Mediation by Placental DNA Methylation of the Association of Prenatal Maternal Smoking and Birth Weight.
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ABSTRACT:
SUBMITTER: Cardenas A
PROVIDER: S-EPMC6825837 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundHigh-dimensional mediation analysis is an extension of unidimensional mediation analysis that includes multiple mediators, and increasingly it is being used to evaluate the indirect omics-layer effects of environmental exposures on health outcomes. Analyses involving high-dimensional mediators raise several statistical issues. Although many methods have recently been developed, no consensus has been reached about the optimal combination of approaches to high-dimensional mediation analyses.ObjectivesWe developed and validated a method for high-dimensional mediation analysis (HDMAX2) and applied it to evaluate the causal role of placental DNA methylation in the pathway between exposure to maternal smoking (MS) during pregnancy and gestational age (GA) and birth weight of the baby at birth.MethodsHDMAX2 combines latent factor regression models for epigenome-wide association studies with max2 tests for mediation and considers CpGs and aggregated mediator regions (AMRs). HDMAX2 was carefully evaluated using simulated data and compared to state-of-the-art multidimensional epigenetic mediation methods. Then, HDMAX2 was applied to data from 470 women of the Etude des Déterminants pré et postnatals du développement de la santé de l'Enfant (EDEN) cohort.ResultsHDMAX2 demonstrated increased power in comparison with state-of-the-art multidimensional mediation methods and identified several AMRs not identified in previous mediation analyses of exposure to MS on birth weight and GA. The results provided evidence for a polygenic architecture of the mediation pathway with a posterior estimate of the overall indirect effect of CpGs and AMRs equal to 44.5g lower birth weight representing 32.1% of the total effect [standard deviation (SD)=60.7g]. HDMAX2 also identified AMRs having simultaneous effects both on GA and on birth weight. Among the top hits of both GA and birth weight analyses, regions located in COASY, BLCAP, and ESRP2 also mediated the relationship between GA and birth weight, suggesting reverse causality in the relationship between GA and the methylome.DiscussionHDMAX2 outperformed existing approaches and revealed an unsuspected complexity of the potential causal relationships between exposure to MS and birth weight at the epigenome-wide level. HDMAX2 is applicable to a wide range of tissues and omic layers. https://doi.org/10.1289/EHP11559.
| S-EPMC10104171 | biostudies-literature
Project description:There is great interest in the role epigenetic variation induced by non-genetic exposures may play in the context of health and disease. In particular, DNA methylation has previously been shown to be highly dynamic during the earliest stages of development and is influenced by in utero exposures such as maternal smoking and medication. In this study we sought to identify the specific DNA methylation differences in blood associated with prenatal and birth factors, including birth weight, gestational age and maternal smoking. We quantified neonatal methylomic variation in 1263 infants using DNA isolated from a unique collection of archived blood spots taken shortly after birth (mean = 6.08 days; s.d. = 3.24 days). An epigenome-wide association study (EWAS) of gestational age and birth weight identified 4299 and 18 differentially methylated positions (DMPs) respectively, at an experiment-wide significance threshold of p < 1 × 10-7. Our EWAS of maternal smoking during pregnancy identified 110 DMPs in neonatal blood, replicating previously reported genomic loci, including AHRR. Finally, we tested the hypothesis that DNA methylation mediates the relationship between maternal smoking and lower birth weight, finding evidence that methylomic variation at three DMPs may link exposure to outcome. These findings complement an expanding literature on the epigenomic consequences of prenatal exposures and obstetric factors, confirming a link between the maternal environment and gene regulation in neonates. This article is part of the theme issue 'Developing differences: early-life effects and evolutionary medicine'.
