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Background: Few studies have used longitudinal ultrasound measurements to assess the effect of traffic-related air pollution on fetal growth./nObjective: We examined the relationship between exposure to nitrogen dioxide (NO2) and aromatic hydrocarbons [benzene, toluene, ethylbenzene, m/p-xylene, and o-xylene (BTEX)] on fetal growth assessed by 1,692 ultrasound measurements among 562 pregnant women from the Sabadell cohort of the Spanish INMA (Environment and Childhood) study./nMethods: We used temporally adjusted land-use regression models to estimate exposures to NO2 and BTEX. We fitted mixed-effects models to estimate longitudinal growth curves for femur length (FL), head circumference (HC), abdominal circumference (AC), biparietal diameter (BPD), and estimated fetal weight (EFW). Unconditional and conditional SD scores were calculated at 12, 20, and 32 weeks of gestation. Sensitivity analyses were performed considering time–activity patterns during pregnancy./nResults: Exposure to BTEX from early pregnancy was negatively associated with growth in BPD during weeks 20–32. None of the other fetal growth parameters were associated with exposure to air pollution during pregnancy. When considering only women who spent 2 hr/day in nonresidential outdoor locations, effect estimates were stronger and statistically significant for the association between NO2 and growth in HC during weeks 12–20 and growth in AC, BPD, and EFW during weeks 20–32./nConclusions: Our results lend some support to an effect of exposure to traffic-related air pollutants from early pregnancy on fetal growth during mid-pregnancy. ; This study was funded by grants from the European Union: NEWGENERIS FP6-2003- Food-3-A-016320, FP7-ENV-2011 cod 282957, HEALTH.2010.2.4.5-1; and by grants from Spain: Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0031, and FIS-FEDER PI03/1615, PI04/1509, PI04/1112, PI04/1931, PI04/2018, PI04/1436, PI05/1079, PI05/1052, PI06/1213, PI07/0314, PI08/1151, PI09/02647, PI09/02311, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/02429, PI14/0891, PI14/1687, and Miguel Servet CP11/00178 and MS13/00054), Conselleria de Sanitat Generalitat Valenciana, Generalitat de Catalunya (CIRIT 1999SGR 00241), Diputación Foral de Guipúzcoa (DFG/004), Departamento de Sanidad y Consumo Gobierno Vasco (2005111093), Obra Social Cajastur, and Oviedo University.

Background: Prenatal and early-life periods may be critical windows for harmful effects of air pollution on infant health. Objectives: We studied the association of air pollution exposure during pregnancy and the first year of life with respiratory illnesses, ear infections, and eczema during the first 12–18 months of age in a Spanish birth cohort of 2,199 infants. Methods: We obtained parentally reported information on doctor-diagnosed lower respiratory tract infections (LRTI) and parental reports of wheezing, eczema, and ear infections. We estimated individual exposures to nitrogen dioxide (NO2) and benzene with temporally adjusted land use regression models. We used log-binomial regression models and a combined random-effects meta-analysis to estimate the effects of air pollution exposure on health outcomes across the four study locations. Results: A 10-µg/m3 increase in average NO2 during pregnancy was associated with LRTI [relative risk (RR) = 1.05; 95% CI: 0.98, 1.12] and ear infections (RR = 1.18; 95% CI: 0.98, 1.41). The RRs for an interquartile range (IQR) increase in NO2 were 1.08 (95% CI: 0.97, 1.21) for LRTI and 1.31 (95% CI: 0.97, 1.76) for ear infections. Compared with NO2, the association for an IQR increase in average benzene exposure was similar for LRTI (RR = 1.06; 95% CI: 0.94, 1.19) and slightly lower for ear infections (RR = 1.17; 95% CI: 0.93, 1.46). Associations were slightly stronger among infants whose mothers spent more time at home during pregnancy. Air pollution exposure during the first year was highly correlated with prenatal exposure, so we were unable to discern the relative importance of each exposure period. Conclusions: Our findings support the hypothesis that early-life exposure to ambient air pollution may increase the risk of upper and lower respiratory tract infections in infants. ; This study was funded by grants from Spanish Ministry of Health–Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041, FIS-PI041436, FIS- PI081151, FIS-PI042018, FIS-PI09/02311, FIS-PI06/0867, FIS-PS09/00090, FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314, and 09/02647), Generalitat de Catalunya-CIRIT (Consejo Interdepartamental de Investigación e Innovación Tecnológica) (1999SGR 00241), Conselleria de Sanitat Generalitat Valenciana, Universidad de Oviedo, Obra social Cajastur, Department of Health of the Basque Government (2005111093 and 2009111069), Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001), and Fundación Roger Torné. M.P. holds a Juan de la Cierva post-doctoral fellowship awarded from the Spanish Ministry of Science and Innovation (JCI-2011-09479)

