Dataset Information

Genome-wide DNA methylation at birth in relation to in utero arsenic exposure and the associated health in later life.

ABSTRACT:

Background

In utero arsenic exposure may alter fetal developmental programming by altering DNA methylation, which may result in a higher risk of disease in later life. We evaluated the association between in utero arsenic exposure and DNA methylation (DNAm) in cord blood and its influence in later life.

Methods

Genome-wide DNA methylation in cord blood from 64 subjects in the Taiwanese maternal infant and birth cohort was analyzed. Robust regressions were applied to assess the association of DNA methylation with in utero arsenic exposure. Multiple testing was adjusted by controlling false discovery rate (FDR) of 0.05. The DAVID bioinformatics tool was implemented for functional annotation analyses on the detected CpGs. The identified CpGs were further tested in an independent cohort. For the CpGs replicated in the independent cohort, linear mixed models were applied to assess the association of DNA methylation with low-density lipoprotein (LDL) at different ages (2, 5, 8, 11 and 14 years).

Results

In total, 579 out of 385,183 CpGs were identified after adjusting for multiple testing (FDR = 0.05), of which ~60% were positively associated with arsenic exposure. Functional annotation analysis on these CpGs detected 17 KEGG pathways (FDR = 0.05) including pathways for cardiovascular diseases (CVD) and diabetes mellitus. In the independent cohort, about 46% (252 out of 553 CpGs) of the identified CpGs showed associations consistent with those in the study cohort. In total, 11 CpGs replicated in the independent cohort were in the pathways related to CVD and diabetes mellitus. Via longitudinal analyses, we found at 5 out of the 11 CpGs methylation was associated with LDL over time and interactions between DNA methylation and time were observed at 4 of the 5 CpGs, cg25189764 (coeff = 0.157, p-value = 0.047), cg04986899 (coeff. For interaction [coeff.int] = 0.030, p-value = 0.024), cg04903360 (coeff.int = 0.026, p-value = 0.032), cg08198265 (coeff.int = -0.063, p-value = 0.0021), cg10473311 (coeff.int = -0.021, p-value = 0.027).

Conclusion

In utero arsenic exposure was associated with cord blood DNA methylation at various CpGs. The identified CpGs may help determine pathological epigenetic mechanisms linked to in utero arsenic exposure. Five CpGs (cg25189764, cg04986899, cg04903360, cg08198265 and cg10473311) may serve as epigenetic markers for changes in LDL later in life.

SUBMITTER: Kaushal A

PROVIDER: S-EPMC5450181 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Publications

Genome-wide DNA methylation at birth in relation to in utero arsenic exposure and the associated health in later life.

Kaushal Akhilesh A Zhang Hongmei H Karmaus Wilfried J J WJJ Everson Todd M TM Marsit Carmen J CJ Karagas Margaret R MR Tsai Shih-Fen SF Wen Hui-Ju HJ Wang Shu-Li SL

Environmental health : a global access science source 20170530 1

<h4>Background</h4>In utero arsenic exposure may alter fetal developmental programming by altering DNA methylation, which may result in a higher risk of disease in later life. We evaluated the association between in utero arsenic exposure and DNA methylation (DNAm) in cord blood and its influence in later life.<h4>Methods</h4>Genome-wide DNA methylation in cord blood from 64 subjects in the Taiwanese maternal infant and birth cohort was analyzed. Robust regressions were applied to assess the ass ...[more]