| S-EPMC6460077 | biostudies-literature
Project description:BACKGROUND:Exposure to traffic pollution during fetal development has been associated with reduced fetal growth, and there is evidence to suggest that epigenetic mechanisms in the placenta in the form of variant DNA methylation may be a potential mechanism underlying this effect. OBJECTIVES:To examine the association between residential proximity to nearest major roadway, as a marker of traffic-related pollution, fetal growth and placental DNA methylation. METHODS:We obtained residential addresses, placenta samples, and demographic data from 471 women following delivery of term infants. Using generalized linear models we evaluated the association between living close to a major roadway (defined as living ?150m from a primary highway or primary road or ?50m from a secondary road) and fetal growth and DNA methylation of repetitive elements (LINE-1 and AluYb8). We evaluated epigenome-wide methylation in a subset of 215 women to further investigate specific variation in DNA methylation associated with proximity to major roadways. RESULTS:Living close to a major roadway was associated with a 175.9g (95% CI: -319.4, -32.5; p=0.016) lower birth weight, 1.8 (95% CI: 0.9, 3.8; p=0.09) times the odds of being small for gestational age, and 0.82 percentage points (95% CI: -1.57, -0.07; p=0.03) lower mean placental LINE-1 methylation levels in fully adjusted models. In epigenome-wide analyses, 7 CpG sites were significantly associated with residential proximity to major roadways. Additional adjustment for placental methylation did not attenuate the association between roadway proximity and birth weight. CONCLUSIONS:Living close to major roadways was associated with both lower fetal growth and significant placental epigenetic changes. However, the observed epigenetic changes appear insufficient to explain the observed association between roadway proximity and fetal growth.
| S-EPMC4913202 | biostudies-literature
Project description:BACKGROUND:Cigarette smoking has severe adverse health consequences in adults and in the offspring of mothers who smoke during pregnancy. One of the most widely reported effects of smoking during pregnancy is reduced birth weight which is in turn associated with chronic disease in adulthood. Epigenome-wide association studies have revealed that smokers show a characteristic "smoking methylation pattern", and recent authors have proposed that DNA methylation mediates the impact of maternal smoking on birth weight. The aims of the present study were to replicate previous reports that methylation mediates the effect of maternal smoking on birth weight, and for the first time to investigate whether the observed mediation effects are sex-specific in order to account for known sex-specific differences in methylation levels. METHODS:Methylation levels in the cord blood of 313 newborns were determined using the Illumina HumanMethylation450K Beadchip. A total of 5,527 CpG sites selected on the basis of evidence from the literature were tested. To determine whether the observed association between maternal smoking and birth weight was attributable to methylation, mediation analyses were performed for significant CpG sites. Separate analyses were then performed in males and females. RESULTS:Following quality control, 282 newborns eventually remained in the analysis. A total of 25 mothers had smoked consistently throughout the pregnancy. The birthweigt of newborns whose mothers had smoked throughout pregnancy was reduced by >200g. After correction for multiple testing, 30 CpGs showed differential methylation in the maternal smoking subgroup including top "smoking methylation pattern" genes AHRR, MYO1G, GFI1, CYP1A1, and CNTNAP2. The effect of maternal smoking on birth weight was partly mediated by the methylation of cg25325512 (PIM1); cg25949550 (CNTNAP2); and cg08699196 (ITGB7). Sex-specific analyses revealed a mediating effect for cg25949550 (CNTNAP2) in male newborns. CONCLUSION:The present data replicate previous findings that methylation can mediate the effect of maternal smoking on birth weight. The analysis of sex-dependent mediation effects suggests that the sex of the newborn may have an influence. Larger studies are warranted to investigate the role of both the identified differentially methylated loci and the sex of the newborn in mediating the association between maternal smoking during pregnancy and birth weight.