Background: Few studies have investigated the 24-hour respiratory health effects of personal black carbon (BC) and ultrafine particles (UFP) exposure in schoolchildren. The objective of this study was to investigate these associations with the lung function in children 10-years old with and without persistent respiratory symptoms. Methods: We conducted a cross-sectional study in 305 children (147 and 158 with and without persistent respiratory symptoms, respectively) from three European birth-cohorts: PARIS (France) and INMA Sabadell and Valencia (Spain). Personal 24-hour measurements of exposure concentrations to BC and UFP were performed by portable devices, before lung function testing. Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and the fraction of exhaled nitric oxide (FeNO) were determined. Results: There was no association of UFP with lung function parameters or FeNO whereas the increase in 24-hour BC exposure concentrations was related to a statistically significant decrease in lung function parameters only among children with persistent respiratory symptoms [-96.8 mL (95% Confidence Interval CI: -184.4 to -9.1 mL) in FVC, and -107.2 mL (95% CI: -177.5 to -36.9 mL) in FEV1 for an inter-quartile range of 1160 ng/m3 exposure increase]. A significant positive association between BC and FeNO was observed only in children with persistent respiratory symptoms with current wheezing and/or medication to improve breathing [FeNO increases with +6.9 ppb (95% CI: 0.7 to 13.1 ppb) with an inter-quartile range BC exposure increase]. Conclusion: Children suffering from persistent respiratory symptoms appear to be more vulnerable to BC exposure. ; The study in Sabadell was funded by grants from Instituto de Salud Carlos III Red INMA (G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds; PI12/01890 incl. FEDER funds; CP13/00054 incl. FEDER funds), CIBERESP, Generalitat de Catalunya-CIRIT 19995GR 00241, Generalitat de Catalunya-AGAUR (2009 SGR 501, 2014 SGR 822), Fundació la Marató de TV3 (090430), Spanish Ministry of Economy and Competitiveness (SAF2012-32991 incl. FEDER funds), EU Commission (261357, 308333 and 603794), the European Community's Seventh Framework Programme (FP7/2007/2013) under grant agreements 308333-HELIX Project and 308610-EXPOSOMICS Project. Dr Maribel Casas received funding from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness) (MS16/00128). The study in Valencia was funded by grants from European Union (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), Spain: Instituto de Salud Carlos III (FIS-FEDER funds: PI11/01007, PI11/02591, PI11/02038, PI12/00610, PI13/1944, PI13/02032, PI14/00891, PI14/01687, and PI16/1288; Miguel Servet-FEDER CP11/00178, CP15/00025, and CPII16/00051), and Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249).

BACKGROUND: To date, no epidemiological studies have explored the impact and persistence of in utero exposure to mixtures of xenoestrogens on the developing brain. We aimed to assess whether the cumulative effect of xenoestrogens in the placenta is associated with altered infant neuropsychological functioning at two and at four years of age, and if associations differ among boys and girls. METHODS: Cumulative prenatal exposure to xenoestrogens was quantified in the placenta using the biomarker Total Effective Xenoestrogen Burden (TEXB-alpha) in 489 participants from the INMA (Childhood and the Environment) Project. TEXB-alpha was split in tertiles to test its association with the mental and psychomotor scores of the Bayley Scales of Infant Development (BSID) at 1-2 years of age, and with the McCarthy Scales of Children׳s Abilities (MSCA) general cognitive index and motor scale assessed at 4-5 years of age. Interactions with sex were investigated. RESULTS: /nAfter adjustment for potential confounders, no association was observed between TEXB-alpha and mental scores at 1-2 years of age. We found a significant interactions with sex for the association between TEXB-alpha and infant psychomotor development (interaction p-value=0.029). Boys in the third tertile of exposure scored on average 5.2 points less than those in the first tertile on tests of motor development at 1-2 years of age (p-value=0.052), while no associations were observed in girls. However, this association disappeared in children at 4-5 years of age and no association between TEXB-alpha and children׳s cognition was