Maternal environmental exposure to bisphenols and epigenome-wide DNA methylation in infant cord blood

Abstract Maternal prenatal exposures, including bisphenol A (BPA), are associated with offspring’s risk of disease later in life. Alterations in DNA methylation may be a mechanism through which altered prenatal conditions (e.g. maternal exposure to environmental toxicants) elicit this disease risk. In the Michigan Mother and Infant Pairs Cohort, maternal first-trimester urinary BPA, bisphenol F, and bisphenol S concentrations were tested for association with DNA methylation patterns in infant umbilical cord blood leukocytes (N = 69). We used the Illumina Infinium MethylationEPIC BeadChip to quantitatively evaluate DNA methylation across the epigenome; 822 020 probes passed pre-processing and quality checks. Single-site DNA methylation and bisphenol models were adjusted for infant sex, estimated cell-type proportions (determined using cell-type estimation algorithm), and batch as covariates. Thirty-eight CpG sites [false discovery rate (FDR) <0.05] were significantly associated with maternal BPA exposure. Increasing BPA concentrations were associated with lower DNA methylation at 87% of significant sites. BPA exposure associated DNA methylation sites were enriched for 38 pathways significant at FDR <0.05. The pathway or gene-set with the greatest odds of enrichment for differential methylation (FDR <0.05) was type I interferon receptor binding. This study provides a novel understanding of fetal response to maternal bisphenol exposure through epigenetic change.

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Maternal lipodome across pregnancy is associated with the neonatal DNA methylome

Epigenomics ◽

10.2217/epi-2020-0234 ◽

2020 ◽

Vol 12 (23) ◽

pp. 2077-2092

Author(s):

Jennifer L LaBarre ◽

Carolyn F McCabe ◽

Tamara R Jones ◽

Peter XK Song ◽

Steven E Domino ◽

...

Keyword(s):

Dna Methylation ◽

Cell Proliferation ◽

Cord Blood ◽

Empirical Bayes ◽

First Trimester ◽

Maternal Plasma ◽

Biological Pathways ◽

Blood Leukocytes ◽

Dna Methylome ◽

Blood Leukocyte

Aim: To classify the association between the maternal lipidome and DNA methylation in cord blood leukocytes. Materials & methods: Untargeted lipidomics was performed on first trimester maternal plasma (M1) and delivery maternal plasma (M3) in 100 mothers from the Michigan Mother-Infant Pairs cohort. Cord blood leukocyte DNA methylation was profiled using the Infinium EPIC bead array and empirical Bayes modeling identified differential DNA methylation related to maternal lipid groups. Results: M3-saturated lysophosphatidylcholine was associated with 45 differentially methylated loci and M3-saturated lysophosphatidylethanolamine was associated with 18 differentially methylated loci. Biological pathways enriched among differentially methylated loci by M3 saturated lysophosphatidylcholines were related to cell proliferation and growth. Conclusion: The maternal lipidome may be influential in establishing the infant epigenome.

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DNA methylation and gene expression integration in cardiovascular disease

Clinical Epigenetics ◽

10.1186/s13148-021-01064-y ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Guillermo Palou-Márquez ◽

Isaac Subirana ◽

Lara Nonell ◽

Alba Fernández-Sanlés ◽

Roberto Elosua

Keyword(s):

Gene Expression ◽

Cardiovascular Disease ◽

Dna Methylation ◽

Cardiovascular Diseases ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Risk Function ◽

Predictive Biomarkers ◽

Independent Study ◽

Cell Type

Abstract Background The integration of different layers of omics information is an opportunity to tackle the complexity of cardiovascular diseases (CVD) and to identify new predictive biomarkers and potential therapeutic targets. Our aim was to integrate DNA methylation and gene expression data in an effort to identify biomarkers related to cardiovascular disease risk in a community-based population. We accessed data from the Framingham Offspring Study, a cohort study with data on DNA methylation (Infinium HumanMethylation450 BeadChip; Illumina) and gene expression (Human Exon 1.0 ST Array; Affymetrix). Using the MOFA2 R package, we integrated these data to identify biomarkers related to the risk of presenting a cardiovascular event. Results Four independent latent factors (9, 19, 21—only in women—and 27), driven by DNA methylation, were associated with cardiovascular disease independently of classical risk factors and cell-type counts. In a sensitivity analysis, we also identified factor 21 as associated with CVD in women. Factors 9, 21 and 27 were also associated with coronary heart disease risk. Moreover, in a replication effort in an independent study three of the genes included in factor 27 were also present in a factor identified to be associated with myocardial infarction (CDC42BPB, MAN2A2 and RPTOR). Factor 9 was related to age and cell-type proportions; factor 19 was related to age and B cells count; factor 21 pointed to human immunodeficiency virus infection-related pathways and inflammation; and factor 27 was related to lifestyle factors such as alcohol consumption, smoking and body mass index. Inclusion of factor 21 (only in women) improved the discriminative and reclassification capacity of the Framingham classical risk function and factor 27 improved its discrimination. Conclusions Unsupervised multi-omics data integration methods have the potential to provide insights into the pathogenesis of cardiovascular diseases. We identified four independent factors (one only in women) pointing to inflammation, endothelium homeostasis, visceral fat, cardiac remodeling and lifestyles as key players in the determination of cardiovascular risk. Moreover, two of these factors improved the predictive capacity of a classical risk function.

