ENVIRONAGE Birth Cohort Research Articles

Children\u2019s microvascular traits and ambient air pollution exposure during pregnancy and early childhood: prospective evidence to elucidate the developmental origin of particle-induced disease

BackgroundParticulate matter exposure during in utero life may entail adverse health outcomes later in life. The microvasculature undergoes extensive, organ-specific prenatal maturation. A growing body of evidence shows that cardiovascular disease in adulthood is rooted in a dysfunctional fetal and perinatal development, in particular that of the microcirculation. We investigate whether prenatal or postnatal exposure to PM2.5 (particulate matter with a diameter ≤ 2.5 μm) or NO2 is related to microvascular traits in children between the age of four and six.MethodsWe measured the retinal microvascular diameters, the central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE), and the vessel curvature by means of the tortuosity index (TI) in young children (mean [SD] age 4.6 [0.4] years), followed longitudinally within the ENVIRONAGE birth cohort. We modeled daily prenatal and postnatal PM2.5 and NO2 exposure levels for each participant’s home address using a high-resolution spatiotemporal model.ResultsAn interquartile range (IQR) increase in PM2.5 exposure during the entire pregnancy was associated with a 3.85-μm (95% CI, 0.10 to 7.60; p = 0.04) widening of the CRVE and a 2.87-μm (95% CI, 0.12 to 5.62; p = 0.04) widening of the CRAE. For prenatal NO2 exposure, an IQR increase was found to widen the CRVE with 4.03 μm (95% CI, 0.44 to 7.63; p = 0.03) and the CRAE with 2.92 μm (95% CI, 0.29 to 5.56; p = 0.03). Furthermore, a higher TI score was associated with higher prenatal NO2 exposure. We observed a postnatal effect of short-term PM2.5 exposure on the CRAE and a childhood NO2 exposure effect on both the CRVE and CRAE.ConclusionsOur results link prenatal and postnatal air pollution exposure with changes in a child’s microvascular traits as a fundamental novel mechanism to explain the developmental origin of cardiovascular disease.

Variability of iodine concentrations in the human placenta

Iodine is an essential trace element, necessary for the production of thyroid hormones, which play a key role in optimal foetal growth and (neuro-) development. To date, iodine deficiency remains a health burden in many countries. We investigated the variability of placental iodine concentrations within and between individuals. We used 20 mother-neonate pairs from the ENVIRONAGE birth cohort, took samples at three standardized locations of the placentas, pooled and digested them, and determined the iodine concentrations using an ICP-MS method as an alternative for the Sandell-Kolthoff method. The variability between and within the three sample regions was calculated using the intra-class correlation coefficient (ICC) from the variance components of mixed models. With the Friedman test, the differences between placental biopsies were assessed. The ICC showed a higher between-placenta (68.6%) than within-placenta (31.4%) variability. Subsequently, we used our optimized method to determine iodine concentrations in 498 mother-neonate pairs, which averaged 26.1 μg/kg. For 96 mothers, the urinary iodine concentrations were also determined, which showed no correlation with the placental iodine storage, as was expected. Future studies are necessary to explore the effects of these placental iodine concentrations in relation to health outcomes of mother and child at birth and later in life.