| S-EPMC5922319 | biostudies-literature
Project description:Selenium (Se) is an essential element and also toxic at an excessive level for human body. However, few studies have investigated adverse effects of Se exposure on birth weight and placental weight.MethodsAll participants were selected from the Prenatal Environment and Offspring Health cohort conducted in 2016 in Guangzhou, China. Se in each participant was measured by inductively coupled plasma mass spectrometry in their urine samples. The urinary Se concentrations were corrected by creatinine and transformed by natural logarithm (ln-Se). Multiple-linear regression models were applied to estimate the associations among Se exposure levels, placenta weight, and birth weight.ResultsA total of 2758 mother-newborn pairs were included in this study. Each interquartile range (0.53 μg/g creatinine) increment in urine ln-Se concentration during the first trimester was associated with a mean 21.7 g (95% CI = -41.3g to -2.1g) decrease in birth weight and 3.6g (95% CI = -6.3g to -0.9g) decrease in placental weight. Compared with the lowest quartile (Q1) of ln-Se concentrations during the first trimester, significantly lower birth weight was found in the highest quartile (Q4) (β = -45.7g; 95% CI = -90.7g to -0.7g). Similar dose-response associations with birthweight and placental weight were found for Se exposure during the third trimester. Mediation analyses showed that 44.2% and 18.2% of the effects of Se exposure in first and third trimester on birth weight were mediated by decreased placental weight, respectively.ConclusionMaternal Se exposure during pregnancy was negatively associated with birth weight, the reduction of placental weight may partially mediate the association of prenatal Se exposure with birth weight.
| S-EPMC8043733 | biostudies-literature
Project description:The associations among maternal diet, birth weight, and gestational weight gain are still inconclusive. This study aimed to investigate the associations between maternal dietary patterns and birth weight, and further explore whether GWG mediates these associations. A total of 3,334 pregnant women who completed a validated semi-quantitative food frequency questionnaire from the Tongji Maternal and Child Health Cohort were included. Dietary patterns were extracted by using principal component analysis. Regression models and mediation analyses were performed to explore the associations between dietary patterns and birth weight and the effects of GWG on these associations. Five dietary patterns were identified: "Beans-vegetables," "Fish-meat-eggs," "Nuts-whole grains," "Organ-poultry-seafood" and "Rice-wheat-fruits." Only women following the "Beans-vegetables" pattern had heavier newborns (β = 47.39; 95% CI: 12.25, 82.54). Women following the "Beans-vegetables" pattern had significantly lower GWG (β = -0.7; 95% CI: -1.15, -0.25) and had a 16% lower risk of excessive GWG and 11% higher odd of adequate GWG. The association between the "Beans-vegetables" pattern and birth weight was negatively mediated by GWG. A dietary pattern enriched in beans and vegetables is beneficial for effectively controlling GWG and increasing birth weight. GWG serves. Clinical Trial Registry: This trial was registered at ClinicalTrials.gov (NCT03099837).
| S-EPMC8664542 | biostudies-literature
Project description:Maternal smoking during pregnancy is associated with both reduced birth weight and adverse neurobehavioral outcomes. The aim of this study was to investigate longitudinal associations between maternal smoking during pregnancy and childhood behavioral outcomes, and to determine the role of birth weight in mediating such associations. The study included 489 mother-child pairs. Prenatal exposures were assessed via maternal interviews conducted on average 1 year after delivery and child behavior assessments were completed at 5-12 years of age using the Child Behavior Checklist (CBCL) and Teacher Report Form (TRF). Maternal smoking during pregnancy was associated with externalizing and total behavior problems according to both mother and teacher report. Maternal smoking was also associated with the following percentage increases in scores: 41% (CBCL) and 44% (TRF) for aggressive behavior and 65% (CBCL) and 47% (TRF) for attention problems. Associations with behavior problems were attenuated or no longer observed for mothers that quit smoking in early pregnancy. The proportion of the total effect of maternal smoking on behavioral outcomes explained by differences in birth weight was small and ranged from 6.6% for externalizing behavior on the CBCL to 20.1% for rule-breaking behavior on the CBCL. Our results suggest that birth weight differences explain only a small proportion of the magnitude of association between maternal smoking during pregnancy and selected behavioral outcomes.