found. CONCLUSIONS: Our results suggest that boys' early motor development might be more vulnerable to prenatal exposure to mixtures of xenoestrogens, but associations do not persist in preschool children. ; This work was supported by grants from the Spanish Ministry of Health [FIS-PI042018; FIS-PI060867; FIS-PI081151; FIS-PI09/02311; FIS-PI09/02647; FIS-PI11/00610 Council of Innovation, Science and Enterprise (Excellence Project P09-CTS-5488) and Council of Health (SAS PI-0675-2010), Instituto de Salud Carlos III [Red INMA G03/176 and CB06/02/0041]; the EU Commission (QLK4-1999-01422, QLK4-2002-00603 and CONTAMED FP7-ENV-212502), the Generalitat de Catalunya-CIRIT [1999SGR 00241]; the Fundació La Marató de TV3 (Grant no. 090430); the Consejería de Salud de la Junta de Andalucía (Grant number 183/07 and 0675/10), the Diputación Foral de Gipuzkoa (DFG06/004), the Department of Health of the Basque Government (2005111093), the University of Oviedo, Obra Social Cajastur, and the Fundación Roger Torné. NV was supported by an FPI Grant from the Spanish Ministry of Health (BES-2009-023933) and a Formación de Personal Investigador Grant for Short Research Stays in Foreign Institutions (BES-2009-023933). The HUSC BioBank, integrated in the Andalusia Public Health System (SSPA) and the National Biobank Network, is financed by the Institute of Health Carlos III, (Project RD09/0076/00148) and the Regional Government of Andalusia

BACKGROUND: Exposure to perfluoroalkyl substances (PFASs) may increase risk for metabolic diseases; however, epidemiologic evidence is lacking at the present time. Pregnancy is a period of enhanced tissue plasticity for the fetus and the mother and may be a critical window of PFAS exposure susceptibility. OBJECTIVE: We evaluated the associations between PFAS exposures and metabolic outcomes in pregnant women. METHODS: We analyzed 1,240 pregnant women from the Spanish INMA [Environment and Childhood Project (INfancia y Medio Ambiente)] birth cohort study (recruitment period: 2003-2008) with measured first pregnancy trimester plasma concentrations of four PFASs (in nanograms/milliliter). We used logistic regression models to estimate associations of PFASs (log10-transformed and categorized into quartiles) with impaired glucose tolerance (IGT) and gestational diabetes mellitus (GDM), and we used linear regression models to estimate associations with first-trimester serum levels of triglycerides, total cholesterol, and C-reactive protein (CRP). RESULTS: Perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) were positively associated with IGT (137 cases) [OR per log10-unit increase=1.99 (95% CI: 1.06, 3.78) and OR=1.65 ( 95% CI: 0.99, 2.76), respectively]. PFOS and PFHxS associations with GDM (53 cases) were in a similar direction, but less precise. PFOS and perfluorononanoate (PFNA) were negatively associated with triglyceride levels [percent median change per log10-unit increase=-5.86% (95% CI: -9.91%, -1.63%) and percent median change per log10-unit increase=-4.75% (95% CI: -8.16%, -0.61%, respectively], whereas perfluorooctanoate (PFOA) was positively associated with total cholesterol [percent median change per log10-unit increase=1.26% (95% CI: 0.01%, 2.54%)]. PFASs were not associated with CRP in the subset of the population with available data (n=640). CONCLUSIONS: Although further confirmation is required, the findings from this study suggest that PFAS exposures during pregnancy may influence lipid metabolism and glucose tolerance and thus may impact the health of the mother and her child. https://doi.org/10.1289/EHP1062. ; This study was funded in part by grants from the European Union (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), the Instituto de Salud Carlos III, the Spanish Ministry of Health (Red INMA G03/176; CB06/02/0041; FIS-PI12/01890, FIS-PI041436, FIS- PI081151, FIS-PI06/0867, FIS-PS09/00090; FIS-FEDER: 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314, 09/02647, 11/01007, 11/02591, 11/02038, 13/1944, 13/2032, 14/00891, and 14/01687; Miguel Servet-FEDER CP11/0178, MS13/00054, and CPII16/00051; and PFIS-FI14/00099), Generalitat Valenciana (FISABIO: UGP 15-230, UGP-15-244, and UGP-15-249), the Department of Health of the Basque Government (2005111093 and 2009111069), the Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001), the Generalitat de Catalunya-CIRIT (1999SGR 00241), and the National Institutes of Health/National Institute of Environmental Health Sciences (grant number ES021477). This study has been reviewed and approved by the accredited committees of the following institutions: The Municipal Institute of Sanitary Assistance of Barcelona, La Fe University Hospital of Valencia, and The Donostia Hospital.

