Patterns of perinatal polyunsaturated fatty acid status and associated dietary or candidate-genetic factors.

Perinatal exposure to omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) can be characterized through biomarkers in maternal or cord blood or breast milk. Objectives were to describe perinatal PUFA status combining multiple biofluids and to investigate how it was influenced by dietary intake during pregnancy and maternal FADS and ELOVL gene polymorphisms. This study involved 1,901 mother-child pairs from the EDEN cohort, with PUFA levels measured in maternal and cord erythrocytes, and colostrum. Maternal dietary PUFA intake during the last trimester was derived from a food frequency questionnaire. Twelve single-nucleotide polymorphisms in FADS and ELOVL genes were genotyped from maternal DNA. Principal component analysis incorporating PUFA levels from the three biofluids identified patterns of perinatal PUFA status. Spearman's correlations explored associations between patterns and PUFA dietary intake, and linear regression models examined pattern associations with FADS or ELOVL haplotypes. Five patterns were retained: "High omega-3 LC-PUFAs, low omega-6 LC-PUFAs"; "Omega-6 LC-PUFAs"; "Colostrum LC-PUFAs"; "Omega-6 precursor (LA) and DGLA"; "Omega-6 precursor and colostrum ALA". Maternal omega-3 LC-PUFA intakes were correlated with "High omega-3 LC-PUFAs, low omega-6 LC-PUFAs" (r(DHA) = 0.33) and "Omega-6 LC-PUFAs" (r(DHA) = -0.19) patterns. Strong associations were found between FADS haplotypes and PUFA patterns except for "High omega-3 LC-PUFAs, low omega-6 LC-PUFAs". Lack of genetic association with the "High omega-3 LC-PUFAs, low omega-6 LC-PUFAs" pattern, highly correlated with maternal omega-3 LC-PUFA intake, emphasizes the importance of adequate omega-3 LC-PUFA intake during pregnancy and lactation. This study offers a more comprehensive assessment of perinatal PUFA status and its determinants.

The Nutrition in Early Life and Asthma (NELA) birth cohort study: Rationale, design, and methods.

BACKGROUND: Primary prevention strategies for asthma are lacking. Its inception probably starts in utero and/or during the early postnatal period as the developmental origins of health and disease (DOHaD) paradigm suggests. OBJECTIVES: The main objective of Nutrition in Early Life and Asthma (NELA) cohort study is to unravel whether the following factors contribute causally to the developmental origins of asthma: (1) maternal obesity/adiposity and foetal growth; (2) maternal and child nutrition; (3) outdoor air pollution; (4) endocrine disruptors; and (5) maternal psychological stress. Maternal and offspring biological samples are used to assess changes in offspring microbiome, immune system, epigenome and volatilome as potential mechanisms influencing disease susceptibility. POPULATION: Randomly selected pregnant women from three health areas of Murcia, a south-eastern Mediterranean region of Spain, who fulfilled the inclusion criteria were invited to participate at the time of the follow-up visit for routine foetal anatomy scan at 19-22 weeks of gestation, at the Maternal-Fetal Medicine Unit of the "Virgen de la Arrixaca" University Clinical Hospital over a 36-month period, from March 2015 to April 2018. DESIGN: Prospective, population-based, maternal-child, birth cohort study. METHODS: Questionnaires on exposures and outcome variables were administered to mothers at 20-24 gestation week; 32-36 gestation week; and delivery. Children were surveyed at birth, 3 and 18 months of age and currently at 5 years. Furthermore, physical examinations were performed; and different measurements and biological samples were obtained at these time points. PRELIMINARY RESULTS: Among the 1350 women invited to participate, 738 (54%) were finally enrolled in the study and 720 of their children were eligible at birth. The adherence was high with 612 children (83%) attending the 3 months' visit and 532 children (72%) attending the 18 months' visit. CONCLUSION: The NELA cohort will add original and unique knowledge to the developmental origins of asthma.

Serum cytokines associated with behavior: A cross-sectional study in 5-year-old children.