A Multi-Omic Analysis of Birthweight in Newborn Cord Blood

Background: Birthweight reflects in utero exposures and later health evolution. Despite existing studies employing high-dimensional molecular measurements, the understanding of underlying mechanisms of birthweight remains limited. Methods: To investigate the systems biology of birthweight, we integrated methylome, transcriptome, metabolome and a set of inflammatory proteins measured in cord blood samples from four birth-cohorts (n=489). We focused on two sets of 68 metabolites and 903 CpGs previously related to birthweight and investigated the correlation structures existing between these two sets and all the other variables from different groups of omic data via bipartite Pearson correlations. Findings: Results substantiated previously identified biomarkers related to birthweight in cord blood, mostly involved in the regulation of the immune system, and identified new multiple omic features. Three metabolic features [PC(34:2), plasmalogen PC(36:4)/PC(O-36:5), and a compound with m/z of 781.0545], two CpGs (on the DHCR24 and SC4MOL gene), and two proteins (periostin and CCL22), were identified as key signals related to birthweight. Due to importance of the epigenetic signals in cholesterol biosynthesis, we further studied the association of cholesterol levels in cord blood with birthweight in the ENVIRONAGE cohort (n=1,096), finding that the increase of birthweight an was associated with increment of high-density lipoprotein cholesterol. Interpretation: Our data suggested that cholesterol metabolism in cord blood is involved in the birthweight mechanism and that integration of different omic layers is a useful approach to generate new hypotheses about biological mechanisms. Funding Statement: This work is supported by the Bijzonder Onderzoeksfonds (BOF) Hasselt University through a PhD fellowship [to RA], the “EXPOsOMICS” grant [grant number 308610-FP7 European Commission to PV], and the “STOP” grant [grant number 774548-European Commission H2020 to PV]. The ENVIRONAGE birth-cohort is supported by the EU Program “Ideas” (ERC-2012-StG 310898) and the FWO (G082317N). Piccolipiu cohort has been approved and initially funded by the CCM grant 2010 and by the Italian Ministry of Health. Declaration of Interests: The authors declare that they have no conflict of interests. Ethics Approval Statement: Piccolipiu cohort has been approved and initially funded by the CCM grant 2010 and by the Italian Ministry of Health.

Children’s microvascular traits and air pollution exposure

TPS 671: Cardiometabolic effects of long-term air pollution exposure, Exhibition Hall, Ground floor, August 26, 2019, 3:00 PM - 4:30 PM Background:Particulate matter air pollution exposure during in utero development may entail adverse health outcomes later in life. The microvasculature undergoes extensive, organ-specific prenatal maturation. There is a growing body of evidence that cardiovascular disease in adulthood is rooted in a dysfunctional fetal and perinatal development, in particular that of the microcirculation. Objectives: We investigate whether prenatal or postnatal exposure to PM2.5 or NO2 air pollution is related to microvascular traits in children at the age of four. Methods: In young children (mean age 4.6 ± 0.4), followed longitudinally within the ENVIRONAGE birth cohort, we measured the retinal microvascular diameters, the central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE), and the curvature of the vessel system by means of the tortuosity index (TI). We modelled prenatal and postnatal PM2.5 (particulate matter with a diameter ≤ 2.5 µm) and NO2 exposure levels for each mother’s home address using a high resolution spatiotemporal model. Results: An interquartile range (IQR) increase in prenatal PM2.5 exposure was associated with a 3.64 µm (95% CI: -0.07 to 7.41; p = 0.05), increase in CRVE and a 2.83 µm (95% CI: 0.05 to 5.61; p = 0.05) higher CRAE. Prenatal NO2 exposure was also associated with a widening of both the CRVE and CRAE. In addition, an augmented TI was observed in association with prenatal NO2 exposure. For postnatal exposure, we observe a short-term exposure effect of PM2.5 on the CRAE and a life-time exposure effect of NO2 on the CRAE, CRVE and TI. Conclusions: Our results link both prenatal and postnatal particulate matter air pollution exposure with changes in children’s microvascular traits as a fundamental novel mechanism to explain the developmental origin of cardiovascular disease by ambient air pollution.

Sex-specific associations between telomere length and candidate miRNA expression in placenta

