS-FEDER: PI03/1615, PI04/1509, PI04/1112, PI04/1931, PI05/1079, PI05/1052, PI06/1213, PI07/0314, PI09/02647, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, and PI17/00663…, Tahaei, Hana ; Gignac, Florence ; Pinar, Ariadna ; Fernandez-Barrés, Silvia ; Romaguera, Dora ; Vioque, Jesus ; Santa-Marina, Loreto ; Subiza-Pérez, Mikel ; Llop, Sabrina ; Soler-Blasco, Raquel ; Arija, Victoria ; Salas-Salvadó, Jordi ; Tardón, Adonina ; Riaño-Galán, Isolina ; Sunyer, Jordi ; Guxens, Monica ; Julvez, Jordi

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. The INMA study was funded by grants from the European Union (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1) , and from Spain: Instituto de Salud Carlos III and Ministry of Health (Red INMA G03/176; CB06/02/0041; PI041436, PI081151, PI06/0867, PS09/00090, PI13/02187; FIS-FEDER: PI03/1615, PI04/1509, PI04/1112, PI04/1931, PI05/1079, PI05/1052, PI06/1213, PI07/0314, PI09/02647, PI11/01007, PI11/02591, PI11/02038, PI12/01890, PI13/1944, PI13/2032, PI14/00891, PI14/1687, PI17/01194, and PI17/00663; MV16/00015; predoctoral grant PFIS - FI14/00099, pre-doctoral grant PFIS FIS-FSE: 17/00260, FIS19/1338, MV16/00015, Miguel Servet-FEDER: CP11/0178, and Miguel Servet-FSE: MS13/00054, MSII16/00051, and MS16/00128) , CIBERESP; Department of Health of the Basque Government (2005111093 and 2009111069) ; the Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001) ; and the Generalitat de Catalunya-CIRIT (1999SGR 00241) . ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. We acknowledge support from the Spanish Ministry of Science and Innovation through the "Centro de Excelencia Severo Ochoa 2019-2023" Program (CEX 2018-000806-S) , and support from the Generalitat de Catalunya through the CERCA Program.

This study was funded by Grants from EU (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1); Spain: ISCIII (Red INMA G03/176, CB06/02/0041; FIS-FEDER: PI03/1615, PI04/1509, PI04/1112, PI04/1931, PI05/1079, PI05/1052, PI06/0867, PI06/1213, PI07/0314, PI09/00090, PI09/02647, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI13/02187, PI14/00891, PI14/01687, PI16/1288, PI17/00663, PI18/01142 and PI19/1338; Miguel Servet FEDER MS15/00025, MS20/0006, CPII16/00051, and FIS-FSE: 17/00260); CIBERESP; Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249), AICO/2020/285, and Alicia Koplowitz Foundation 2017; Generalitat de Catalunya-CIRIT 1999SGR 00241; Department of Health of the Basque Government (2005111093, 2009111069, 2013111089 and 2015111065); Provincial Government of Gipuzkoa (DFG06/002, DFG08/001 and DFG15/221). We acknowledge support from the Spanish Ministry of Science, Innovation and Universities through the "Centro de Excelencia Severo Ochoa 2019-2023" Programme (CEX2018000806-S), and from the Generalitat de Catalunya through the CERCA Programme, as well as the municipalities in the study area., 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., European Commission 282957 HEALTH.2010.2.4.5-1, Spain: ISCIII Red INMA G03/176 CB06/02/0041 CIBERESP, Generalitat Valenciana: FISABIO UGP 15-230 UGP-15-244 UGP-15-249 AICO/2020/285, Alicia Koplowitz Foundation, Generalitat de Catalunya, General Electric CIRIT 1999SGR 00241, Department of Health of the Basque Government 2005111093 2009111069 2013111089 2015111065, Provincial Government of Gipuzkoa DFG06/002 DFG08/001 DFG15/221, Spanish Ministry of Science, Innovation and Universities CEX2018000806-S, General Electric, Spain (FIS-FEDER) PI03/1615 PI04/1509 PI04/1112 PI04/1931 PI05/1079 PI05/1052 PI06/0867 PI06/1213 PI07/0314 PI09/00090 PI09/02647 PI11/01007 PI11/02591 PI11/02038 PI13/1944 PI13/2032 PI13/02187, Spain (Miguel Servet FEDER) MS15/00025 MS20/0006 CPII16/00051, Spain (FIS-FSE) 17/00260, the Spain (FIS-FEDER) PI14/00891 PI14/01687 PI16/1288 PI17/00663 PI18/01142 PI19/1338