Nearly 10% of 5-year-old children experience social, emotional or behavioral problems and are at increased risk of developing mental disorders later in life. While animal and human studies have demonstrated that cytokines can regulate brain functions, it is unclear whether individual cytokines are associated with specific behavioral dimensions in population-based pediatric samples. Here, we used data and biological samples from 786 mother-child pairs participating to the French national mother-child cohort EDEN. At the age of 5, children were assessed for behavioral difficulties using the Strengths and Difficulties Questionnaire (SDQ) and had their serum collected. Serum samples were analyzed for levels of well-characterized effector or regulatory cytokines. We then used a penalized logistic regression method (Elastic Net), to investigate associations between serum levels of cytokines and each of the five SDQ-assessed behavioral dimensions after adjustment for relevant covariates and confounders, including psychosocial variables. We found that interleukin (IL)-6, IL-7, and IL-15 were associated with increased odds of problems in prosocial behavior, emotions, and peer relationships, respectively. In contrast, eight cytokines were associated with decreased odds of problems in one dimension: IL-8, IL-10, and IL-17A with emotional problems, Tumor Necrosis Factor (TNF)-α with conduct problems, C-C motif chemokine Ligand (CCL)2 with hyperactivity/inattention, C-X-C motif chemokine Ligand (CXCL)10 with peer problems, and CCL3 and IL-16 with abnormal prosocial behavior. Without implying causation, these associations support the notion that cytokines regulate brain functions and behavior and provide a rationale for launching longitudinal studies.

Immune components of early breastmilk: Association with maternal factors and with reported food allergy in childhood.

BACKGROUND: Breastmilk (BM) may participate in driving gut barrier function and immunity in the neonate. We analyzed immune and growth factor concentrations in early BM and their association with maternal/environmental characteristics and with food allergy (FA) in childhood. METHODS: One BM sample was collected in maternity from some mothers in the EDEN birth cohort (n = 2002 mother-child dyads). A random selection was performed among available samples (subcohort, n = 272), for which all deliveries were full-term, various maternal/environmental characteristics were recorded, and parents answered yearly the question "Has a medical doctor diagnosed a FA in your child?" (26 parent-reported FA cases). Only samples collected between day 2 and day 6 post-partum were considered for descriptive analysis (n = 263). Samples for all other FA cases available were added to the subcohort (46 additional cases; "casecohort" design). Fifty cytokines, antibodies, and growth factor concentrations were determined using multiplexed kits and analyzed using robust statistical procedures. RESULTS: BM components exhibited wide concentration ranges and global day-to-day variation. Different clusters of correlated factors appeared, with components from the main cluster related to maternal diet during pregnancy. Primiparity was positively associated with eleven other components, whereas other factors (eg, maternal atopy and smoking) were related to fewer components. Finally, the casecohort design highlighted a positive association between CXCL10, TNFß, and IL-2 concentrations and reported FA in childhood. CONCLUSION: Beyond the unique description of early BM composition, we show that immune information transmitted to the neonate is related to various maternal factors and identified components associated with FA diagnosis in childhood.

Cord serum 25-hydroxyvitamin D and risk of early childhood transient wheezing and atopic dermatitis.

BACKGROUND: There is increasing evidence of the effect of maternal vitamin D intake during pregnancy on the risk of asthma and allergic outcomes in offspring. However, studies on the relationship between cord levels of 25-hydroxyvitamin D (25[OH]D) and asthma and allergic diseases are very few. OBJECTIVE: Our aim was to investigate the associations between cord serum 25(OH)D levels and asthma, wheezing, allergic rhinitis, and atopic dermatitis in the offspring from birth to 5 years. METHODS: Cord blood samples were collected at birth and analyzed for 25(OH)D levels in 239 newborns from the Etude des Déterminants pré et post natals du développement et de la santé de l'Enfant (EDEN) birth cohort. The children were followed up until age 5 years by using International Study of Asthma and Allergies in Childhood-based symptom questionnaires. RESULTS: The median cord serum level of 25(OH)D was 17.8 ng/mL (interquartile range, 15.1 ng/mL). By using multivariable-adjusted logistic regression models, a significant inverse association was observed between cord serum 25(OH)D levels and risk of transient early wheezing and early- and late-onset atopic dermatitis, as well as atopic dermatitis, by the ages of 1, 2, 3, and 5 years. We found no association between cord serum 25(OH)D levels and asthma and allergic rhinitis at age 5 years. CONCLUSIONS: Cord serum 25(OH)D levels were inversely associated with the risk of transient early wheezing and atopic dermatitis by the age of 5 years, but no association was found with asthma and allergic rhinitis.