BackgroundIn the early-life environment, proper development of the placenta is essential for both fetal and maternal health. Telomere length at birth has been related to life expectancy. MicroRNAs (miRNAs) as potential epigenetic determinants of telomere length at birth have not been identified. In this study, we investigate whether placental miRNA expression is associated with placental telomere length at birth.MethodsWe measured the expression of seven candidate miRNAs (miR-16-5p, -20a-5p, -21-5p, -34a-5p, 146a-5p, -210-3p and -222-3p) in placental tissue at birth in 203 mother-newborn (51.7% girls) pairs from the ENVIRONAGE birth cohort. We selected miRNAs known to be involved in crucial cellular processes such as inflammation, oxidative stress, cellular senescence related to aging. Placental miRNA expression and relative average placental telomere length were measured using RT-qPCR.ResultsBoth before and after adjustment for potential covariates including newborn’s ethnicity, gestational age, paternal age, maternal smoking status, maternal educational status, parity, date of delivery and outdoor temperature during the 3rd trimester of pregnancy, placental miR-34a, miR-146a, miR-210 and miR-222 expression were significantly (p ≤ 0.03) and positively associated with placental relative telomere length in newborn girls. In newborn boys, only higher expression of placental miR-21 was weakly (p = 0.08) associated with shorter placental telomere length. Significant miRNAs explain around 6–8% of the telomere length variance at birth.ConclusionsPlacental miR-21, miR-34a, miR-146a, miR-210 and miR-222 exhibit sex-specific associations with telomere length in placenta. Our results indicate miRNA expression in placental tissue could be an important determinant in the process of aging starting from early life onwards.

Placental hypoxia-regulating network in relation to birth weight and ponderal index: the ENVIRONAGE Birth Cohort Study

BackgroundHIF1α, miR-210 and its downstream targets ISCU, COX-10, RAD52 and PTEN are all part of the placental hypoxia-responsive network. Tight regulation of this network is required to prevent development of maternal–fetal complications such as fetal growth restriction. HIF1α expression is increased in preeclamptic placentae, but little is known about its association with birth weight in normal pregnancies.MethodsWe measured placental levels of HIF1α, miR-20a, miR-210, ISCU, COX-10, RAD52 and PTEN in 206 mother–newborn pairs of the ENVIRONAGE birth cohort.ResultsPlacental HIF1α gene expression was inversely associated with the ponderal index (PI): for a doubling in placental HIF1α expression, PI decreased by 6.7% (95% confidence interval [CI] 1.3 to 12.0%, p = 0.01). Placental RAD52 expression also displayed an inverse association with PI, a doubling in gene expression was associated with a 6.2% (CI 0.2 to 12.1% p = 0.04) decrease in PI. As for birth weight, we observed a significant association with placental miR-20a expression only in boys, where a doubling in miR-20a expression is associated with a 54.2 g (CI 0.6 to 108 g, p = 0.05) increase in birth weight.ConclusionsThe decrease in fetal growth associated with expression of hypoxia-network members HIF1a, RAD52 and miR-20a indicates that this network is important in potential intrauterine insults.

Mother\u2019s Pre-pregnancy BMI and Placental Candidate miRNAs: Findings from the ENVIRONAGE Birth Cohort

There is increasing evidence that the predisposition for development of chronic diseases arises at the earliest times of life. In this context, maternal pre-pregnancy weight might modify fetal metabolism and the child’s predisposition to develop disease later in life. The aim of this study is to investigate the association between maternal pre-pregnancy body mass index (BMI) and miRNA alterations in placental tissue at birth. In 211 mother-newborn pairs from the ENVIRONAGE birth cohort, we assessed placental expression of seven miRNAs important in crucial cellular processes implicated in adipogenesis and/or obesity. Multiple linear regression models were used to address the associations between pre-pregnancy BMI and placental candidate miRNA expression. Maternal pre-pregnancy BMI averaged (±SD) 23.9 (±4.1) kg/m2. In newborn girls (not in boys) placental miR-20a, miR-34a and miR-222 expression was lower with higher maternal pre-pregnancy BMI. In addition, the association between maternal pre-pregnancy BMI and placental expression of these miRNAs in girls was modified by gestational weight gain. The lower expression of these miRNAs in placenta in association with pre-pregnancy BMI, was only evident in mothers with low weight gain (<14 kg). The placental expression of miR-20a, miR-34a, miR-146a, miR-210 and miR-222 may provide a sex-specific basis for epigenetic effects of pre-pregnancy BMI.

