Associations of LINE-1 DNA Methylation with Preterm Birth in a Prospective Cohort Study

Preterm birth affects over 12% of all infants born in the US yet the biology of early delivery remains unclear, including whether epigenetic mechanisms are involved. We examined associations of maternal and umbilical cord blood long interspersed nuclear element-1 (LINE-1) DNA methylation with length of gestation and odds of preterm birth in singleton pregnancies in Project Viva. In white blood cells from maternal blood during 1(st) trimester (n=914) and 2(nd) trimester (n=922), and from venous cord blood at delivery (n=557), we measured LINE-1 by pyrosequencing (expressed as %5 methyl cytosines within the LINE-1 region analyzed [%5mC]). We ran linear regression models to analyze differences in gestation length, and logistic models for odds of preterm birth (<37 v. 6537 weeks gestation), across quartiles of LINE-1. Mean(SD) LINE-1 levels were 84.3(0.6), 84.5(0.4), and 84.6(0.7) %5mC for 1(st) trimester, 2(nd) trimester and cord blood, respectively. Mean(SD) gestational age was 39.5(1.8) weeks, and 6.5% of infants were born preterm. After adjustment for maternal age, race/ethnicity, BMI, education, smoking status, and fetal sex, women with the highest vs. lowest quartile of 1(st) trimester LINE-1 had longer gestations (0.45 weeks [95% CI 0.12, 0.78]) and lower odds of preterm birth (OR 0.40 [0.17, 0.94]), whereas associations with cord blood LINE-1 were in the opposite direction (-0.45 weeks, -0.83, -0.08) and (OR 4.55 [1.18, 17.5]). In conclusion, higher early pregnancy LINE-1 predicts lower risk of preterm birth. In contrast, preterm birth is associated with lower LINE-1 in cord blood

Hypertensive Disorders of Pregnancy and DNA Methylation in Newborns Findings From the Pregnancy and Childhood Epigenetics Consortium

Hypertensive disorders of pregnancy (HDP) are associated with low birth weight, shorter gestational age, and increased risk of maternal and offspring cardiovascular diseases later in life. The mechanisms involved are poorly understood, but epigenetic regulation of gene expression may play a part. We performed meta-analyses in the Pregnancy and Childhood Epigenetics Consortium to test the association between either maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219 [cases=135]) and epigenome-wide DNA methylation in cord blood using the Illumina HumanMethylation450 BeadChip. In models adjusted for confounders, and with Bonferroni correction, HDP and preeclampsia were associated with DNA methylation at 43 and 26 CpG sites, respectively. HDP was associated with higher methylation at 27 (63%) of the 43 sites, and across all 43 sites, the mean absolute difference in methylation was between 0.6% and 2.6%. Epigenome-wide associations of HDP with offspring DNA methylation were modestly consistent with the equivalent epigenome-wide associations of preeclampsia with offspring DNA methylation (R2=0.26). In longitudinal analyses conducted in 1 study (n=108 HDP cases; 550 controls), there were similar changes in DNA methylation in offspring of those with and without HDP up to adolescence. Pathway analysis suggested that genes located at/near HDP-associated sites may be involved in developmental, embryogenesis, or neurological pathways. HDP is associated with offspring DNA methylation with potential relevance to development

Hypertensive Disorders of Pregnancy and DNA Methylation in Newborns

Hypertensive disorders of pregnancy (HDP) are associated with low birth weight, shorter gestational age, and increased risk of maternal and offspring cardiovascular diseases later in life. The mechanisms involved are poorly understood, but epigenetic regulation of gene expression may play a part. We performed meta-analyses in the Pregnancy and Childhood Epigenetics Consortium to test the association between either maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219 [cases=135]) and epigenome-wide DNA methylation in cord blood using the Illumina HumanMethylation450 BeadChip. In models adjusted for confounders, and with Bonferroni correction, HDP and preeclampsia were associated with DNA methylation at 43 and 26 CpG sites, respectively. HDP was associated with higher methylation at 27 (63%) of the 43 sites, and across all 43 sites, the mean absolute difference in methylation was between 0.6% and 2.6%. Epigenome-wide associations of HDP with offspring DNA methylation were modestly consistent with the equivalent epigenome-wide associations of preeclampsia with offspring DNA methylation (R2=0.26). In longitudinal analyses conducted in 1 study (n=108 HDP cases; 550 controls), there were similar changes in DNA methylation in offspring of those with and without HDP up to adolescence. Pathway analysis suggested that genes located at/near HDP-associated sites may be involved in developmental, embryogenesis, or neurological pathways. HDP is associated with offspring DNA methylation with potential relevance to development

Gestational intake of methyl donors and global LINE-1 DNA methylation in maternal and cord blood : prospective results from a folate-replete population