PMID: 28558807

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Project description:BackgroundStudies suggest that arsenic exposure influences birth outcomes; however, findings are mixed.ObjectiveWe assessed in utero arsenic exposure in relation to birth outcomes and whether maternal prepregnancy weight and infant sex modified the associations.MethodsAmong 706 mother-infant pairs exposed to low levels of arsenic through drinking water and diet, we assessed in utero arsenic exposure using maternal second-trimester urinary arsenic, maternal prepregnancy weight through self-report, and birth outcomes from medical records.ResultsMedian (interquartile range) of total urinary arsenic [tAs; inorganic arsenic (iAs) + monomethylarsonic acid (MMA) + dimethylarsinic acid (DMA)] was 3.4 ?g/L (1.7-6.0). In adjusted linear models, each doubling of tAs was associated with a 0.10-cm decrease (95% CI: -0.19, -0.01) in head circumference. Results were similar for MMA and DMA. Ln(tAs) and ln(DMA) were positively associated with birth length in infant males only; among males, each doubling of tAs was associated with a 0.28-cm increase (95% CI: 0.09, 0.46) in birth length (pinteraction = 0.04). Results were similar for DMA. Additionally, arsenic exposure was inversely related to ponderal index, and associations differed by maternal weight. Each ln(tAs) doubling of tAs was associated with a 0.55-kg/m3 lower (95% CI: -0.82, -0.28, p < 0.001) ponderal index for infants of overweight/obese, but not normal-weight, mothers (pinteraction < 0.01). Finally, there was a significant interaction between maternal weight status, infant sex, and arsenic exposure on birth weight (pinteraction = 0.03). In girls born of overweight/obese mothers, each doubling of tAs was associated with a 62.9-g decrease (95% CI: -111.6, -14.2) in birth weight, though the association was null in the other strata.ConclusionsLow-level arsenic exposure may affect fetal growth, and the associations may be modified by maternal weight status and infant sex.CitationGilbert-Diamond D, Emond JA, Baker ER, Korrick SA, Karagas MR. 2016. Relation between in utero arsenic exposure and birth outcomes in a cohort of mothers and their newborns from New Hampshire. Environ Health Perspect 124:1299-1307;?http://dx.doi.org/10.1289/ehp.1510065.

Project description:BackgroundWe have previously reported that in utero arsenic exposure is associated with increased length and other anthropometric outcomes at birth in a U.S. cohort. However, it is unknown whether these anthropometric differences persist through early life.ObjectivesWe assessed in utero arsenic exposure in relation to attained anthropometry and growth trajectories through the first year of life.MethodsAmong 760 mother-infant pairs from the New Hampshire Birth Cohort Study, we assessed in utero arsenic exposure using maternal second trimester urinary arsenic and assessed infant growth from medical records.ResultsMedian maternal second trimester total urinary arsenic (tAs; inorganic arsenic + monomethylarsonic acid + dimethylarsinic acid) was 3.96 μg/L (IQR: 2.02, 6.72). In adjusted linear mixed effects models, each doubling of maternal urinary tAs was associated with a 0.05 increase in length WHO Z score (95% CI: 0, 0.09) over the first year of life which corresponds to an approximately 0.12 cm increase in males and 0.13 cm increase in females at 12 months. No associations were observed between urinary tAs and attained weight, weight-for-length, or head circumference. In adjusted piecewise linear mixed effects models, each doubling of urinary tAs was associated with a 0.07 (95% CI: 0.02, 0.12) cm per month decreased length growth rate through 3.5 months with no evidence of an association thereafter. No associations were observed between urinary tAs and infant weight gain or change in weight-for-length and head circumference through one year.ConclusionsOn average, infants exposed to higher in utero arsenic attained modestly longer length during the first year, despite having slower linear growth in the first 3.5 months of life. This suggests that the previously demonstrated arsenic-associated longer length among study infants at birth persists through the first year of life. No other anthropometric associations with in utero arsenic exposure were observed across the full study population.