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Differences in DNA methylation of white blood cell types at birth and in adulthood reflect postnatal immune maturation and influence accuracy of cell type prediction

10.1101/399279 ◽

2018 ◽

Cited By ~ 3

Author(s):

Meaghan J Jones ◽

Louie Dinh ◽

Hamid Reza Razzaghian ◽

Olivia de Goede ◽

Julia L MacIsaac ◽

...

Keyword(s):

Dna Methylation ◽

Immune System ◽

Blood Cell ◽

Cord Blood ◽

White Blood Cell ◽

Blood Cells ◽

Cell Types ◽

Cell Type ◽

Cell Type Specific ◽

The Impact

AbstractBackgroundDNA methylation profiling of peripheral blood leukocytes has many research applications, and characterizing the changes in DNA methylation of specific white blood cell types between newborn and adult could add insight into the maturation of the immune system. As a consequence of developmental changes, DNA methylation profiles derived from adult white blood cells are poor references for prediction of cord blood cell types from DNA methylation data. We thus examined cell-type specific differences in DNA methylation in leukocyte subsets between cord and adult blood, and assessed the impact of these differences on prediction of cell types in cord blood.ResultsThough all cell types showed differences between cord and adult blood, some specific patterns stood out that reflected how the immune system changes after birth. In cord blood, lymphoid cells showed less variability than in adult, potentially demonstrating their naïve status. In fact, cord CD4 and CD8 T cells were so similar that genetic effects on DNA methylation were greater than cell type effects in our analysis, and CD8 T cell frequencies remained difficult to predict, even after optimizing the library used for cord blood composition estimation. Myeloid cells showed fewer changes between cord and adult and also less variability, with monocytes showing the fewest sites of DNA methylation change between cord and adult. Finally, including nucleated red blood cells in the reference library was necessary for accurate cell type predictions in cord blood.ConclusionChanges in DNA methylation with age were highly cell type specific, and those differences paralleled what is known about the maturation of the postnatal immune system.

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DHA supplementation during pregnancy and DNA methylation in cord blood leukocytes

American Journal of Clinical Nutrition ◽

10.3945/ajcn.113.072074 ◽

2013 ◽

Vol 98 (6) ◽

pp. 1594-1595 ◽

Cited By ~ 2

Author(s):

Graham C Burdge

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Blood Leukocytes

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Prenatal metal exposure, cord blood DNA methylation and persistence in childhood: an epigenome-wide association study of 12 metals

Clinical Epigenetics ◽

10.1186/s13148-021-01198-z ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Anne K. Bozack ◽

Sheryl L. Rifas-Shiman ◽

Brent A. Coull ◽

Andrea A. Baccarelli ◽

Robert O. Wright ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Linear Models ◽

Human Leukocyte ◽

First Trimester ◽

Metal Exposure ◽

Future Research ◽

Biologically Relevant ◽

Illumina Humanmethylation450 Beadchip ◽

Relevant Variables

Abstract Background Prenatal exposure to essential and non-essential metals impacts birth and child health, including fetal growth and neurodevelopment. DNA methylation (DNAm) may be involved in pathways linking prenatal metal exposure and health. In the Project Viva cohort, we analyzed the extent to which metals (As, Ba, Cd, Cr, Cs, Cu, Hg, Mg, Mn, Pb, Se, and Zn) measured in maternal erythrocytes were associated with differentially methylated positions (DMPs) and regions (DMRs) in cord blood and tested if associations persisted in blood collected in mid-childhood. We measured metal concentrations in first-trimester maternal erythrocytes, and DNAm in cord blood (N = 361) and mid-childhood blood (N = 333, 6–10 years) with the Illumina HumanMethylation450 BeadChip. For each metal individually, we tested for DMPs using linear models (considered significant at FDR < 0.05), and for DMRs using comb-p (Sidak p < 0.05). Covariates included biologically relevant variables and estimated cell-type composition. We also performed sex-stratified analyses. Results Pb was associated with decreased methylation of cg20608990 (CASP8) (FDR = 0.04), and Mn was associated with increased methylation of cg02042823 (A2BP1) in cord blood (FDR = 9.73 × 10–6). Both associations remained significant but attenuated in blood DNAm collected at mid-childhood (p < 0.01). Two and nine Mn-associated DMPs were identified in male and female infants, respectively (FDR < 0.05), with two and six persisting in mid-childhood (p < 0.05). All metals except Ba and Pb were associated with ≥ 1 DMR among all infants (Sidak p < 0.05). Overlapping DMRs annotated to genes in the human leukocyte antigen (HLA) region were identified for Cr, Cs, Cu, Hg, Mg, and Mn. Conclusions Prenatal metal exposure is associated with DNAm, including DMRs annotated to genes involved in neurodevelopment. Future research is needed to determine if DNAm partially explains the relationship between prenatal metal exposures and health outcomes.