Exposures to perfluoroalkyl substances and asthma phenotypes in childhood: an investigation of the COPSAC2010 cohort.

BACKGROUND: Exposure to perfluoroalkyl substances may affect offspring immune development and thereby increase risk of childhood asthma, but the underlying mechanisms and asthma phenotype affected by such exposure is unknown. METHODS: In the Danish COPSAC2010 cohort of 738 unselected pregnant women and their children plasma PFOS and PFOA concentrations were semi-quantified by untargeted metabolomics analyses and calibrated using a targeted pipeline in mothers (gestation week 24 and 1 week postpartum) and children (age ½, 1½ and 6 years). We examined associations between pregnancy and childhood PFOS and PFOA exposure and childhood infections, asthma, allergic sensitization, atopic dermatitis, and lung function measures, and studied potential mechanisms by integrating data on systemic low-grade inflammation (hs-CRP), functional immune responses, and epigenetics. FINDINGS: Higher maternal PFOS and PFOA exposure during pregnancy showed association with a non-atopic asthma phenotype by age 6, a protection against sensitization, and no association with atopic asthma or lung function, or atopic dermatitis. The effect was primarily driven by prenatal exposure. There was no association with infection proneness, low-grade inflammation, altered immune responses or epigenetic changes. INTERPRETATIONS: Prenatal exposure to PFOS and PFOA, but not childhood exposure, specifically increased the risk of low prevalent non-atopic asthma, whereas there was no effect on atopic asthma, lung function, or atopic dermatitis. FUNDING: All funding received by COPSAC are listed on www.copsac.com. The Lundbeck Foundation (Grant no R16-A1694); The Novo Nordic Foundation (Grant nos NNF20OC0061029, NNF170C0025014, NNF180C0031764); The Ministry of Health (Grant no 903516); Danish Council for Strategic Research (Grant no 0603-00280B); and The Capital Region Research Foundation have provided core support to the COPSAC research center. COPSAC acknowledges the National Facility for Exposomics (SciLifeLab, Sweden) for supporting calibration of the untargeted metabolomics PFAS data. BC and AS has received funding for this project from the European Union's Horizon 2020 research and innovation programme (BC: grant agreement No. 946228 DEFEND; AS: grant agreement No. 864764 HEDIMED).

In utero exposure to bisphenols and asthma, wheeze, and lung function in school-age children: a prospective meta-analysis of 8 European birth cohorts.

BACKGROUND: In utero exposure to bisphenols, widely used in consumer products, may alter lung development and increase the risk of respiratory morbidity in the offspring. However, evidence is scarce and mostly focused on bisphenol A (BPA) only. OBJECTIVE: To examine the associations of in utero exposure to BPA, bisphenol F (BPF), and bisphenol S (BPS) with asthma, wheeze, and lung function in school-age children, and whether these associations differ by sex. METHODS: We included 3,007 mother-child pairs from eight European birth cohorts. Bisphenol concentrations were determined in maternal urine samples collected during pregnancy (1999-2010). Between 7 and 11 years of age, current asthma and wheeze were assessed from questionnaires and lung function by spirometry. Wheezing patterns were constructed from questionnaires from early to mid-childhood. We performed adjusted random-effects meta-analysis on individual participant data. RESULTS: Exposure to BPA was prevalent with 90% of maternal samples containing concentrations above detection limits. BPF and BPS were found in 27% and 49% of samples. In utero exposure to BPA was associated with higher odds of current asthma (OR = 1.13, 95% CI = 1.01, 1.27) and wheeze (OR = 1.14, 95% CI = 1.01, 1.30) (p-interaction sex = 0.01) among girls, but not with wheezing patterns nor lung function neither in overall nor among boys. We observed inconsistent associations of BPF and BPS with the respiratory outcomes assessed in overall and sex-stratified analyses. CONCLUSION: This study suggests that in utero BPA exposure may be associated with higher odds of asthma and wheeze among school-age girls.

Effect of perfluoroalkyl exposure in pregnancy and infancy on intrauterine and childhood growth and anthropometry. Sub study from COPSAC2010 birth cohort.

