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Quality control and statistical modeling for environmental epigenetics: a study on in utero lead exposure and DNA methylation at birth.

ABSTRACT: DNA methylation data assayed using pyrosequencing techniques are increasingly being used in human cohort studies to investigate associations between epigenetic modifications at candidate genes and exposures to environmental toxicants and to examine environmentally-induced epigenetic alterations as a mechanism underlying observed toxicant-health outcome associations. For instance, in utero lead (Pb) exposure is a neurodevelopmental toxicant of global concern that has also been linked to altered growth in human epidemiological cohorts; a potential mechanism of this association is through alteration of DNA methylation (e.g., at growth-related genes). However, because the associations between toxicants and DNA methylation might be weak, using appropriate quality control and statistical methods is important to increase reliability and power of such studies. Using a simulation study, we compared potential approaches to estimate toxicant-DNA methylation associations that varied by how methylation data were analyzed (repeated measures vs. averaging all CpG sites) and by method to adjust for batch effects (batch controls vs. random effects). We demonstrate that correcting for batch effects using plate controls yields unbiased associations, and that explicitly modeling the CpG site-specific variances and correlations among CpG sites increases statistical power. Using the recommended approaches, we examined the association between DNA methylation (in LINE-1 and growth related genes IGF2, H19 and HSD11B2) and 3 biomarkers of Pb exposure (Pb concentrations in umbilical cord blood, maternal tibia, and maternal patella), among mother-infant pairs of the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort (n = 247). Those with 10 ?g/g higher patella Pb had, on average, 0.61% higher IGF2 methylation (P = 0.05). Sex-specific trends between Pb and DNA methylation (P < 0.1) were observed among girls including a 0.23% increase in HSD11B2 methylation with 10 ?g/g higher patella Pb.

SUBMITTER: Goodrich JM

PROVIDER: S-EPMC4622744 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Quality control and statistical modeling for environmental epigenetics: a study on in utero lead exposure and DNA methylation at birth.

Goodrich Jaclyn M JM Sánchez Brisa N BN Dolinoy Dana C DC Zhang Zhenzhen Z Hernández-Ávila Mauricio M Hu Howard H Peterson Karen E KE Téllez-Rojo Martha M MM

Epigenetics 20150127 1

DNA methylation data assayed using pyrosequencing techniques are increasingly being used in human cohort studies to investigate associations between epigenetic modifications at candidate genes and exposures to environmental toxicants and to examine environmentally-induced epigenetic alterations as a mechanism underlying observed toxicant-health outcome associations. For instance, in utero lead (Pb) exposure is a neurodevelopmental toxicant of global concern that has also been linked to altered g ...[more]

PMID: 25580720

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Project description:BackgroundIn 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.MethodsGenome-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).ResultsIn 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).ConclusionIn 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.

Project description:IMPORTANCE:Preterm birth is a leading cause of neonatal mortality, with a variety of contributing causes and risk factors. Environmental exposures represent a group of understudied, but potentially important, factors. Phthalate diesters are used extensively in a variety of consumer products worldwide. Consequently, exposure in pregnant women is highly prevalent. OBJECTIVE:To assess the relationship between phthalate exposure during pregnancy and preterm birth. DESIGN, SETTING, AND PARTICIPANTS:This nested case-control study was conducted at Brigham and Women's Hospital, Boston, Massachusetts. Women were recruited for a prospective observational cohort study from 2006-2008. Each provided demographic data, biological samples, and information about birth outcomes. From within this group, we selected 130 cases of preterm birth and 352 randomly assigned control participants, and we analyzed urine samples from up to 3 time points during pregnancy for levels of phthalate metabolites. EXPOSURE:Phthalate exposure during pregnancy. MAIN OUTCOMES AND MEASURES:We examined associations between average levels of phthalate exposure during pregnancy and preterm birth, defined as fewer than 37 weeks of completed gestation, as well as spontaneous preterm birth, defined as preterm preceded by spontaneous preterm labor or preterm premature rupture of the membranes (n?=?57). RESULTS:Geometric means of the di-2-ethylhexyl phthalate (DEHP) metabolites mono-(2-ethyl)-hexyl phthalate (MEHP) and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), as well as mono-n-butyl phthalate (MBP), were significantly higher in cases compared with control participants. In adjusted models, MEHP, MECPP, and? ??DEHP metabolites were associated with significantly increased odds of preterm birth. When spontaneous preterm births were examined alone, MEHP, mono-(2-ethyl-5-oxohexyl) phthalate, MECPP, ???DEHP, MBP, and mono-(3-carboxypropyl) phthalate metabolite levels were all associated with significantly elevated odds of prematurity. CONCLUSIONS AND RELEVANCE:Women exposed to phthalates during pregnancy have significantly increased odds of delivering preterm. Steps should be taken to decrease maternal exposure to phthalates during pregnancy.

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.

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Quality control and statistical modeling for environmental epigenetics: a study on in utero lead exposure and DNA methylation at birth.

Publications

Quality control and statistical modeling for environmental epigenetics: a study on in utero lead exposure and DNA methylation at birth.

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