Project description:BACKGROUND:Fetal epigenetic programming plays a critical role in development. DNA methyltransferase 3 alpha (DNMT3A), which is involved in de novo DNA methylation (DNAm), is a prime candidate gene as a mediator between prenatal exposures and birth outcomes. We evaluated the relationships between in utero arsenic (As) exposure, birth outcomes, and DNMT3A DNAm. METHODS:In a prospective Bangladeshi birth cohort, cord blood DNAm of three DNMT3A CpGs was measured using bisulfite pyrosequencing. Maternal toenail As concentrations at birth were measured to estimate in utero exposure. Among vaginal births (N = 413), structural equation models (SEMs) were used to evaluate relationships between DNMT3A methylation, log2 (toenail As), birth weight, and gestational age. RESULTS:In an adjusted SEM including birth weight and gestational age, maternal toenail As levels were associated with DNMT3A DNAm (B = 0.40; 95% CI: 0.15, 0.66) and gestational age (B = -0.19 weeks; 95% CI: 0.36, -0.03). DNMT3A DNAm was associated with gestational age (B = -0.10 weeks; 95% CI: 0.16, -0.04) and birth weight (B = -11.0 g; 95% CI: 21.5, 0.4). There was an indirect effect of As on gestational age mediated through DNMT3A DNAm (B = -0.04; 95% CI: 0.08, -0.01), and there were indirect effects of maternal toenail As levels on birth weight through pathways including gestational age (B = -14.4 g; 95% CI: 29.2, -1.9), DNMT3A DNAm and gestational age (B = -3.1 g; 95% CI: 6.6, -0.8), and maternal weight gain and gestational age (B = -5.1 g; 95% CI: 9.6, -1.5). The total effect of a doubling in maternal toenail As concentration is a decrease in gestational age of 2.1 days (95% CI: 0.9, 3.3) and a decrease in birth weight of 29 g (95% CI: 14, 46). CONCLUSIONS:DNMT3A plays a critical role in fetal epigenetic programming. In utero arsenic exposure was associated with greater methylation of CpGs in DNMT3A which partially mediated associations between prenatal As exposure and birth outcomes. Additional studies are needed to verify this finding.

Project description:BackgroundThe associations of individual antiepileptic drugs (AEDs) with pregnancy duration and size at birth, and potential dose relations, are not well characterized.MethodsThis cohort study used nationwide Swedish register data (1996-2013). Adjusting for smoking, epilepsy and other AED indications, we used linear and quantile regression to explore associations with pregnancy duration, and birth weight, length, and head circumference (the last three operationalized as z-scores). We used logistic regression for preterm delivery, small for gestational age, and microcephaly. Lamotrigine was the reference drug.Results6,720 infants were exposed to AEDs in utero; AED exposure increased over the study period. Relative to lamotrigine-exposed infants, carbamazepine-exposed infants were born, on average, 1.3 days earlier (mean [95% confidence interval]: -1.3 [-2.3 to -0.3]); were 0.1 standard deviations (SDs) lighter (-0.1 [-0.2 to 0.0]); and had a head circumference that was 0.2 SDs smaller (-0.2 [-0.3 to -0.1]). Pregabalin-exposed infants were born, on average, 1.1 days earlier (-1.1 [-3.0 to 0.8]); were 0.1 SDs lighter (-0.1 [-0.3 to 0.0]); and had the same head circumference as lamotrigine-exposed infants. Levetiracetam-exposed infants were born, on average, 0.5 days earlier (-0.5 [-2.6 to 1.6]); were 0.1 SDs lighter (-0.1 [-0.3 to 0.0]); and had a head circumference 0.1 SDs smaller (-0.1 [-0.3 to 0.1]). Valproic acid-exposed infants had, on average, the same duration of gestation and birth weight z-score as lamotrigine-exposed infants, but had a head circumference 0.2 SDs smaller (-0.2 [-0.2 to -0.1]). Associations between carbamazepine exposure and pregnancy duration and between valproic acid exposure and pregnancy duration and birth weight z-score were more negative at the left than at the right tails of the outcome distributions. Effect-measure modification and dose-response relations were noted for some of the associations.ConclusionsRelative to lamotrigine, valproic acid and carbamazepine were associated with smaller head circumference.

Dataset Information

Genome-wide DNA methylation at birth in relation to in utero arsenic exposure and the associated health in later life.

Background

Methods

Results

Conclusion

Publications

Genome-wide DNA methylation at birth in relation to in utero arsenic exposure and the associated health in later life.

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