Maternal diet affects offspring DNA methylation in animal models, but evidence from humans is limited. We investigated the extent to which gestational intake of methyl donor nutrients affects global DNA methylation in maternal and umbilical cord blood. Among mother-infant pairs in Project Viva, a folate-replete US population, we estimated maternal intakes of vitamin B12, betaine, choline, folate, cadmium, zinc and iron periconceptionally and during the second trimester. We examined associations of these nutrients with DNA methylation, measured as %5-methyl cytosines (%5mC) in Long Interspersed Nuclear Element-1 (LINE-1), in first trimester (n = 830) and second trimester (n = 671) maternal blood and in cord blood at delivery (n = 516). Cord blood methylation was higher for male than female infants {mean [standard deviation (SD)] 84.8 [0.6] vs. 84.4 [0.7]%}. In the multivariable-adjusted model, maternal intake of methyl donor nutrients periconceptionally and during the second trimester of pregnancy was not positively associated with first trimester, second trimester or cord blood LINE-1 methylation. Periconceptional betaine intake was inversely associated with cord blood methylation [regression coefficient = -0.08% (95% confidence interval (CI): -0.14,-0.01)] but this association was attenuated after adjustment for dietary cadmium, which itself was directly associated with first trimester methylation and inversely associated with cord blood methylation. We also found an inverse association between periconceptional choline [-0.10%, 95% CI: -0.17,-0.03 for each SD (~63 mg/day)] and cord blood methylation in males only. In this folate-replete population, we did not find positive associations between intake of methyl donor nutrients during pregnancy and DNA methylation overall, but among males, higher early pregnancy intakes of choline were associated with lower cord blood methylation

Maternal inflammation during pregnancy and childhood adiposity

Objective: Maternal pre-pregnancy obesity is associated with offspring obesity. Underlying mechanisms may involve a maternal obesity-mediated proinflammatory state during pregnancy. Maternal C-reactive protein (CRP) level during pregnancy is a biomarker of low-grade systemic inflammation. Methods: Among 1,116 mother-child pairs, this study examined associations of maternal second-trimester CRP plasma level, measured by high-sensitivity CRP arrays, with mid-childhood DXA fat mass index (FMI), trunk fat mass index (trunkFMI), fat-free mass index (FFMI), and early and mid-childhood BMI-z and waist circumference (WC). Main analyses were adjusted for maternal sociodemographic and lifestyle-related characteristics, gestational age at blood draw, and child's age and sex. Results: Higher maternal CRP level was associated with higher mid-childhood FMI and trunkFMI (adjusted difference: 0.15 kg/m2 [95% CI: 0.01, 0.29] [P = 0.04] and 0.06 kg/m2 [95% CI: 0.00, 0.12] [P = 0.06], per SD increment in maternal CRP, respectively), but not FFMI. Higher maternal CRP level was associated with higher early and mid-childhood BMI-z and WC in the basic models [P < 0.05], but these associations attenuated after adjustment for maternal characteristics (adjusted difference in early and mid-childhood BMI-z and WC: 0.05 [95% CI: −0.03, 0.13] [P = 0.20], 0.10 cm [95% CI: −0.17, 0.37] [P = 0.46], 0.07 [95% CI: −0.01, 0.14] [P = 0.09], 0.34 cm [95% CI: −0.25, 0.94] [P = 0.26], per SD increment in maternal CRP, respectively). Conclusions: Higher second-trimester maternal CRP level was associated with higher mid-childhood overall and central adiposity

Prenatal exposure to traffic pollution and childhood body mass index trajectory

10.3389/fendo.2018.00771Frontiers in Endocrinology10JA

Breastfeeding during infancy and neurocognitive function in adolescence: 16-year follow-up of the PROBIT cluster-randomized trial

10.1371/journal.pmed.1002554PLoS Medicine154e100255

Cumulative exposure to environmental pollutants during early pregnancy and reduced fetal growth: The Project Viva cohort

Background: Reduced fetal growth is associated with perinatal and later morbidity. Prenatal exposure to environmental pollutants is linked to reduced fetal growth at birth, but the impact of concomitant exposure to multiple pollutants is unclear. The purpose of this study was to examine interactions between early pregnancy exposure to cigarette smoke, traffic pollution, and select perfluoroalkyl substances (PFASs) on birth weight-for-gestational age (BW/GA). Methods: Among 1597 Project Viva mother-infant pairs, we assessed maternal cigarette smoking by questionnaire, traffic pollution at residential address by black carbon land use regression model, and plasma concentration of select PFASs in early pregnancy. We calculated sex-specific BW/GA z-scores, an index of fetal growth, from national reference data. We fit covariate-adjusted multi-pollutant linear regression models and examined interactions between exposures, using a likelihood-ratio test to identify a best-fit model. Results: Two hundred six (13%) mothers smoked during pregnancy. Mean [standard deviation (SD)] for black carbon was 0.8 (0.3) μg/m3, perfluorooctane sulfonate (PFOS) was 29.1 (16.5) ng/mL, and BW/GA z-score was 0.19 (0.96). In the best-fit model, BW/GA z-score was lower in infants of mothers exposed to greater black carbon [- 0.08 (95% CI: -0.15, - 0.01) per interquartile range (IQR)]. BW/GA z-score (95% CI) was also lower in infants of mothers who smoked [- 0.09 (- 0.23, 0.06)] or were exposed to greater PFOS [- 0.03 (- 0.07, 0.02) per IQR], although confidence intervals crossed the null. There were no interactions between exposures. In secondary analyses, instead of PFOS, we examined perfluorononanoate (PFNA) [mean (SD): 0.7 (0.4) ng/mL], a PFAS more closely linked to lower BW/GA in our cohort. The best-fit multi-pollutant model included positive two-way interactions between PFNA and both black carbon and smoking (p-interactions = 0.03). Conclusions: Concurrent prenatal exposures to maternal smoking, black carbon, and PFOS are additively associated with lower fetal growth, whereas PFNA may attenuate associations of smoking and black carbon with lower fetal growth. It is important to examine interactions between multiple exposures in relation to health outcomes, as effects may not always be additive and may shed light on biological pathways. © 2018 The Author(s)