BACKGROUND: Perfluoroalkyl substances PFOS and PFOA are persistent and bioaccumulative exogenous chemicals in the human body with a range of suspected negative health effects. It is hypothesised that exposure during prenatal and early postnatal life might have particularly detrimental effects on intrauterine and childhood growth. In a Danish longitudinal mother-child cohort we investigate effect of PFOS and PFOA in pregnancy and infancy on intrauterine and childhood growth and anthropometry. METHODS: COPSAC2010 is an ongoing population based mother-child cohort of 738 pregnant women and their children followed from 24 week gestation with longitudinal deep clinical phenotyping until age 10 years. In this observational cohort sub study plasma PFOS and PFOA concentrations were semi-quantified by untargeted metabolomics in the mothers at week 24 and 1 week postpartum and in the children at ages 6 and 18 months and calibrated using a targeted pipeline. We examined associations to intrauterine and childhood growth and anthropometry, including interactions with child sex. Untargeted and targeted blood metabolomics profiles were integrated to investigate underlying mechanisms. FINDINGS: Pregnancy plasma PFOA concentrations were associated with lower birth size -0.19 [-0.33; -0.05] BMI z-score per 1-ng/mL and increased childhood height (z-scored) at age 6: 0.18 [0.05; 0.31], but there was no association between childs' own infancy plasma PFOA concentration and height. Pregnancy plasma PFOS concentrations were also associated with lower birth BMI (-0.04 [-0.08; -0.01]), but in childhood pregnancy plasma PFOS concentration interacted with child sex on BMI and fat percentage at 6 years with negative associations in girls and positive in boys. The effect of maternal plasma PFOS concentration on lower girl BMI was borderline mediated through increasing child plasma lactosyl-ceramide levels (p-mediation=0.08). Similarly the effect of maternal plasma PFOS concentration on higher boy fat percentage was borderline mediated through increasing child plasma lactosyl-ceramide levels (p-mediation=0.07). Infancy concentrations of plasma PFOS associated with lower height in childhood, -0.06 z-score at age 6 [-0.19; -0.03]. INTERPRETATION: Higher PFOS and PFOA plasma concentrations during pregnancy had detrimental effects on fetal growth. The effects on childhood growth were not similar as PFOA increased child height, opposite of PFOS in multipollutant models suggesting a differing fetal programming effect. Sex specific growth effects were borderline mediated through an altered lactosyl-ceramide metabolism, proposing a possible mechanism of PFOS that has long-lasting health consequences in this observational study. FUNDING: All funding received by COPSAC are listed on www.copsac.com. The Lundbeck Foundation (Grant no R16-A1694); The Novo Nordic Foundation (Grant nos NNF20OC0061029, NNF170C0025014, NNF180C0031764) The Ministry of Health (Grant no 903516); Danish Council for Strategic Research (Grant no 0603-00280B) and The Capital Region Research Foundation have provided core support to the COPSAC research center. Effort from JALS is supported by R01HL123915, R01HL141826, and R01HL155742 from NIH/NHLBI. CEW was supported by the Swedish Heart Lung Foundation (HLF 20180290, HLF 20200693). BC has received funding for this project from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No. 946228). The funding agencies did not have any role in design and conduct of the study; collection, management, and interpretation of the data; or preparation, review, or approval of the manuscript.

The association between maternal urinary phthalate metabolites concentrations and pregnancy induced hypertension: Results from the EDEN Mother-Child Cohort.

BACKGROUND: Studies have suggested that exposure to endocrine disruptors such as phthalates that are widely used in our daily life (food wrapping, cosmetics, toys, medical devices, polyvinyl chloride flooring, and building materials) might be related to raised blood pressure and increased risk of cardiovascular diseases. Phthalates might induce a pro-inflammatory response and increased oxidative stress and may be a cause of pregnancy induced hypertension. METHODS: We evaluated the association between maternal exposure to phthalates during pregnancy and pregnancy induced hypertension. 604 pregnant women were included and eleven phthalate metabolites were quantified in spot maternal urine samples collected between the 23rd and 28th week of gestation in a French EDEN mother-child cohort. The associations were assessed by applying multiple logistic regression analysis. RESULTS: Twenty nine (4,8%) mothers developed pregnancy induced hypertension. Two low molecular weight phthalate metabolites: Monoethyl phthalate (MEP) and Mono-n­butyl phthalate (MBP) were positively associated with pregnancy induced hypertension in crude (Odds Ratio: 1.43, 95% Confidence Interval: 1.04-1.96, p-value = 0.02 and 1.48, 1.10-2.01, p-value =0.01) and in adjusted (1.47, 1.01-2.14, p-value = 0.04 and 1.66, 1.11-2.47, p-value = 0.01) models respectively. CONCLUSION: Our data suggest that prenatal exposure to some phthalates, including MEP and MBP, might play a role in pregnancy induced hypertension.