[EN]Background: The urban environment may influence neurodevelopment from conception onwards, but there is no evaluation of the impact of multiple groups of exposures simultaneously. We investigated the association between early-life urban environment and cognitive and motor function in children. Methods: We used data from 5403 mother-child pairs from four population-based birth-cohorts (UK, France, Spain, and Greece). We estimated thirteen urban home exposures during pregnancy and childhood, including: built environment, natural spaces, and air pollution. Verbal, non-verbal, gross motor, and fine motor functions were assessed using validated tests at five years old. We ran adjusted multi-exposure models using the Deletion-Substitution-Addition algorithm. Results: Higher greenness exposure within 300 m during pregnancy was associated with higher verbal abilities (1.5 points (95% confidence interval 0.4, 2.7) per 0.20 unit increase in greenness). Higher connectivity density within 100 m and land use diversity during pregnancy were related to lower verbal abilities. Childhood exposure to PM2.5 mediated 74% of the association between greenness during childhood and verbal abilities. Higher exposure to PM2.5 during pregnancy was related to lower fine motor function (-1.2 points (-2.1, -0.4) per 3.2 mu g/m3 increase in PM2.5). No associations were found with non-verbal abilities and gross motor function. Discussion: This study suggests that built environment, greenness, and air pollution may impact child cognitive and motor function at five years old. This study adds evidence that well-designed urban planning may benefit children's cognitive and motor development. Acknowledgements We are grateful to all the participating children, parents, practi-tioners and researchers in the four countries who took part in this study. This work was supported by funding from the European Community's Seventh Framework Programme [FP7/2007-206 n 308333; the HELIX project] . This INMA cohort was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds, FIS PI06/0867, FIS-PI09/00090, FIS and FIS-PI18/01142 incl. FEDER funds, FIS-FEDER: PI03/1615, PI04/1509, PI04/1112, PI04/1931, PI05/1079, PI05/1052, PI06/1213, PI07/0314, PI09/02647, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, PI16/00118 and PI17/00663; FIS-FSE: 17/00260; Miguel Servet-FEDER CP11/00178, CP15/00025, CPII16/00051, and CPII18/00018) , from UE (FP7-ENV-2011 cod 282957, HEALTH.2010.2.4.5-1, and H2020 n 824989) , Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundacio La marato de TV3 (090430) , Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249) , Alicia Koplowitz Foundation 2017, CIBERESP, Department of Health of the Basque Government (2013111089, 2009111069, 2013111089, 2015111065 and 2018111086) , Provincial Government of Gipuzkoa (DFG06/002, DFG08/001, DFG15/221 and DFG 89/17) and annual agreements with the municipalities of the study area (Zumarraga, Urretxu , Legazpi, Azkoitia y Azpeitia y Beasain) . We acknowledge support from the Spanish Ministry of Science and Inno-vation and the State Research Agency through the "Centro de Excelencia