BACKGROUND: In 2003 the INMA-INfancia y Medio Ambiente (Environment and Childhood) project, a Spanish national network of birth cohorts including more than 3500 participants, was set up with the aim to assess the health impacts of pre- and postnatal environmental exposures on children. The project has published more than 60 papers on maternal and environmental factors related to neuropsychological development in children, one of the main research interests within the project. With the present review, we evaluate the evidence provided by the INMA project on this topic and discuss how the data can contribute to cover the challenges that children's environmental health research will face in the coming years. RESULTS: The INMA project has contributed to provide increasing evidence of the association between prenatal exposure to persistent organic pollutants (POPs) and child neuropsychological development, but it has also shown, using innovative methodologies, that postnatal exposure to these compounds does not play a role in this association. The project has also contributed to show the detrimental influence of certain air pollutants on child neuropsychological development, as well as how a balanced maternal fish intake can protect from the potential adverse effects of prenatal exposure to mercury. Also, the project has contributed to the understanding of impacts of nutritional factors including supplement intake and vitamin D levels during pregnancy and the role of breastfeeding on the neuropsychological benefits. CONCLUSIONS: INMA findings underscore the importance of continued research on the delineation of the sensitive windows of exposure both during pregnancy and postnatally and on the combined effects of environmental exposures, denoted the exposome. In terms of health policy, INMA findings have important implications for the development of public health policies to advance the health and development of children. ; This study was supported Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041, 97/0588, 00/0021-2, PI04/1436, PI06/1756, PI08/1151, PS09/01958, PI12/01890, PI14/00677, MS13/00054, CP13/00054 including FIS-FEDER funds 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314, 09/02311, 09/02647, 11/0178, 11/02591, 11/02038, 13/1944, 13/2032, 13/02429, 14/0891, 14/1687, and 16/1288) and Miguel Servet-FEDER MS15/00025, Spanish Ministry of Health - CIBERESP (FIS-97/1102, FIS-PS09/00362, FIS-07/0252, FIS-PI11/00610, FISPI07/0252, FISPI11/0610, FIS-PI04/2018, FIS-PI09/02311, FIS-PI13/02429, FIS-PI06/0867, FIS-PS09/00090, FIS-PI13/02187, PI13/02406, MS13/00054), Spanish Ministry of Economy and Competitiveness (SAF2012-32991 incl. FEDER funds), EU Comission (QLK4-CT-2000-00263, QLK4-1999-01422, QLK4-2002-00603 and CONTAMED FP7-ENV-212502, FP7-ENV-2011 cod 282957, 261357, 308333 and 603794 and HEALTH.2010.2.4.5-1), Generalitat de Catalunya-CIRIT 1999SGR 00241, Generalitat de Catalunya-AGAUR (2009 SGR501, 2014 SGR 822), Department of Health of the Basque Government (2005111093, 2009111069, 2013111089 and 2015111065), the Provincial Government of Gipuzkoa (DFG06/002, DFG08/001 and DFG15/221), Consejería de Salud de la Junta de Andalucía (grant number 183/07 and SAS-PI-0675-2010), Conselleria de Sanitat, Generalitat Valenciana, Andalusia Regional Government – Consejería de Salud (Grants P09-CTS-5488 Project of Excellence, and SAS PI-0133-2007; PI-0675–2010), Agence Nationale de Securite Sanitaire de l'Alimentation de l'Environnement et du Travail (1262C0010), beca de la IV convocatoria de Ayudas a la Investigación en Enfermedades Neurodegenerativas de La Caixa, Fundació La Caixa (97/009-00 and 00/077-00), Fundació La Marató de TV3 (090430), Obra Social Cajastur/Fundación Liberbank and University of Oviedo, and annual agreements with the municipalities of the area of study (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain)

Background: Disinfection by-products (DBPs) constitute a complex mixture of prevalent chemicals in drinking water and there is evidence of neurotoxicity for some of them. Objectives: We evaluated the association between estimates of DBP exposure during pregnancy and child neuropsychological outcomes at 1 and 4–5 years of age. Methods: We conducted a population-based mother-child cohort study in Spain with recruitment at first trimester of gestation (INMA Project, 2003–2008). Neuropsychological development was measured at 1 year of age using the Bayley Scales of Infant Development and at 4–5 years with the McCarthy Scales of Children's Abilities. Modeled tap water concentrations of trihalomethanes (THM) were combined with personal ingestion, showering and bathing habits to estimate exposure as ingestion uptake, all route (showering, bathing, ingestion) uptake (μg/day) and crude levels (μg/l) in the residence. Chloroform, brominated THMs (bromodichloromethane, dibromochloromethane, bromoform) and total THMs (chloroform and brominated THMs) were analysed separately. Nine haloacetic acids levels were available in one of the areas. Linear regression was used to estimate associations in 1855 subjects adjusting for covariables. Results: The median concentration of total THMs, chloroform, brominated THMs, total haloacetic acids, dichloroacetic acid, and trichloroacetic acid were, respectively 30.3 μg/L, 9.4 μg/L, 11.6 μg/L, 10.5 μg/L, 2.7 μg/L, and 3.1 μg/L. The associations between THM exposure and neuropsychological outcomes were null, except for total and brominated THM uptake though all routes and the general cognitive score at 4–5 years, with a decrease in − 0.54 points (95%CI − 1.03, − 0.05) and − 0.64 (95%CI − 1.16, − 0.12), respectively, for doubling total and brominated THM uptake. A positive association found between dichloroacetic acid and the mental score at 1 year did not persist at 4–5 years. Conclusions: Minor associations observed between DBP exposure during gestation and child neuropsychological development at 1 year disappeared at 4–5 years. Although a suggestive association is identified for exposure to brominated THMs and the cognitive score at 4–5 years, chance cannot be ruled out. ; This study was funded by Grants from UE (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), and from Spain: Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041, FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, PI041436, FIS-PI042018, 05/1079, 05/1052, 06/1213, FIS-PI06/0867, 07/0314, 081151, 09/02647, 09/02311, 09/00090, 11/0178, 11/02591, 11/02038, 13/1944, 13/2032, 13/02429, 13/02187, 14/0891, 14/1687, CP14/00108, CP16/00261 and Miguel Servet-FEDER MS15/0025, MS13/00054, CP0610034, MS14/00108), CIBERESP (Ref. AA08_012), the Conselleria de Sanitat de la Generalitat Valenciana, Generalitat de Catalunya (CIRIT 1999SGR 00241), Fundació La Marató de TV3 (090430), Obra Social Cajastur/Fundación Liberbank, Universidad de Oviedo, Department of Health of the Basque Government (2005111093, 2009111069, 2013111089 and 2015111065), and the Provincial Government of Gipuzkoa (DFG06/002, DFG08/001 and DFG15/221). Annual agreements with the city council of the study area in Gipuzkoa (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain). ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya.