Immune activity at birth and later psychopathology in childhood.

Disruption of neurodevelopmental trajectories can alter brain circuitry and increase the risk of psychopathology later in life. While preclinical studies have demonstrated that the immune system and cytokines influence neurodevelopment, whether immune activity and in particular which cytokines at birth are associated with psychopathology remains poorly explored in children. We used data and biological samples from 869 mother-child pairs participating in the French mother-child cohort EDEN. As proxies for immune activity at birth, we measured the levels of 27 cytokines in umbilical cord blood sera (CBS). We then explored the association between CBS cytokine levels and five psychopathological dimensions assessed in 5-year-old children using the Strengths and Difficulties Questionnaire (SDQ). Five cytokines were positively associated with psychopathology: C-X-C motif chemokine Ligand (CXCL)10, interleukin (IL)-10 and IL-12p40 with emotional symptoms, C-C motif chemokine Ligand (CCL)11 with conduct problems, and CCL11, and IL-17A with peer relationships problems. In contrast, seven cytokines were negatively associated with psychopathology: IL-7, IL-15 and Tumor Necrosis Factor (TNF)-ß with emotional symptoms, CCL4 and IL-6 with conduct problems, CCL26 and IL-15 with peer relationships problems, and CCL26, IL-7, IL-15, and TNF-α with abnormal prosocial behavior. Without implying causation, these associations support the notion that cytokines influence neurodevelopment in humans and the risk of psychopathology later in life.

Informal and formal social support during pregnancy and joint maternal and paternal postnatal depression: Data from the French representative ELFE cohort study.

BACKGROUND: Insufficient social support has been intensively studied as a risk factor of postpartum depression (PPD) among mothers. However, to date, no study has examined the role of informal and formal dimensions of social support during pregnancy with regard to joint maternal and paternal depression after birth. AIM: Study associations between insufficient informal and formal support during pregnancy and joint parental PPD. METHODS: Using data from the nationally representative French ELFE (Etude Longitudinale Française depuis l'Enfance) cohort study (N = 12,350), we estimated associations between insufficient informal and formal support received by the mother during pregnancy and joint parental PPD in multi-imputed multivariate multinomial regression models. RESULTS: In 166 couples (1.3%), both parents were depressed. The likelihood of joint parental PPD was increased in case of insufficient informal support (insufficient partner support: odds ratio (OR) = 1.68 (95% confidence interval (CI): 1.57-1.80); frequent quarrels: OR = 1.38 (95% CI: 1.19-1.60)). We also observed associations between formal support during pregnancy and joint parental PPD (early prenatal psychosocial risk assessment: OR = 1.13 (95% CI: 1.05-1.22); antenatal education: OR = 1.13 (95% CI: 1.05-1.23)), which disappeared when analyses were restricted to women with no psychological difficulties during pregnancy. CONCLUSION: Insufficient informal social support during pregnancy appears to predict risk of joint PPD in mothers and fathers and should be identified early on to limit complications and the impact on children.

Maternal vitamin D in pregnancy and offspring bone measures in childhood: The Vitamin D in Pregnancy study.