Severo Ochoa 2019-2023" Program (CEX2018-000806-S) , and support from the Generalitat de Catalunya through the CERCA Program. The work was also supported by MICINN [MTM2015-68140-R] and Centro Nacional de Genotipado-CEGEN-PRB2-ISCIII (Spain) . The Rhea project was financially supported by European projects, and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011-2014; "Rhea Plus": Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-15) . This paper presents independent research funded by the National Institute for Health Research (NIHR) under its Collaboration for Applied Health Research and Care (CLAHRC) for Yorkshire and Humber (UK) . The EDEN study was supported by Foundation for medical research (FRM) , National Agency for Research (ANR) , National Institute for Research inPublic health (IRESP: TGIR cohorte sante 2008 program) , French Min-istry of Health (DGS) , French Ministry of Research, INSERM Bone and Joint Diseases National Research (PRO-A) , and Human Nutrition Na-tional Research Programs, Paris-Sud University, Nestle, French National Institute for Population Health Surveillance (InVS) , French National Institute for Health Education (INPES) , the European Union FP7 pro-grams (ESCAPE, ENRIECO, Medall projects) , Diabetes National Research Program (through a collaboration with the French Association of Diabetic Patients (AFD) ) , French Agency for Environmental Health Safety and French National Agency for Food Security (now ANSES) , Mutuelle Generale de l'Education Nationale a complementary health insurance (MGEN) , French-speaking association for the study of diabetes and metabolism (ALFEDIAM) . Core support for Born in Bradford is also provided by the Wellcome Trust (WT101597MA, UK) . Born in Bradford (BiB) is only possible because of the enthusiasm and commitment of the children and parents in BiB. We are grateful to all the participants, health professionals, schools and researchers who have made BiB happen. BiB receives funding from the ESRC/MRC, the Wellcome Trust (WT101597MA) and the National Institute for Health Research York-shire and Humber ARC (reference: NIHR20016) . M. Mon-Williams was supported by a Fellowship from the Alan Turing Institute. Additional funding from the National Institute of Environmental Health Science supported Dr Chatzi (R01ES030691, R01ES029944, R01ES030364, R21ES029681, and P30ES007048) . The views expressed are those of the authors, and not necessarily those of the NHS or the NIHR. None of the funders were involved in designing the study, collecting the data, analyzing or interpreting the data, deciding to submit the article for publication, or the writing of the report. Data sharing statement The HELIX data warehouse has been established as an accessible resource for collaborative research involving researchers external to the project. Access to HELIX data is based on approval by the HELIX Project Executive Committee and by the individual cohorts. Further details on the content of the data warehouse (data catalogue) and procedures for external access are described on the project website (http:// www.proj-ecthelix.eu/index.php/es/data-inventory) .