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DNA methylation at LRP1 gene locus mediates the association between maternal total cholesterol changes in pregnancy and cord blood leptin levels

Journal of Developmental Origins of Health and Disease ◽

10.1017/s204017441900076x ◽

2019 ◽

Vol 11 (4) ◽

pp. 369-378 ◽

Cited By ~ 1

Author(s):

Simon-Pierre Guay ◽

Andrée-Anne Houde ◽

Edith Breton ◽

Jean-Patrice Baillargeon ◽

Patrice Perron ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Total Cholesterol ◽

Scavenger Receptor ◽

Ldl Receptor ◽

Density Lipoprotein ◽

First Trimester ◽

Blood Cholesterol ◽

Changes In Pregnancy ◽

In Pregnancy

AbstractPlacental lipids transfer is essential for optimal fetal development, and alterations of these mechanisms could lead to a higher risk of adverse birth outcomes. Low-density lipoprotein receptor (LDLR), LDL receptor-related protein 1 (LRP1), and scavenger receptor class B type 1 (SCARB1) genes are encoding lipoprotein receptors expressed in the placenta where they participate in cholesterol exchange from maternal to fetal circulation. The aim of this study was thus to investigate the association between maternal lipid changes occurring in pregnancy, placental DNA methylation (DNAm) variations at LDLR, LRP1, and SCARB1 gene loci, and newborn’s anthropometric profile at birth. Sixty-nine normoglycemic women were followed from the first trimester of pregnancy until delivery. Placental DNAm was quantified at 43 Cytosine-phosphate-Guanines (CpGs) at LDLR, LRP1, and SCARB1 gene loci using pyrosequencing: 4 CpGs were retained for further analysis. Maternal clinical data were collected at each trimester of pregnancy. Newborns’ data were collected from medical records. Statistical models included minimally newborn sex and gestational and maternal age. Maternal total cholesterol changes during pregnancy (ΔT3-T1) were correlated with DNAm variations at LDLR (r = −0.32, p = 0.01) and LRP1 (r = 0.34, p = 0.007). DNAm at these loci was also correlated with newborns’ cord blood triglyceride and leptin levels. Mediation analysis supports a causal relationship between maternal cholesterol changes, DNAm levels at LRP1 locus, and cord blood leptin concentration (pmediation = 0.02). These results suggest that LRP1 DNAm link maternal blood cholesterol changes in pregnancy and offspring adiposity at birth, which provide support for a better follow-up of blood lipids in pregnancy.

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Integrative Analysis of Gene-Specific DNA Methylation and Untargeted Metabolomics Data from the ELEMENT Cohort

Epigenetics Insights ◽

10.1177/2516865720977888 ◽

2020 ◽

Vol 13 ◽

pp. 251686572097788

Author(s):

Jaclyn M Goodrich ◽

Emily C Hector ◽

Lu Tang ◽

Jennifer L LaBarre ◽

Dana C Dolinoy ◽

...

Keyword(s):