| S-EPMC6734934 | biostudies-literature
Project description:BackgroundMaternal obesity prior to or during pregnancy influences fetal growth, predisposing the offspring to increased risk for obesity across the life course. Placental epigenetic mechanisms may underlie these associations. We conducted an epigenome-wide association study to identify placental DNA methylation changes associated with maternal prepregnancy body mass index (BMI) and rate of gestational weight gain at first (GWG1), second (GWG2), and third trimester (GWG3).MethodParticipants of the NICHD Fetal Growth Studies with genome-wide placental DNA methylation (n = 301) and gene expression (n = 75) data were included. Multivariable-adjusted regression models were used to test the associations of 1 kg/m2 increase in prepregnancy BMI or 1 kg/week increase in GWG with DNA methylation levels. Genes harboring top differentially methylated CpGs (FDR P < 0.05) were evaluated for placental gene expression. We assessed whether DNA methylation sites known to be associated with BMI in child or adult tissues, were also associated with maternal prepregnancy BMI in placenta.ResultsPrepregnancy BMI was associated with DNA methylation at cg14568196[EGFL7], cg15339142[VETZ], and cg02301019[AC092377.1] (FDR P < 0.05, P ranging from 1.4 × 10-10 to 1.7 × 10-9). GWG1 or GWG2 was associated with DNA methylation at cg17918270[MYT1L], cg20735365[DLX5], and cg17451688[SLC35F3] (FDR P < 0.05, P ranging from 6.4 × 10-10 to 1.2 × 10-8). Both prepregnancy BMI and DNA methylation at cg1456819 [EGFL7] were negatively correlated with EGFL7 expression in placenta (P < 0.05). Several CpGs previously implicated in obesity traits in children and adults were associated with prepregnancy BMI in placenta. Functional annotations revealed that EGFL7 is highly expressed in placenta and the differentially methylated CpG sites near EGFL7 and VEZT were cis-meQTL targets in blood.ConclusionsWe identified placental DNA methylation changes at novel loci associated with prepregnancy BMI and GWG. The overlap between CpGs associated with obesity traits in placenta and other tissues in children and adults suggests that epigenetic mechanisms in placenta may give insights to early origins of obesity.
| S-EPMC7261634 | biostudies-literature
Project description:AIM:To investigate the role of maternal gestational weight gain (GWG) and prepregnancy BMI on programming offspring DNA methylation. METHODS:Among 589 adult (age = 32) women participants of the Jerusalem Perinatal Study, we quantified DNA methylation in five candidate genes. We used inverse probability-weighting and parametric g-formula to estimate direct effects of maternal prepregnancy BMI and GWG on methylation. RESULTS:Higher maternal GWG, but not prepregnancy BMI, was inversely related to offspring ABCA1 methylation (? = -1.1% per quartile; 95% CI: -2.0, -0.3) after accounting for ancestry, parental and offspring exposures. Total and controlled direct effects were nearly identical suggesting included offspring exposures did not mediate this relationship. Results were robust to sensitivity analyses for missing data and model specification. CONCLUSION:We find some support for epigenetic programming and highlight strengths and limitations of these methods relative to other prevailing approaches.
| S-EPMC5704089 | biostudies-other
Project description:Background: Previous studies have demonstrated the embryotoxicity and fetotoxicity of thallium (Tl). However, the effects of prenatal exposure to Tl on birth weight and placental weight and the mediating role of placental weight in the association of Tl with birth weight remain unclear. Methods: We recruited 2,748 participants from the ongoing Prenatal Environment and Offspring Health Cohort (PEOH Cohort) study, which was initiated in 2016 in Guangzhou, China. The Tl concentrations in maternal urine samples collected during the first and third trimester were determined by inductively coupled plasma mass spectrometry. Birth weight and placental weight were extracted from maternal medical records. Results: Pregnant women exposed to the highest tertile of Tl in the first trimester (β = -42.7 g, 95% CI: -82.3, -3.1 g) and third trimester (β = -50.6 g, 95% CI: -99.0, -2.3 g) had babies with lower birth weights than those exposed to the lowest tertile. We also found significant negative associations of exposure to Tl concentrations in the first and third trimester with placental weight. Mediation analyses showed that 50.3% (95% CI: 15.9, 79.2%) and 33.5% (95% CI: 1.3, 80.3%) of the effects of Tl exposure in the first and third trimester on birth weight were mediated by decreased placental weight. Conclusion: Our results suggest that prenatal exposure to Tl is negatively associated with birth weight and that this association may be mediated by decreased placental weight.
| S-EPMC8283527 | biostudies-literature