Previously we have demonstrated an association between maternal serum 25-hydroxyvitamin D (25(OH)D) during pregnancy and knee-heel length in offspring at birth. However, it is unknown whether maternal serum 25(OH)D is associated with bone measures in childhood. Thus, we aimed to examine associations between 25(OH)D at two stages of pregnancy and offspring bone measures at 11 years. Women were recruited from a single antenatal clinic in Victoria, Australia before 16 weeks gestation and provided two serum samples to determine 25(OH)D status at recruitment and 28-32 weeks gestation. Children and their mothers were followed up at 11 years of age. Children undertook dual energy X-ray absorptiometry scans at the lumbar spine and total body. Maternal 25(OH)D at recruitment (before 16 weeks gestation) was positively associated with the children's bone mineral content and density in boys, but not girls. In boys, a 10 nmol/L (4 ng/mL) increase in maternal 25(OH)D was associated with a median 0.5 g (95% CI 0.1,0.8) and 0.009 g/cm2 (95% CI 0.001,0.017) increase in bone mineral content and density at the spine, respectively, and a median 0.006 g/cm2 (95% CI 0.001,0.011) increase in at the total body. There was no sustained associations with 25(OH)D at the later timepoint (28-32 weeks) with any outcome. At age 11 years, maternal 25(OH)D levels during early pregnancy, but not late were positively associated with bone measures in boys, but not girls.

Exposure to heavy metals during pregnancy related to gestational diabetes mellitus in diabetes-free mothers.

Evidence is cumulating on the adverse health effects of environmental exposures on health of the fetus and the childbearing mothers. Among mother's conditions, gestational diabetes mellitus has been considered rarely in spite of its importance for both mother and child. We determined the role of maternal exposure to lead (Pb), cadmium (Cd) and manganese (Mn) to gestational diabetes mellitus (GDM) on diagnosed GDM and impaired glucose tolerance (IGT) in diabetes-free mothers from the French EDEN mother-child cohort. 623 pregnant women without pre-existing diabetes were included in the study. GDM and IGT were diagnosed by a gynecologist during consultations after blood analysis. Pb, Cd and Mn were measured in second-trimester blood samples. Associations between ln-transformed concentrations of metals and GDM and IGT respectively were examined using multiple logistic regression analysis adjusted for potential confounders. The prevalences of GDM and IGT were 7.1% and 10.1% respectively. After adjustment for confounders, Cd was statistically related to having had a diagnosis of GDM or IGT (Adjusted Odds-Ratio (AOR): 1.61, 1.05-2.48), and Pb to GDM at borderline significance (AOR: 1.65, 0.82-3.34). Our findings add to the growing evidence supporting the role of maternal exposure to heavy toxic metals that persist longtime in the environment as a risk factor for GDM.

Maternal diet before and during pregnancy and risk of asthma and allergic rhinitis in children.

BACKGROUND: Consumption of certain foods during pregnancy has been shown to have beneficial effects on childhood asthma and allergic disease development and aggravation. However, most studies provide conflicting results and the relationships between maternal preconceptional diet and risks of childhood asthma and allergic disease have not previously been explored. The objective of this study was to assess maternal diet during the year before pregnancy and the last 3 months of pregnancy and investigate their associations with the risks of asthma, wheezing, allergic rhinitis and atopic dermatitis in young children. METHODS: The study sample consisted of 1140 mother-child pairs from the EDEN cohort. Mothers had responded to the food frequency questionnaires used to assess diet before and during pregnancy. Children were followed up using health questionnaires. The health outcomes studied were: asthma, wheezing, allergic rhinitis and atopic dermatitis by the age of 3 years. RESULTS: Using multivariable-adjusted logistic regression models, significant inverse associations were observed between cooked green vegetable consumption before pregnancy and childhood asthma; consumption of eggs and raw vegetables before and during pregnancy, consumption of grains before pregnancy, and consumption of cooked green vegetables during pregnancy and allergic rhinitis. For the first time, a significant positive association was found between meat intake during the preconceptional period and a risk of wheezing, allergic rhinitis and atopic dermatitis. CONCLUSIONS: Based on our findings, preconceptional and prenatal maternal intake of certain type of food groups may be preventive against asthma, wheezing and allergic rhinitis, whereas higher maternal intake of meat before pregnancy may increase the risk of wheezing, allergic rhinitis and atopic dermatitis in young children.

Pregnancy exposure to atmospheric pollution and meteorological conditions and placental DNA methylation.