Dna Methylation ◽

Early Life ◽

Regulatory Networks ◽

Tanner Stage ◽

Later Life ◽

Untargeted Metabolomics ◽

Environmental Toxicants ◽

Blood Leukocytes ◽

Cross Sectional ◽

Metabolomics Data

Epigenetic modifications, such as DNA methylation, influence gene expression and cardiometabolic phenotypes that are manifest in developmental periods in later life, including adolescence. Untargeted metabolomics analysis provide a comprehensive snapshot of physiological processes and metabolism and have been related to DNA methylation in adults, offering insights into the regulatory networks that influence cellular processes. We analyzed the cross-sectional correlation of blood leukocyte DNA methylation with 3758 serum metabolite features (574 of which are identifiable) in 238 children (ages 8-14 years) from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) study. Associations between these features and percent DNA methylation in adolescent blood leukocytes at LINE-1 repetitive elements and genes that regulate early life growth ( IGF2, H19, HSD11B2) were assessed by mixed effects models, adjusting for sex, age, and puberty status. After false discovery rate correction (FDR q < 0.05), 76 metabolites were significantly associated with LINE-1 DNA methylation, 27 with HSD11B2, 103 with H19, and 4 with IGF2. The ten identifiable metabolites included dicarboxylic fatty acids (five associated with LINE-1 or H19 methylation at q < 0.05) and 1-octadecanoyl-rac-glycerol ( q < 0.0001 for association with H19 and q = 0.04 for association with LINE-1). We then assessed the association between these ten known metabolites and adiposity 3 years later. Two metabolites, dicarboxylic fatty acid 17:3 and 5-oxo-7-octenoic acid, were inversely associated with measures of adiposity ( P < .05) assessed approximately 3 years later in adolescence. In stratified analyses, sex-specific and puberty-stage specific (Tanner stage = 2 to 5 vs Tanner stage = 1) associations were observed. Most notably, hundreds of statistically significant associations were observed between H19 and LINE-1 DNA methylation and metabolites among children who had initiated puberty. Understanding relationships between subclinical molecular biomarkers (DNA methylation and metabolites) may increase our understanding of genes and biological pathways contributing to metabolic changes that underlie the development of adiposity during adolescence.

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Reference-Based Versus Reference-Free Cell Type Estimation In DNA Methylation Studies Using Human Placental Tissue

10.21203/rs.3.rs-848651/v1 ◽

2021 ◽

Author(s):

Linda Dieckmann ◽

Cristiana Cruceanu ◽

Marius Lahti-Pulkkinen ◽

Jari Lahti ◽

Tuomas Kvist ◽

...

Keyword(s):

Dna Methylation ◽

Human Placenta ◽

Disease Risk ◽

Placental Tissue ◽

Predictive Performance ◽

Cell Types ◽

Free Cell ◽

Estimation Methods ◽

Cell Type ◽

Chorion Villus

Abstract The placenta is a central organ during early development, influencing trajectories of health and disease. DNA methylation (DNAm) studies of human placenta improve our understanding of how its function relates to disease risk. However, DNAm studies can be biased by cell type heterogeneity, so it is essential to control for this in order to reduce confounding and increase precision. Computational cell type deconvolution approaches have proven to be very useful for this purpose. For human placenta, however, an assessment of the performance of these estimation methods is still lacking. Here, we compare the predictive performance of reference-based versus reference-free estimated proportions of cell types from genome-wide DNAm in placental samples taken at birth and from chorion villus biopsies early in pregnancy using three independent studies comprising over 1,000 samples. We found both reference-free and reference-based estimated cell type proportions to have predictive value for DNAm, however, reference-based cell type estimation outperformed reference-free estimation for the majority of data sets. Reference-based cell type estimations mirror previous histological knowledge on changes in cell type proportions through gestation. Further, CpGs whose variation in DNAm was largely explained by reference-based estimated cell type proportions were in the proximity of genes that are highly tissue-specific for placenta. This was not the case for reference-free estimated cell type proportions. We provide a list of these CpGs as a resource to help researchers to interpret results of existing studies and improve future DNAm studies of human placenta.

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Epigenetics

Examining the Causal Relationship Between Genes, Epigenetics, and Human Health - Advances in Bioinformatics and Biomedical Engineering ◽

10.4018/978-1-5225-8066-9.ch011 ◽

2019 ◽

pp. 239-268

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Air Pollution ◽

Disease Risk ◽

Environmental Pollutants ◽

State Regulation ◽

Metal Exposure ◽

Environmental Toxicants ◽

Water Chlorination ◽

Epigenetic Patterns

This chapter focuses on epigenetics: the study of stable, often heritable changes that influence gene expression but are not mediated by DNA sequence. These changes play crucial roles in chromatin state regulation which influences processes such as gene expression, DNA repair, and recombination. Evidence demonstrates that epigenetic patterns are altered by environmental factors which are associated with disease risk including diet, smoking, alcohol intake, environmental toxicants, and stress. Studiers have linked environmental pollutants with epigenetic variations particularly changes in DNA methylation, histone modifications, and microRNAs. Growing data have linked epigenetic alterations with heavy metal exposure, organic toxicants, and water chlorination by-products. Studies focusing on the effects of air pollution in humans demonstrate an association between exposure to air pollution and DNA methylation. Several classes of pesticides can modify epigenetic marks, including endocrine disruptors, persistent organic pollutants, arsenic, several herbicides, and insecticides. This chapter explores epigenetics.

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