Newborn sex-specific transcriptome signatures and gestational exposure to fine particles: findings from the ENVIRONAGE birth cohort

BackgroundAir pollution exposure during pregnancy has been associated with adverse birth outcomes and health problems later in life. We investigated sex-specific transcriptomic responses to gestational long- and short-term exposure to particulate matter with a diameter < 2.5 μm (PM2.5) in order to elucidate potential underlying mechanisms of action.MethodsWhole genome gene expression was investigated in cord blood of 142 mother-newborn pairs that were enrolled in the ENVIRONAGE birth cohort. Daily PM2.5 exposure levels were calculated for each mother’s home address using a spatial-temporal interpolation model in combination with a dispersion model to estimate both long- (annual average before delivery) and short- (last month of pregnancy) term exposure. We explored the association between gene expression levels and PM2.5 exposure, and identified modulated pathways by overrepresentation analysis and gene set enrichment analysis.ResultsSome processes were altered in both sexes for long- (e.g. DNA damage) or short-term exposure (e.g. olfactory signaling). For long-term exposure in boys neurodevelopment and RhoA pathways were modulated, while in girls defensin expression was down-regulated. For short-term exposure we identified pathways related to synaptic transmission and mitochondrial function (boys) and immune response (girls).ConclusionsThis is the first whole genome gene expression study in cord blood to identify sex-specific pathways altered by PM2.5. The identified transcriptome pathways could provide new molecular insights as to the interaction pattern of early life PM2.5 exposure with the biological development of the fetus.

Cohort Profile: The ENVIRonmental influence ON early AGEing (ENVIRONAGE): a birth cohort study.

The ENVIRONAGE birth cohort is supported by the European Research Council [ERC-2012-StG.310898], and by funds of the Flemish Scientific Research council [FWO, G.0.733.15.N]. Bianca Cox, Janneke Hogervorst and Karen Vrijens have a postdoctoral fellowship from the Research Foundation - Flanders (FWO).

Neonatal Cord Blood Oxylipins and Exposure to Particulate Matter in the Early-Life Environment: An ENVIRONAGE Birth Cohort Study.

Background:As part of the lipidome, oxylipins are bioactive lipid compounds originating from oxidation of different fatty acids. Oxylipins could provide a new target in the developmental origins model or the ability of early life exposure to change biology.Objectives:We studied the association between in utero PM2.5 (particulate matter with aerodynamic diameter < 2.5 μm) exposure and oxylipin profiles in newborns.Methods:Thirty-seven oxylipins reflecting the cyclooxygenase (COX), lipoxygenase (5-LOX and 12/15-LOX), and cytochrome P450 (CYP) pathways were assayed in 197 cord blood plasma samples from the ENVIRONAGE birth cohort. Principal component (PC) analysis and multiple regression models were used to estimate associations of in utero PM2.5 exposure with oxylipin pathways and individual metabolites.Results:A principal component representing the 5-LOX pathway (6 metabolites) was significantly positively associated with PM2.5 exposure during the entire (multiple testing–adjusted q-value = 0.05) and second trimester of pregnancy (q = 0.05). A principal component representing the 12/15-LOX pathway (11 metabolites) was positively associated with PM2.5 exposure during the second trimester of pregnancy (q = 0.05). PM2.5 was not significantly associated with the COX pathway during any time period. There was a positive but nonsignificant association between second-trimester PM2.5 and the CYP pathway (q = 0.16).Conclusion: In utero exposure to particulate matter, particularly during the second trimester, was associated with differences in the cord blood levels of metabolites derived from the lipoxygenase pathways. These differences may indicate an effect of air pollution during in utero life on the inflammatory state of the newborn at birth. Oxylipins may be important mediators between early life exposures and health outcomes later in life.Citation:Martens DS, Gouveia S, Madhloum N, Janssen BG, Plusquin M, Vanpoucke C, Lefebvre W, Forsberg B, Nording M, Nawrot TS. 2017. Neonatal cord blood oxylipins and exposure to particulate matter in the early-life environment: an ENVIRONAGE birth cohort study. Environ Health Perspect 125:691–698; http://dx.doi.org/10.1289/EHP291

Maternal pre-pregnancy body mass index and newborn telomere length.