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. 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.

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 effi-ciency 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 & ndash;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. Socio-demographic 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 lig/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., beta [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. This study was supported by grants from Instituto de Salud Carlos III, Spain [FIS-FEDER: 07/0314; FIS 11/01007, 13/1944, 16/1288, 19/1338; Miguel Servet-FEDER: CP15/0025, CPII20/00006; FIS-FSE: 17/00260; Miguel Servet-FSE: MS15/0025, MS20/0006; PI06/0867 and FIS-PI18/01142 incl. FEDER funds] , Generalitat Valenciana, Spain BEST/2020/059, Department of Health of the Basque Government, Spain (2005111093) , Provincial Government of Gipuzkoa (DFG06/002) , and annual agreements with the municipalities in the study area (Zumarraga, Urretxu, Legazpi, Azkoitia, Azpeitia and Beasain) .

This study was funded by grants from Spanish Institute of Health Carlos III-Ministry of Economy and Competitiveness (INMA Network G03/176, CB06/02/0041, and FIS-FEDER: PI03/1615, PI04/1436, PI08/1151, PI04/2018, PI04/1509, PI04/1112, PI04/1931, PI05/1079, PI05/1052, PI06/1213, PI06/0867, PI07/0314, PI09/02647, PS09/00090, PI09/02311, MS11/0178, PI13/1944, PI13/2032, PI14/00891, PI16/1288, and PI17/00663). Miguel Servet-FEDER: MSII16/ 00051, CP14/00108 & PI16/00261 (Co-funded by European Regional Development Fund “A way to make Europe”), FEDER funds, MS13/00054. Generalitat de Catalunya-CIRIT 1999SGR 00241, JCI2011–09771–MICINN, Generalitat Valenciana (Conselleria de Sanitat048/2010 and 060/2010 and FISABIO-UGP 15-230, 15-244, and 15-249). Generalitat de Catalunya-CIRIT 1999SGR 00241, and Fundació La Marató de TV3 (090430). Alicia Koplowitz Foundation (2017). Universidad de Oviedo. FISS-PI13/2429. Fundación CajasturLiberbank. Department of Health of the Basque Government (2005111093 and 2009111069). The Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001). The Fundación Roger Torné. ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. Mònica Guxens is funded by a Miguel Servet fellowship (MS13/00054) awarded by the Spanish Institute of Health Carlos III (Ministry of Economy and Competitiveness). Antonio J. Signes-Pastor and Margaret R. Karagas are funded by the following projects P01ES022832, RD 83544201, R25CA134286 and P42ES007373., Signes-Pastor, A.J., Vioque, J., Navarrete-Muñoz, E.M., Carey, M., García-Villarino, M., Fernández-Somoano, A., Tardón, A., Santa-Marina, L., Irizar, A., Casas, M., Guxens, M., Llop, S., Soler-Blasco, R., García-de-la-Hera, M., Karagas, M.R., Meharg, A.A.

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.

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.

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.

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.

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.

W know that non-invasive ventilation (NIV) is a basic ventilator support, but sometimes it fails, because of intolerance, lack of adherence, breach, etc. How can we anticipate that failure? We intend to explore the qualitative evidence on the experiences of people with this treatment and their formal and informal caregivers.Systematic literature review of original articles indexed from 2005 to 2015, which study the NIV in adult population with qualitative methodology in six databases. Peer review of scientific quality with tool of the CASPe Program. Qualitative metasynthesis of the findings.15 articles met selection criteria, based on Grounded Theory and Phenomenology, which use interviews, observation and focus group, directed both patients, and families and health professionals. Its studies emphasize the feeling of anxiety and loss of control, although the NIV relieves them dyspnea (ambivalence). Search daily well-being through routines and active participation. Interaction dependence/autonomy, especially in decision-making, finding differences that make complex the process information and advance directives. Practical wisdom of nursing care 24 hours with patients id described basic, and difficulties being narrated: lack of time, overload of work, technocentrism, inexperience.The qualitative evidence of treatment with VNI is varied although scarce; different plots (acute situations, chronic, terminals) are explored, from different points of view. The integration of these findings in our practice will help us to increase adherence and become the treatment successful, but especially to improve the quality of life of ventilated patients and their families.

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.