BACKGROUND: Air pollution exposure represents a major health threat to the developing foetus. DNA methylation is one of the most well-known molecular determinants of the epigenetic status of cells. Blood DNA methylation has been proven sensitive to air pollutants, but the molecular impact of air pollution on new-borns has so far received little attention. OBJECTIVES: We investigated whether nitrogen dioxide (NO2), particulate matter (PM10), temperature and humidity during pregnancy are associated with differences in placental DNA methylation levels. METHODS: Whole-genome DNA-methylation was measured using the Illumina's Infinium HumanMethylation450 BeadChip in the placenta of 668 newborns from the EDEN cohort. We designed an original strategy using a priori biological information to focus on candidate genes with a specific expression pattern in placenta (active or silent) combined with an agnostic epigenome-wide association study (EWAS). We used robust linear regression to identify CpGs and differentially methylated regions (DMR) associated with each exposure during short- and long-term time-windows. RESULTS: The candidate genes approach identified nine CpGs mapping to 9 genes associated with prenatal NO2 and PM10 exposure [false discovery rate (FDR) p < 0.05]. Among these, the methylation level of 2 CpGs located in ADORA2B remained significantly associated with NO2 exposure during the 2nd trimester and whole pregnancy in the EWAS (FDR p < 0.05). EWAS further revealed associations between the environmental exposures under study and variations of DNA methylation of 4 other CpGs. We further identified 27 DMRs significantly (FDR p < 0.05) associated with air pollutants exposure and 13 DMRs with meteorological conditions. CONCLUSIONS: The methylation of ADORA2B, a gene whose expression was previously associated with hypoxia and pre-eclampsia, was consistently found here sensitive to atmospheric pollutants. In addition, air pollutants were associated to DMRs pointing towards genes previously implicated in preeclampsia, hypertensive and metabolic disorders. These findings demonstrate that air pollutants exposure at levels commonly experienced in the European population are associated with placental gene methylation and provide some mechanistic insight into some of the reported effects of air pollutants on preeclampsia.

The association between cooking oil fume exposure during pregnancy and birth weight: A prospective mother-child cohort study.

Effects of indoor air pollution on neonatal birth weight has been studied for many years. In China, cooking oil fumes are important parts of indoor air pollution. However, whether cooking oil fume exposure during pregnancy affects birth weight in China remains poorly understood. The objective of this study was to examine the association between pregnancy exposure to cooking oil fumes and birth weight in a newly established prospective mother-child cohort in China. We finally included 1420 pregnant women from 2013 to 2015 and follow up for one year until the offspring was born. According to self-reported exposure status, we categorized mothers into non-exposure group and exposed group or three exposure time subgroups, including 0h/day, 0-1h/day and >1h/day respectively. By using multinomial logistics regression models, we found that pregnancy exposure to cooking oil fumes significantly increased the risk of large for gestational age (LGA, OR=1.58, 95% CI=1.15-2.18, P=4.88×10-3). Additionally, compared to pregnant women who were in non-exposure group, 0-1h/day exposure elevated the risk of LGA (OR=1.69, 95% CI=1.22-2.33, P=1.63×10-3), while >1h/day exposure elevated the risk of small for gestational age, but were not significant (SGA, OR=2.15, 95% CI=0.61-7.66, P=0.24). In the stratification analysis, women aged 25-29years and ≥30years were predisposed to the influence of cooking oil fumes and have LGA newborns (OR=1.73, 95% CI=1.09-2.75, P=0.02; OR=1.72, 95% CI=1.07-2.77, P=0.02, respectively). In conclusion, the present study suggests inverse U-shape dose response association between maternal exposure to cooking oil fumes during pregnancy and birth weight, and further studies are needed to verify the effect of cooking oil fumes on the birth weight.

Prenatal exposure to selenium may protect against wheezing in children by the age of 3.

INTRODUCTION: It has been suggested that human in utero exposure to heavy metals such as selenium can reduce the prevalence of childhood asthma and allergic diseases. However, data on this topic are scarce. The objective of the present study was to assess the putative associations between maternal selenium level during pregnancy and the risk of asthma, wheezing, allergic rhinitis, and atopic dermatitis in children from the EDEN birth cohort by the age of 1 and 3 years. METHODS: Plasma selenium concentrations were measured in maternal blood during mid-pregnancy (24-28 weeks of gestation) in 861 mothers. Cohort children were followed up from birth to 3 years using health questionnaires filled out by the parents for asthma, wheezing, allergic rhinitis, and atopic dermatitis. Maternal plasma selenium was related to the childhood outcomes by the age of 1 and 3 years. RESULTS: Our results showed a significant negative association between a high maternal plasma selenium level during pregnancy and the risk of wheezing in the child by the age of 1 and 3 years. However, maternal plasma selenium during pregnancy was not associated with the prevalence of asthma, allergic rhinitis or atopic dermatitis. CONCLUSIONS: The results of this study suggest that the level of fetal exposure to maternal selenium could have an influence on the risk of wheezing in infancy and potentially on the risk of developing asthma later in life.