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. ; 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).

Background: Air pollution effects on children's neurodevelopment have recently been suggested to occur most likely through the oxidative stress pathway. Objective: We aimed to assess whether prenatal exposure to residential air pollution is associated with impaired infant mental development, and whether antioxidant/detoxification factors modulate this association. Methods: In the Spanish INfancia y Medio Ambiente (INMA; Environment and Childhood) Project, 2,644 pregnant women were recruited during their first trimester. Nitrogen dioxide (NO2) and benzene were measured with passive samplers covering the study areas. Land use regression models were developed for each pollutant to predict average outdoor air pollution levels for the entire pregnancy at each residential address. Maternal diet was obtained at first trimester through a validated food frequency questionnaire. Around 14 months, infant mental development was assessed using Bayley Scales of Infant Development. Results: Among the 1,889 children included in the analysis, mean exposure during pregnancy was 29.0 μg/m3 for NO2 and 1.5 μg/m3 for benzene. Exposure to NO2 and benzene showed an inverse association with mental development, although not statistically significant, after adjusting for potential confounders [β (95% confidence interval) = –0.95 (–3.90, 1.89) and –1.57 (–3.69, 0.56), respectively, for a doubling of each compound]. Stronger inverse associations were estimated for both pollutants among infants whose mothers reported low intakes of fruits/vegetables during pregnancy [–4.13 (–7.06, –1.21) and –4.37 (–6.89, –1.86) for NO2 and benzene, respectively], with little evidence of associations in the high-intake group (interaction p-values of 0.073 and 0.047). Inverse associations were also stronger in non-breast-fed infants and infants with low maternal vitamin D, but effect estimates and interactions were not significant. Conclusions: Our findings suggest that prenatal exposure to residential air pollutants may adversely affect infant mental development, but potential effects may be limited to infants whose mothers report low antioxidant intakes. ; This study was funded by grants from the Spanish Ministry of Health-Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041, FIS-PI041436, FIS- PI081151, FIS-PI042018, FIS-PI09/02311, FIS-PI06/0867, FIS-PS09/00090, FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314, and 09/02647), Generalitat de Catalunya-CIRIT (Consell Interdepartamental de Recerca i Innovació Tecnològica) (1999SGR 00241), Conselleria de Sanitat Generalitat Valenciana, Universidad de Oviedo, Obra social Cajastur, Department of Health of the Basque Government (2005111093 and 2009111069), the Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001), and Fundación Roger Torné

BACKGROUND: Prenatal perfluorooctanoate (PFOA) exposure has been associated with reduced birth weight but maternal glomerular filtration rate (GFR) may attenuate this association. Further, this association remains unclear for other perfluoroalkyl substances (PFAS), such as perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), and perfluorononanoate (PFNA). We estimated associations between prenatal PFAS exposure and birth outcomes, and the influence of GFR, in a Spanish birth cohort. METHODS: We measured PFHxS, PFOS, PFOA, and PFNA in 1st-trimester maternal plasma (years: 2003-2008) in 1202 mother-child pairs. Continuous birth outcomes included standardized weight, length, head circumference, and gestational age. Binary outcomes included low birth weight (LBW), small-for-gestational-age, and preterm birth. We calculated maternal GFR from plasma-creatinine measurements in the 1st-trimester of pregnancy (n=765) using the Cockcroft-Gault formula. We used mixed-effects linear and logistic models with region of residence as random effect and adjustment for maternal age, parity, pre-pregnancy BMI, and fish intake during pregnancy. RESULTS: Newborns in this study weighted on average 3263g and had a median gestational age of 39.8weeks. The most abundant PFAS were PFOS and PFOA (median: 6.05 and 2.35ng/mL, respectively). Overall, PFAS concentrations were not significantly associated to birth outcomes. PFOA, PFHxS, and PFNA showed weak, non-statistically significant associations with reduced birth weights ranging from 8.6g to 10.3g per doubling of exposure. Higher PFOS exposure was associated with an OR of 1.90 (95% CI: 0.98, 3.68) for LBW (similar in births-at-term) in boys. Maternal GFR did not confound the associations. CONCLUSIONS: In this study, PFAS showed little association with birth outcomes. Higher PFHxS, PFOA, and PFNA concentrations were non-significantly associated with reduced birth weight. The association between PFOS and LBW seemed to be sex-specific. Finally, maternal GFR measured early during pregnancy had little influence on the estimated associations. ; This 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, Ministry of Health CIBERESP, the Conselleria de Sanitat, Generalitat Valenciana, (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, and PI14/1687; pre-doctoral grant PFIS - FI14/00099 and; Miguel Servet-FEDER: CP11/0178 and CPII16/00051), 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)