BackgroundNewborn telomere length sets telomere length for later life. At birth, telomere length is highly variable among newborns and the environmental factors during in utero life for this observation remain largely unidentified. Obesity during pregnancy might reflect an adverse nutritional status affecting pregnancy and offspring outcomes, but the association of maternal pre-pregnancy body mass index (BMI) with newborn telomere length, as a mechanism of maternal obesity, on the next generation has not been addressed.MethodsAverage relative telomere lengths were measured in cord blood (n = 743) and placental tissue (n = 702) samples using a quantitative real-time PCR method from newborns from the ENVIRONAGE birth cohort in Belgium. By using univariate and multivariable adjusted linear regression models we addressed the associations between pre-pregnancy BMI and cord blood and placental telomere lengths.ResultsMaternal age was 29.1 years (range, 17–44) and mean (SD) pre-pregnancy BMI was 24.1 (4.1) kg/m2. Decline in newborn telomere length occurred in parallel with higher maternal pre-pregnancy BMI. Independent of maternal and paternal age at birth, maternal education, gestational age, newborn gender, ethnicity, birthweight, maternal smoking status, parity, cesarean section, and pregnancy complications, each kg/m2 increase in pre-pregnancy BMI was associated with a −0.50 % (95 % CI, −0.83 to −0.17 %; P = 0.003) shorter cord blood telomere length and a −0.66 % (95 % CI, −1.06 to −0.25 %; P = 0.002) shorter placental telomere length.ConclusionsMaternal pre-pregnancy BMI is associated with shorter newborn telomere lengths as reflected by cord blood and placental telomeres. These findings support the benefits of a pre-pregnancy healthy weight for promoting molecular longevity from early life onwards.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0689-0) contains supplementary material, which is available to authorized users.

Lower Placental Leptin Promoter Methylation in Association with Fine Particulate Matter Air Pollution during Pregnancy and Placental Nitrosative Stress at Birth in the ENVIRONAGE Cohort.

Background:Particulate matter with a diameter ≤ 2.5 μm (PM2.5) affects human fetal development during pregnancy. Oxidative stress is a putative mechanism by which PM2.5 may exert its effects. Leptin (LEP) is an energy-regulating hormone involved in fetal growth and development.Objectives:We investigated in placental tissue whether DNA methylation of the LEP promoter is associated with PM2.5 and whether the oxidative/nitrosative stress biomarker 3-nitrotyrosine (3-NTp) is involved.Methods:LEP DNA methylation status of 361 placentas from the ENVIRONAGE birth cohort was assessed using bisulfite-PCR-pyrosequencing. Placental 3-NTp (n = 313) was determined with an ELISA assay. Daily PM2.5 exposure levels were estimated for each mother’s residence, accounting for residential mobility during pregnancy, using a spatiotemporal interpolation model.Results:After adjustment for a priori chosen covariates, placental LEP methylation was 1.4% lower (95% CI: –2.7, –0.19%) in association with an interquartile range increment (7.5 μg/m3) in second-trimester PM2.5 exposure and 0.43% lower (95% CI: –0.85, –0.02%) in association with a doubling of placental 3-NTp content.Conclusions:LEP methylation status in the placenta was negatively associated with PM2.5 exposure during the second trimester, and with placental 3-NTp, a marker of oxidative/nitrosative stress. Additional research is needed to confirm our findings and to assess whether oxidative/nitrosative stress might contribute to associations between PM2.5 and placental epigenetic events. Potential consequences for health during the neonatal period and later in life warrant further exploration.Citation:Saenen ND, Vrijens K, Janssen BG, Roels HA, Neven KY, Vanden Berghe W, Gyselaers W, Vanpoucke C, Lefebvre W, De Boever P, Nawrot TS. 2017. Lower placental leptin promoter methylation in association with fine particulate matter air pollution during pregnancy and placental nitrosative stress at birth in the ENVIRONAGE cohort. Environ Health Perspect 125:262–268; http://dx.doi.org/10.1289/EHP38