Vitamin D insufficient levels during pregnancy and micronuclei frequency in peripheral blood T lymphocytes mothers and newborns (Rhea cohort, Crete).

BACKGROUND & AIMS: Vitamin D deficiency is common among pregnant women and may be associated with several adverse health outcomes including cancer. Micronuclei frequency is a biomarker of early genetic effects and has been used to examine the association between genotoxic exposures and cancer. We examined maternal vitamin D levels during pregnancy in associations with micronuclei frequency in maternal blood and in cord blood. METHODS: 173 mothers and 171 newborns born between 2007 and 2008 in Heraklion (Crete, Greece) were included in the study. Between 14th and 18th weeks of gestation we collected information on maternal diet using food frequency questionnaires (FFQs). We measured maternal serum concentrations of 25-hydroxyvitamin D [25(OH)D] between the first and second trimester of pregnancy. We estimated dietary vitamin D intake using information from FFQ. After delivery we collected cord blood and maternal peripheral blood. We used the cytokinesis-block micronucleus (CBMN) assay to assess the frequencies of micronucleated cells in binucleated T lymphocytes (MNBN). RESULTS: Maternal insufficient serum levels of 25(OH)D (<50 nmol/L) during pregnancy were associated with increased MNBN frequency in cord blood [IRR = 1.32 (95%CI: 1.00, 1.72)]. This increase was higher for newborns with birth weight above the third quartile [≥3.500 kg; IRR = 2.21 (1.26, 3.89)]. Similarly, low levels of dietary vitamin D were associated with increased MNBN frequency in cord blood [middle tertile IRR = 1.08 (0.78, 1.47), lower tertile IRR = 1.51 (1.06, 2.14)]. Insufficient levels of vitamin D were not associated with MNBN in mothers. CONCLUSION: Our results suggest that vitamin D deficiency during pregnancy increases genotoxic risks in newborns. The prevalence of vitamin D deficiency globally is high and it is important to further investigate whether vitamin D supplementation or similar interventions during pregnancy could prevent DNA damage at early stages of life.

Cord serum 25-hydroxyvitamin D correlates with early childhood viral-induced wheezing.

BACKGROUND: There are investigations concluding that reduced vitamin D status in pregnancy, may be a risk factor for the development of allergic outcomes in offspring. However, studies on the relationship between cord levels of 25-hydroxyvitamin D (25[OH]D) and risk of early childhood wheezing and early-onset atopic dermatitis/food allergy are very limited. OBJECTIVE: To assess the associations between cord blood concentration of 25[OH]D and occurrence of the incidence of wheezing, atopic dermatitis, food allergy, during the first two years of life. METHODS: We evaluated 240 children by the age of 2 years from the Polish Mother and Child Cohort Study. Women were interviewed during pregnancy to collect demographic and socioeconomic data, the medical and reproductive history. At delivery, umbilical cord blood plasma was sampled. The child's health status were examined at approximately 2 years. In the analyses multivariable model was used. RESULTS: Data from 190 participants were included into the analysis. The median value and quartile range of 25[OH]D in cord blood [ng/ml] were as follows: 6.33, 4.16-8.53. 25[OH]D in cord blood below lower quartile increases the risk of multi-triggered wheezing (MTW) in children during first 2 years of life (OR: 2.81; 95% CI: 1.13-7.00). Higher cord serum level of 25[OH]D reduces the risk of viral induced wheezing (VIW). The cord serum level of 25[OH]D below median value (OR: 6.06; 95% CI: 1.3-28.3) or below lower quartile (OR: 5.43; 95% CI: 1.66-17.7) increases the risk of VIW. All above effects of vitamin D level in cord blood were corrected for the effects other independent risk factors of wheezing and VIW in this cohort. CONCLUSIONS: Cord serum 25[OH]D levels were inversely associated with the risk of multi-triggered wheezing, and especially viral-induced wheezing by the age of 2 years, but no association was found with food allergy, atopic dermatitis and frequencies of infections.