BACKGROUND: Prenatal and postnatal exposure to air pollution has been linked to cognitive impairment in children, but very few studies have assessed its association with attentional function. OBJECTIVES: To evaluate the association between prenatal and postnatal exposure to nitrogen dioxide (NO2) and attentional function in children at 4-5years of age. METHODS: We used data from four regions of the Spanish INMA-Environment and Childhood-Project, a population-based birth cohort. Using land-use regression models (LUR), we estimated prenatal and postnatal NO2 levels in all of these regions at the participants' residential addresses. We assessed attentional function using the Kiddie-Conners Continuous Performance Test (K-CPT). We combined the region-specific adjusted effect estimates using random-effects meta-analysis. RESULTS: We included 1298 children with complete data. Prenatal exposure to NO2 was associated with an impaired standard error of the hit reaction time (HRT(SE)) (increase of 1.12ms [95% CI; 0.22 a 2.02] per 10μg/m3 increase in prenatal NO2) and increased omission errors (6% [95% CI; 1.01 to 1.11] per 10μg/m3 increase in prenatal NO2). Postnatal exposure to NO2 resulted in a similar but borderline significant increase of omission errors (5% [95% CI; =0.99 to 1.11] per 10μg/m3 increase in postnatal NO2). These associations did not vary markedly between regions, and were mainly observed in girls. Commission errors and lower detectability were associated with prenatal and postnatal exposure to NO2 only in some regions. CONCLUSIONS: This study indicates that higher exposure to ambient NO2, mainly during pregnancy and to a lesser extent postnatally, is associated with impaired attentional function in children at 4-5years of age. ; This study was funded by grants from the Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041 and PI031615; PI041931; PI041112; PI041436; PI041509; PI042018; PI051079; PI051052; PI060867; PI061213; PI070314; CP1100178; PI081151 incl. FEDER funds; PS0900090 incl. FEDER funds; PI0902311 incl. FEDER funds; PI0902647 incl. FEDER funds; PI1102591 incl. FEDER funds; PI1102038 incl. FEDER funds; PI131944 incl. FEDER funds; PI132032 incl. FEDER funds; PI1302429 incl. FEDER funds; PI1302187 incl. FEDER funds; PI140891 incl. FEDER funds; PI141687 incl. FEDER funds and MS13/00054), Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundació La marató de TV3 (090430), Department of Health of the Basque Government (2005111093, 2009111069 and 2013111089), the Provincial Government of Gipuzkoa (DFG06/002 and DFG08/001), Convenios anuales con los ayuntamientos de la zona del estudio (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain), from UE (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), from the European Research Council under the ERC Grant Agreement number ERC-AdG 2010 GA#268479 – the BREATHE project, from the Conselleria de Sanitat of Generalitat Valenciana (AP212/11, 002/008, 012/009, 013/2009, 014/009, 015/008, 016/009, 021/007, 021/008, 023/008 and 024/007) and from Obra Social Cajastur/Fundación Liberbank and Universidad de Oviedo. ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya

Background: Several studies have investigated the possible association between prenatal exposure to perfluoroalkyl substances (PFASs) and birth anthropometry. However, none has assessed fetal size longitudinally. We studied the possible association between PFASs and fetal biometry. Methods: In 1230 mother-child pairs of three cohorts from the Spanish INMA-Project, we analyzed perfluorohexanesulfonic acid (PFHxS), perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) in first-trimester maternal plasma (collection: 2003-2008). We measured abdominal circumference (AC), femur length (FL), biparietal diameter (BPD), and estimated fetal weight (EFW) by ultrasounds at 12, 20, and 34 gestational weeks. We conducted multivariable linear regression analyses between log2-transformed (PFASs) and SD-scores of fetal parameters in each cohort and subsequent meta-analysis. We also assessed effect modification by sex and maternal smoking. Results: PFHxS, PFOA, PFOS, and PFNA medians were: 0.58, 2.35, 6.05, and 0.65 ng/mL, respectively. There were no associations for the whole population in any trimester of pregnancy. However, we found an indication that maternal smoking modified the effect in different directions depending on the PFAS. Among smokers (31%), we found negative associations between both PFOA and PFNA and FL or EFW at week 20 (% change ranging between -6.8% and -5.7% per twofold PFAS increase) and positive associations between PFHxS or PFOS and BPD at week 34 (6.8% and 6.3%, respectively). Conclusions: Results did not suggest an overall association between prenatal PFASs and fetal growth. The results among smokers should be taken with caution and further studies are warranted to elucidate the possible role of smoking in this association. ; This work was supported 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 [Red INMA G03/176, CB06/02/0041, FIS-FEDER: PI03/1615, PI041436, PI04/1509, PI04/1112, PI04/1931, PI05/1079, PI05/1052, PI06/0867, PI06/1213, PI07/0314, PI081151, PI09/02647, PI09/00090, PI11/01007, PI11/02591, PI11/02038, PI12/01890, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, and PI17/00663; Miguel Servet-FEDER CP11/0178, Miguel Servet-FSE: MS16/00128, and MSII16/00051; and PFIS-FI14/00099]; Alicia Koplowitz Foundation 2017; Generalitat Valenciana [FISABIO-UGP 15-230, 15-244, and 15-249]; 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].

BACKGROUND: Prenatal exposure to endocrine disrupting compounds (EDCs) has previously shown to alter epigenetic marks. OBJECTIVES: In this work we explore whether prenatal exposure to mixtures of xenoestrogens has the potential to alter the placenta epigenome, by studying DNA methylation in retrotransposons as a surrogate of global DNA methylation. METHODS: The biomarker total effective xenoestrogen burden (TEXB) was measured in 192 placentas from participants in the longitudinal INMA Project. DNA methylation was quantitatively assessed by bisulfite pyrosequencing on 10 different retrotransposons including 3 different long interspersed nuclear elements (LINEs), 4 short interspersed nuclear elements (SINEs) and 3 human endogenous retroviruses (HERVs). Associations were tested using linear mixed-effects regression models and sex interaction was evaluated.RESULTS: A significant sex interaction was observed for AluYb8 (p-value for interaction <0.001, significant at Bonferroni corrected p-value threshold of 0.0025). Boys with the highest TEXB-alpha levels of exposure (third tertile) presented on average a decrease of 0.84% in methylation compared to those in the first tertile (p-value<0.001), while no significant effects were found in girls (p-value=0.134). CONCLUSIONS: Our findings suggest that boys may be more susceptible to the effect of exposure to xenoestrogens during prenatal development, producing shifts in DNA methylation of certain sensitive genomic repetitive sequences in a tissue important for fetal growth and development. ; This work was supported by grants from the Spanish Ministry of Health (FIS-PI042018; FIS-PI060867; FIS-PI081151; FIS-PI09/02311; FIS-PI09/02647; FIS-PI11/00610); Instituto de Salud Carlos III [Red INMA G03/176 and CB06/02/0041]; the EU Commission (QLK4-1999-01422, QLK4-2002-00603 and CONTAMED FP7-ENV-212502), the Generalitat de Catalunya—CIRIT [1999SGR 00241]; the Consejería de Salud de la Junta de Andalucía (183/07 and 0675/10), the Diputación Foral de Gipuzkoa (DFG06/004), the Department of Health of the Basque Government (2005111093), and by the University of Oviedo, Obra Social Cajastur, the Fundación Roger Torné and La Fundació La Marató de TV3. NV was supported by an FPI Grant from the Spanish Ministry of Health (BES-2009-023933) and a Formación de Personal Investigador Grant for Short Research Stays in Foreign Institutions (BES-2009-023933). AA Baccarelli receives support from the Harvard School of Public Health and National Institute of Environmental Health Sciences Center for Environmental Health (R01 ES021357).The HUSC BioBank, integrated in the Andalusia Public Health System (SSPA) and the National Biobank Network, is financed by the Institute of Health Carlos III, (RD09/0076/00148) and the Regional Government of Andalucia

