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Objective: To investigate the possible association between birth size or gestational length and maternal serum concentrations of hexachlorobenzene (HCB) in a population exposed to background levels. Methods: A total of 1568 mother-child pairs recruited in three Spanish areas (INMA Project) from 2004 to 2008 participated in the study. Multivariate analysis was performed between birth weight and length, weeks of gestation, preterm birth or small for gestational age and HCB concentrations in maternal serum. Results: The median concentration of HCB was 45.45. ng/g lipids. No association was found between HCB exposure levels and birth weight (β 50.42 [109.88; 9.04]), birth length (β: 0.07 [0.32; 0.18]), gestation age (HR: 1.07 [0.94; 1.22]), small for gestational age (OR: 0.95 [0.56; 1.61]) and preterm birth (OR: 0.60 [0.29; 1.28]). Results remain similar after adjustment for other organochlorines. Conclusion: Our findings support the idea that exposure to low levels of HCB does not affect the intrauterine growth nor the duration of gestation. ; a Public Health Division of Gipuzkoa, Basque Government, Spain b Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Spain c Health Research Institute, Biodonostia, San Sebastián, Spain d University of the Basque Country, Spain e Unit of Environment and Health, Centre for Public Health Research (CSISP), Valencia, Spain f University of Valencia, Spain g Centre for Research in Environmental Epidemiology (CREAL), Hospital del Mar Research Institute (IMIM), Barcelona, Spain h Public Health Laboratory, Basque Government, Spain i Department of Environmental Chemistry, Institute of Environmental Assessment and Water Research (IDAEA-CSIC), Barcelona, Spain j University of Granada, San Cecilio Universitary Hospital, Granada, Spain ; No

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: 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].

Introduction: Prenatal exposure to organochlorine compounds (OCs) can increase the risk of reported respiratory symptoms in children. It remains unclear whether these compounds can also impact on lung function. We assessed the association between prenatal exposure to OCs and lung function during childhood. Methods: We included 1308 mother-child pairs enrolled in a prospective cohort study. Prenatal concentrations of p,p′-dichlorodiphenyltrichloroethane [p,p′-DDT], p,p′-dichlorodiphenyldichloroethylene [p,p′-DDE], hexachlorobenzene [HCB], and seven polychlorinated biphenyls [PCBs] were measured in cord blood. Spirometry was performed in the offspring at ages 4 (n = 636) and 7 years (n = 1192). Results: More than 80% of samples presented quantifiable levels of p,p′-DDE, HCB, PCB-138, PCB-153, and PCB-180; p,p′-DDE was the compound with the highest median concentrations. At 4 years, prenatal p,p′-DDE exposure was associated with a decrease in forced expiratory volume in 1 s (FEV1) in all quartiles of exposure (e.g., third quartile [0.23–0.34 ng/mL]: β for FEV1 −53.61 mL, 95% CI −89.87, −17.35, vs. the lowest). Prenatal p,p′-DDE levels also decreased forced vital capacity (FVC) and FEV1/FVC, but associations did not reach statistical significance in most exposure quartiles. At 7 years, p,p′-DDE was associated with a decrease in FVC and FEV1 in only the second quartile of exposure (e.g. β for FEV1 −36.96 mL, 95% CI −66.22, −7.70, vs. the lowest). Prenatal exposure to HCB was associated with decreased FVC and FEV1, but in only the second quartile and at 7 years (e.g. [0.07–0.14 ng/mL]: β for FEV1 −25.79 mL, 95% CI −55.98, 4.39, vs. the lowest). PCBs were not consistently associated with lung function. Conclusion: Prenatal exposure to p,p′-DDE may decrease lung function during childhood, especially FEV1 and at medium levels of exposure. Further and deeper knowledge on the impact of environmental chemicals during pregnancy on lung development is needed. ; Gipuzkoa: This study was funded by grants from Instituto de Salud Carlos III (FIS-PI06/0867 and FIS-PI09/00090), CIBERESP, 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) and annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain). Sabadell: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds; CP16/00128), CIBERESP, Generalitat de Catalunya-CIRIT 1999SGR 00241, Generalitat de Catalunya-AGAUR 2009 SGR 501, Fundació La marató de TV3 (090430), EU Commission (261357). ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. Valencia: This study was funded by Grants from UE (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), Instituto de Salud Carlos III (G03/176; FIS-FEDER: PI11/01007, PI11/02591, PI11/02038, PI12/00610, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, and PI17/0663; Miguel Servet-FEDER CP11/00178, CP15/00025, and MSII16/00051), Alicia Koplowitz Foundation 2017, and Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249).

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.