Fetal Thyroid Function, Birth Weight, and in Utero Exposure to Fine Particle Air Pollution: A Birth Cohort Study

Background:Thyroid hormones are critical for fetal development and growth. Whether prenatal exposure to fine particle air pollution (≤ 2.5 μm; PM2.5) affects fetal thyroid function and what the impact is on birth weight in normal healthy pregnancies have not been studied yet.Objectives:We studied the impact of third-trimester PM2.5 exposure on fetal and maternal thyroid hormones and their mediating role on birth weight.Methods:We measured the levels of free thyroid hormones (FT3, FT4) and thyroid-stimulating hormone (TSH) in cord blood (n = 499) and maternal blood (n = 431) collected after delivery from mother–child pairs enrolled between February 2010 and June 2014 in the ENVIRONAGE birth cohort with catchment area in the province of Limburg, Belgium.Results:An interquartile range (IQR) increment (8.2 μg/m3) in third-trimester PM2.5 exposure was inversely associated with cord blood TSH levels (–11.6%; 95% CI: –21.8, –0.1) and the FT4/FT3 ratio (–62.7%; 95% CI: –91.6, –33.8). A 10th–90th percentile decrease in cord blood FT4 levels was associated with a 56 g decrease in mean birth weight (95% CI: –90, –23). Assuming causality, we estimated that cord blood FT4 mediated 21% (–19 g; 95% CI: –37, –1) of the estimated effect of an IQR increment in third-trimester PM2.5 exposure on birth weight. Third-trimester PM2.5 exposure was inversely but not significantly associated with maternal blood FT4 levels collected 1 day after delivery (–4.0%, 95% CI: –8.0, 0.2 for an IQR increment in third-trimester PM2.5).Conclusions:In our study population of normal healthy pregnancies, third-trimester exposure to PM2.5 air pollution was associated with differences in fetal thyroid hormone levels that may contribute to reduced birth weight. Additional research is needed to confirm our findings in other populations and to evaluate potential consequences later in life.Citation:Janssen BG, Saenen ND, Roels HA, Madhloum N, Gyselaers W, Lefebvre W, Penders J, Vanpoucke C, Vrijens K, Nawrot TS. 2017. Fetal thyroid function, birth weight, and in utero exposure to fine particle air pollution: a birth cohort study. Environ Health Perspect 125:699–705; http://dx.doi.org/10.1289/EHP508

Placental canonical transient receptor potential channel 6 expression and gestational trimester-specific fine particle air pollution exposure in the ENVIRONAGE birth cohort

INTRODUCTION: Ion channels are indispensable for embryonic development. Transient receptor potential (TRP) channels encompass a family of Ca2+ transporter channels of which canonical channel TRPC6 ...

Fetal Thyroid Function and In Utero Exposure to Fine Particle Air Pollution: a Birth Cohort Study

Background: Thyroid hormones are critical for fetal development and growth. Currently, there is no information available whether prenatal exposure to fine particle air pollution (PM2.5) affects fetal thyroid function and what the impact is on birth weight in normal healthy pregnancies. Methods: We measured the levels of free thyroid hormones (FT3, FT4) and thyroid stimulating hormone (TSH) in cord blood (n=545) and maternal blood (n=472) of mother-child pairs enrolled in the ENVIRONAGE birth cohort. Daily PM2.5 exposure levels were calculated for each participant’s residence. Results: Prenatal PM2.5 exposure during pregnancy did not affect maternal thyroid hormones, whereas an interquartile range (IQR) increment in entire pregnancy PM2.5 exposure changed cord blood TSH levels by -11.0% (95% CI: -18.6, -2.8; p=0.01). The FT4/FT3 ratio was negatively associated with an IQR increment of entire pregnancy PM2.5 exposure (-41.7%; -62.8, -20.6; p=0.0001), which was mainly attributed to a reduction in FT4 concentrations in cord blood. The estimated effect of an IQR increment in third trimester PM2.5 exposure on birth weight was mediated for 26% (-23 g; -42, -4; p=0.02) by decreasing cord blood FT4 levels. Conclusions: In normal healthy pregnancies, exposure to PM2.5 air pollution affects fetal thyroid function. Cord blood FT4 mediates to some extent the association between PM2.5 exposure and birth weight. Whether PM2.5-induced alterations in fetal thyroid function has bearing on pathological consequences later in life requires further elucidation.