BACKGROUND: Air pollution exposure during pregnancy has been associated with impaired fetal growth. However, few studies have measured fetal biometry longitudinally, remaining unclear as to whether there are windows of special vulnerability. OBJECTIVE: The aim was to investigate the impact of nitrogen dioxide (NO2) exposure on fetal and neonatal biometry in the Spanish INMA study. METHODS: Biparietal diameter (BPD), femur length (FL), abdominal circumference (AC), and estimated fetal weight (EFW) were evaluated for up to 2,478 fetuses in each trimester of pregnancy. Size at 12, 20, and 34 weeks of gestation and growth between these points, as well as anthropometry at birth, were assessed by SD scores derived using cohort-specific growth curves. Temporally adjusted land-use regression was used to estimate exposure to NO2 at home addresses for up to 2,415 fetuses. Associations were investigated by linear regression in each cohort and subsequent meta-analysis. RESULTS: A 10-μg/m3 increase in average exposure to NO2 during weeks 0-12 was associated with reduced growth at weeks 0-12 in AC (-2.1%; 95% CI: -3.7, -0.6) and EFW (-1.6%; 95% CI: -3.0, -0.3). The same exposure was inversely associated with reduced growth at weeks 20-34 in BPD (-2.6%; 95% CI: -3.9, -1.2), AC (-1.8%; 95% CI: -3.3, -0.2), and EFW (-2.1%; 95% CI: -3.7, -0.2). A less consistent pattern of association was observed for FL. The negative association of this exposure with BPD and EFW was significantly stronger in smoking versus nonsmoking mothers. CONCLUSIONS: Maternal exposure to NO2 in early pregnancy was associated with reduced fetal growth based on ultrasound measures of growth during pregnancy and measures of size at birth. ; This study was funded by grants from the European Union: NEWGENERIS FP6-2003-Food-3-A-016320, FP7-ENV-2011 cod 282957, HEALTH.2010.2.4.5-1; and by grants from Spain: Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0031, and FIS-FEDER PI03/1615, PI04/1509, PI04/1112, PI04/1931, PI04/2018, PI04/1436, PI05/1079, PI05/1052, PI06/1213, PI07/0314, PI08/1151, PI09/02647, PI09/02311, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/02429, PI14/0891, PI14/1687, and Miguel Servet CP11/00178 and MS13/00054), Conselleria de Sanitat Generalitat Valenciana, Generalitat de Catalunya (CIRIT 1999SGR 00241), Diputación Foral de Guipúzcoa (DFG/004), Departamento de Sanidad y Consumo Gobierno Vasco (2005111093), Obra Social Cajastur, and Oviedo University.

BACKGROUND: Perfluoroalkyl substances (PFAS) may affect body mass index (BMI) and other components of cardiometabolic (CM) risk during childhood, but evidence is scarce and inconsistent. OBJECTIVES: We estimated associations between prenatal PFAS exposures and outcomes relevant to cardiometabolic risk, including a composite CM-risk score. METHODS: We measured perfluorohexanesulfonic acid (PFHxS), perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) in maternal plasma (first trimester). We assessed weight gain from birth until 6 mo. At 4 and 7 y, we calculated the age- and sex-specific z-scores for BMI, waist circumference (WC), and blood pressure (BP) (n≈1,000). At age 4, we calculated the age-, sex-, and region-specific z-scores for cholesterol, triglycerides (TGs), high-density (HDL-C), and low-density lipoprotein cholesterol (LDL-C) (n=627). At age 4, we calculated a CM-risk score (n=386) as the sum of the individual age-, sex-, and region-specific z-scores for WC, BP, HDL-C, and TGs. We used the average between the negative of HDL-C z-score and TGs z-score to give similar weight to lipids and the other components in the score. A higher score indicates a higher cardiometabolic risk at age 4. RESULTS: PFOS and PFOA were the most abundant PFAS (geometric mean: 5.80 and 2.32 ng/mL, respectively). In general, prenatal PFAS concentrations were not associated with individual outcomes or the combined CM-risk score. Exceptions were positive associations between prenatal PFHxS and TGs z-score [for a doubling of exposure, β=0.11; 95% confidence interval (CI): 0.01, 0.21], and between PFNA and the CM-risk score (β=0.60; 95% CI: 0.04, 1.16). There was not clear or consistent evidence of modification by sex. CONCLUSIONS: We observed little or no evidence of associations between low prenatal PFAS exposures and outcomes related to cardiometabolic risk in a cohort of Spanish children followed from birth until 7 y. https://doi.org/10.1289/EHP1330 ; This 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, and PI14/1687; predoctoral grant PFIS - FI14/00099; and Miguel Servet-FEDER: CP11/0178 and CPII16/00051), CIBERESP; the Conselleria de Sanitat, Generalitat Valenciana; 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); and from the United Stated of America: National Institute of Environmental Health Sciences of the National Institutes of Health (NIH) (grant number ES021477). ISGlobal is a member of the Centres de Recerca de Catalunya (CERCA) Programme, Generalitat de Catalunya. This study has been reviewed and approved by the accredited committees of the following institutions: the Municipal Institute of Sanitary Assistance of Barcelona, La Fe University Hospital of Valencia, and Donostia Hospital de Zumarraga.