The prevalence of mental health problems is increasing throughout the world. Certain population groups have more probability to suffer mental disorders, which may generate inequities in health. The main of this paper is analyze the differences in the frecuency of hospital admissions according to different inequities dimensions (age, sex and country of birth) of the populaion between 15 and 49 years old between 2008 and 2015 in the Comunitat Valenciana (Spain).Transversal study based on all admissions for Diagnosis-related group "Psychosis" in public centers in the Comunitat Valenciana. Sources of information were Minimum Basic Data Set and Population Information System. Descriptive analysis of clinical and social variables was conducted, and differences among subgroups were analyzed by t-Student test for the comparison of a quantitative variable and χ2 test for the comparison of a qualitative variable, as well as the exact Wilcoxon and the Fisher test when application conditions were not satisfied.there were studied 23869 admissions for psychosis generated by 11265 patients. Most of these admissions were because of schizophrenia disorders (39.44%). When comparing by sex, differences in diagnosis were observed, being more frequent psychotic mood disorders in women (39.3%). There also observed differences when comparing by country of birth, being more frequent "Other non-organic psychosis" in foreign people (40.5%). Differences were found regarding mortality during admission, being higher in men (5.1% vs. 4%) and in foreign people (5.3% vs. 3.8%).There have been detected inequities in the frequency of psychosis admissions in the Comunitat Valenciana. These differences are observed around different dimensions such as age, gender and country of origin.La prevalencia de problemas de salud mental está aumentando en todo el mundo. Ciertos grupos poblacionales tienen mayor probabilidad de padecer trastornos mentales, generando desigualdades en salud. El objetivo de este trabajo fue analizar las diferencias en la frecuencia de ingresos por psicosis según diferentes dimensiones de desigualdad (edad, sexo y país de nacimiento) de la población entre 15 y 49 años en los años 2008- 2015 en la Comunitat Valenciana.Estudio transversal basado en los ingresos hospitalarios por el Grupo Relacionado por el Diagnóstico “Psicosis” en centros públicos de la Comunitat Valenciana. Las fuentes de información fueron el Conjunto Mínimo Básico de Datos y el Sistema de Información Poblacional. Se realizó un análisis descriptivo de variables clínicas y sociodemográficas y se analizaron diferencias por subgrupos poblacionales mediante el test t- Student para la comparación de una variable cuantitativa y el test χ2 para la comparación de una variable cualitativa, así como el test exacto de Wilcoxon y el test de Fisher cuando no se cumplían condiciones de aplicación.Se estudiaron 23.869 ingresos por psicosis generados por un total de 11.265 personas. La mayoría fueron debidos a trastornos esquizofrénicos (39,44%). Se observaron diferencias en cuanto al diagnóstico al comparar por sexo, siendo más frecuente en mujeres los trastornos episódicos del humor (39,3%) y por país de nacimiento, siendo el diagnóstico principal de “Otras psicosis no orgánicas” el más frecuente en las personas extranjeras (40,5%). Se encontraron diferencias respecto a la mortalidad durante el ingreso, siendo más alta en hombres (5,1% vs. 4%) y en población extranjera (5,3% vs. 3,8%).Se han detectado desigualdades en las frecuencias de ingresos por psicosis en la Comunitat Valenciana. Estas diferencias se observan en torno a distintas dimensiones como son la edad, el género y el país de origen.

The purpose of this study was to examine if the short semi-quantitative food frequency questionnaire (FFQ) is a reliable and valid tool to assess the diet of Spanish children aged 7&ndash, 9 years. We collected data from 156 children of the birth cohort INMA (Infancia y Medio Ambiente (Environment and Childhood)). Children&rsquo, s parents or care-givers completed a 46-item FFQ on two occasions over a 9&ndash, 12-month period about the children&rsquo, s diet. To explore the reproducibility of the FFQ, the nutrient and food group intake collected from the both FFQs were compared, while validity was examined by contrasting the nutrient values from the FFQs and the average of three 24-hour dietary recalls (24hDRs) taken in this period, and also with the concentration of several vitamins in the blood (carotenoids, vitamin D and &alpha, tocopherol). Pearson and de-attenuated correlation coefficients were calculated. The average correlation coefficients for nutrient intake&rsquo, s reproducibility was 0.41, ranging from 0.25 (calcium) to 0.65 (&beta, carotene), and for food group intake was 0.45, ranging from 0.18 (cereals) to 0.68 (sweetened beverages). Correlation coefficients slightly improved when we compared energy-adjusted intakes. The average correlation coefficients for validity against 24hDRs was 0.34 for energy-adjusted intakes, and 0.39 when de-attenuation coefficients were used. The validity coefficients against the blood concentrations of vitamins were 0.38 for &beta, cryptoxanthin, 0.26 for lycopene, 0,23 for &alpha, carotene and 0.15 for &beta, carotene, all of them statistically significant (p &lt, 0.05). This study suggests that our brief FFQ is a suitable tool for the dietary assessment of a wide range of nutrients and food groups in children 7&ndash, 9 years, despite the low to moderate reproducibility and validity observed for some nutrients.