Cord plasma insulin and early life exposure to particulate air pollution

BACKGROUND AND AIM: Cardio-metabolic risk factors including insulin levels are at young age barely perceived as harmful, but over time these risk factors may track and lead to higher risk of metabolic syndrome. Studies showed that exposure to air pollution is associated with increase in the risk of insulin resistance in childhood. Therefore, we studied plasma umbilical cord insulin levels and in utero exposure to particulate air pollution (PM2.5). METHODS: In the ENVIRONAGE birth cohort, we investigated in 605 newborns the association between cord plasma insulin levels and exposure to PM2.5 in various exposure windows during pregnancy. RESULTS: Cord plasma insulin levels averaged (SD) 4.8 mU/L (2.1), while PM2.5 exposure during pregnancy averaged 15.9 (25th-75th percentile: 14.0-17.7) µg/m3. Independent of maternal age, newborn’s gender, birth weight, gestational age, parity, pre-gestational BMI, ethnicity, time of the day, maternal education and season of delivery, cord plasma insulin levels increased with +17% (95% CI: 6.83 to 28.12, p = 0.0008) for each SD increment of PM2.5 levels during the entire pregnancy and was most pronounced in trimester 3 (+13.54%, 95%CI: 3.78 to 24.21, p = 0.006) of pregnancy. Cord plasma insulin levels correlated negatively with gestational age (β = -4.66%/week, p = 0.04) but positively with mother’s pre-gestational BMI (β = +1.87%/kg/m², p = 0.005) and newborn’s birth weight (β = +0.04%/kg, p &lt; 0.0001). CONCLUSION: Exposure to particulate air pollution late in pregnancy is associated with increased levels of cord plasma insulin at birth. The public health relevance is demonstrated by the fact that a SD increase in PM2.5 during pregnancy on cord plasma insulin levels corresponds to a pre-pregnancy 9 kg/m² higher BMI on cord blood insulin. Pollution–induced changes in cord plasma insulin levels during early life might be a risk factor in the development of cardio-metabolic disease later in life.

Lower Placental Leptin DNA Methylation through Gestational Exposure to Particulate Matter Air Pollution

Background: Particulate matter with a diameter ≤ 2.5 µm (PM2.5) affects fetal human development during pregnancy. Oxidative stress is one putative mechanism by which PM2.5 may exert its effects. Leptin (LEP) is an energy regulating hormone involved in fetal growth and development. Objectives: We investigated in placental tissue whether DNA methylation of the LEP promoter is associated with PM2.5 and whether the oxidative/nitrosative stress biomarker 3-nitrotyrosine (3-NTp) is involved. Methods: LEP DNA methylation status of 361 placentas from the ENVIRONAGE birth cohort was assessed using bisulfite-PCR-pyrosequencing. 3-NTp (n = 313) was determined with an ELISA assay. Daily PM2.5 exposure levels were calculated for each mother’s residence using a spatiotemporal interpolation model. Results: After adjustment for a priori chosen covariates, we found a 1.4% lower placental LEP methylation status (p = 0.02) for an interquartile range increment of PM2.5 exposure during the second gestational trimester. For a doubling in placental 3-NTp content, the placental LEP methylation lowered by -0.43% (p = 0.04). Placental 3-NTp mediated the association between second trimester PM2.5 exposure and LEP methylation. Conclusions: The methylation status of the placental LEP region was sensitive to PM2.5 exposure of the second gestational window and to placental oxidative/nitrosative stress. These stressors influenced the PM2.5-LEP methylation association, suggesting an underlying role of oxidative/nitrosative stress in PM2.5-associated placental epigenetic events. The pathophysiological outcomes of these alterations as to newborns’ health and consequences later in life warrant further exploration.

Mitochondrial oxidative DNA damage and exposure to particulate air pollution in mother-newborn pairs.

BackgroundStudies emphasize the importance of particulate matter (PM) in the formation of reactive oxygen species and inflammation. We hypothesized that PM exposure during different time windows in pregnancy influences mitochondrial 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels, which is an established biomarker for oxidative stress, in both maternal and foetal blood.MethodsWe investigated maternal (n = 224) and cord blood (n = 293) from mother-newborn pairs that were enrolled in the ENVIRONAGE birth cohort. We determined mitochondrial 8-OHdG by quantitative polymerase chain reaction (qPCR). Multivariable regression models were used to assess the association between mitochondrial 8-OHdG with PM10 and PM2.5 exposure over various time windows during pregnancy.ResultsIn multivariable analysis, PM10 exposure during the entire pregnancy was positively associated with levels of mitochondrial 8-OHdG in maternal blood. For an IQR increment in PM10 exposure an increase of 18.3 % (95 % confidence interval (CI): 5.6 to 33.4 %, p = 0.004) in 8-OHdG was observed. PM10 exposure during the last trimester of pregnancy was positively associated with levels of 8-OHdG (28.1, 95 % CI: 8.6 to 51.2 %, p = 0.004, for an IQR increment in PM10). In a similar way, PM2.5 exposure was significantly associated with an increase of mitochondrial 8-OHdG levels in maternal blood during the entire pregnancy (13.9, 95 % CI: 0.4 to 29.4 %, p = 0.04 for an IQR increment in PM2.5 exposure) and third trimester of pregnancy (28.1, 95 % CI: 3.6 to 58.4 %, p = 0.02 for an IQR increment in PM2.5 exposure). In umbilical cord blood, 8-OHdG levels were significantly associated with PM10 exposure during first and second trimester of pregnancy with respectively an increase of 23.0 % (95 % CI: 5.9 to 42.8 %, p = 0.007) and 16.6 % (95 % CI: 1.8 to 33.5 %, p = 0.03) for an IQR increment in PM10 exposure.ConclusionsWe found PM-associated increased mitochondrial oxidative DNA damage during pregnancy in both mothers and their newborns. Accordingly, our study showed that particulate air pollution exposure in early life plays a role in increasing systemic oxidative stress, at the level of the mitochondria, both in mother and foetus.Electronic supplementary materialThe online version of this article (doi:10.1186/s12940-016-0095-2) contains supplementary material, which is available to authorized users.

Placental nitrosative stress and in utero exposure to particulate matter

Background and aims A wide variety of adverse health effects on both fetuses and neonates have been ascribed to particulate matter (PM) air pollution. Recent evidence suggests that PM exposure results in increased oxidative and nitrosative stress. In the ENVIRONAGE birth cohort, we investigated the association of placental 3-nitrotyrosine (3-NT) with PM exposure during various time windows of pregnancy.

Placental DNA methylation as a proxy for fetal neurodevelopment and sex-specific associations with in utero particulate air pollution

Background and aims Exposure to particulate matter (PM) air pollution during pregnancy may affect human fetal development. Epigenetic mechanisms are believed to play an essential role in the developmental changes during early life. Within the ENVIRONAGE birth cohort, we investigated whether in utero exposure to PM is associated with differences in placental DNA methylation of genes involved in early neurodevelopment, i.e., Brain-Derived Neurotrophic Factor (BDNF), Leptin (LEP) and 5Hydroxytryptamine (serotonin) receptor 2A (HTR2A).