scholarly journals Arsenic exposure in early pregnancy alters genome-wide DNA methylation in cord blood, particularly in boys

2014 ◽  
Vol 5 (4) ◽  
pp. 288-298 ◽  
Author(s):  
K. Broberg ◽  
S. Ahmed ◽  
K. Engström ◽  
M. B. Hossain ◽  
S. Jurkovic Mlakar ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Mononuclear Cells ◽  
De Novo ◽  
Arsenic Exposure ◽  
Later Life ◽  
Linear Regression Models ◽  
Early Gestation ◽  
Cpg Sites ◽  
Genome Wide

Early-life inorganic arsenic exposure influences not only child health and development but also health in later life. The adverse effects of arsenic may be mediated by epigenetic mechanisms, as there are indications that arsenic causes altered DNA methylation of cancer-related genes. The objective was to assess effects of arsenic on genome-wide DNA methylation in newborns. We studied 127 mothers and cord blood of their infants. Arsenic exposure in early and late pregnancy was assessed by concentrations of arsenic metabolites in maternal urine, measured by high performance liquid chromatography-inductively coupled plasma mass spectrometry. Genome-wide 5-methylcytosine methylation in mononuclear cells from cord blood was analyzed by Infinium HumanMethylation450K BeadChip. Urinary arsenic in early gestation was associated with cord blood DNA methylation (Kolmogorov–Smirnov test, P-value<10–15), with more pronounced effects in boys than in girls. In boys, 372 (74%) of the 500 top CpG sites showed lower methylation with increasing arsenic exposure (rS-values>−0.62), but in girls only 207 (41%) showed inverse correlation (rS-values>−0.54). Three CpG sites in boys (cg15255455, cg13659051 and cg17646418), but none in girls, were significantly correlated with arsenic after adjustment for multiple comparisons. The associations between arsenic and DNA methylation were robust in multivariable-adjusted linear regression models. Much weaker associations were observed with arsenic exposure in late compared with early gestation. Pathway analysis showed overrepresentation of affected cancer-related genes in boys, but not in girls. In conclusion, early prenatal arsenic exposure appears to decrease DNA methylation in boys. Associations between early exposure and DNA methylation might reflect interference with de novo DNA methylation.

scholarly journals Birthweight DNA methylation signatures in infant saliva

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Chiara Moccia ◽  
Maja Popovic ◽  
Elena Isaevska ◽  
Valentina Fiano ◽  
Morena Trevisan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Gestational Age ◽  
Low Birthweight ◽  
Continuous Variable ◽  
Linear Regression Models ◽  
Association Analyses ◽  
Cpg Sites ◽  
Adverse Health Outcomes ◽  
The Look

Abstract Background Low birthweight has been repeatedly associated with long-term adverse health outcomes and many non-communicable diseases. Our aim was to look-up cord blood birthweight-associated CpG sites identified by the PACE Consortium in infant saliva, and to explore saliva-specific DNA methylation signatures of birthweight. Methods DNA methylation was assessed using Infinium HumanMethylation450K array in 135 saliva samples collected from children of the NINFEA birth cohort at an average age of 10.8 (range 7–17) months. The association analyses between birthweight and DNA methylation variations were carried out using robust linear regression models both in the exploratory EWAS analyses and in the look-up of the PACE findings in infant saliva. Results None of the cord blood birthweight-associated CpGs identified by the PACE Consortium was associated with birthweight when analysed in infant saliva. In saliva EWAS analyses, considering a false discovery rate p-values < 0.05, birthweight as continuous variable was associated with DNA methylation in 44 CpG sites; being born small for gestational age (SGA, lower 10th percentile of birthweight for gestational age according to WHO reference charts) was associated with DNA methylation in 44 CpGs, with only one overlapping CpG between the two analyses. Despite no overlap with PACE results at the CpG level, two of the top saliva birthweight CpGs mapped at genes associated with birthweight with the same direction of the effect also in the PACE Consortium (MACROD1 and RPTOR). Conclusion Our study provides an indication of the birthweight and SGA epigenetic salivary signatures in children around 10 months of age. DNA methylation signatures in cord blood may not be comparable with saliva DNA methylation signatures at about 10 months of age, suggesting that the birthweight epigenetic marks are likely time and tissue specific.

scholarly journals Trimester-Specific Associations of Prenatal Lead Exposure With Infant Cord Blood DNA Methylation at Birth

2020 ◽  
Vol 13 ◽  
pp. 251686572093866 ◽  
Author(s):  
Christine A Rygiel ◽  
Dana C Dolinoy ◽  
Wei Perng ◽  
Tamara R Jones ◽  
Maritsa Solano ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Differential Methylation ◽  
P Value ◽  
Environmental Toxicants ◽  
Linear Regression Models ◽  
Birth Cohorts ◽  
Tibia Bone ◽  
Cpg Sites ◽  
Pb Exposure

Gestational exposure to lead (Pb) adversely impacts offspring health through multiple mechanisms, one of which is the alteration of the epigenome including DNA methylation. This study aims to identify differentially methylated CpG sites associated with trimester-specific maternal Pb exposure in umbilical cord blood (UCB) leukocytes. Eighty-nine mother-child dyads from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) longitudinal birth cohorts with available UCB samples were selected for DNA methylation analysis via the Infinium Methylation EPIC BeadChip, which quantifies methylation at >850 000 CpG sites. Maternal blood lead levels (BLLs) during each trimester (T1: 6.56 ± 5.35 µg/dL; T2: 5.93 ± 5.00 µg/dL; T3: 6.09 ± 4.51 µg/dL), bone Pb (patella: 11.8 ± 9.25 µg/g; tibia: 11.8 ± 6.73 µg/g), a measure of cumulative Pb exposure, and UCB Pb (4.86 ± 3.74 µg/dL) were measured. After quality control screening, data from 786 024 CpG sites were used to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) by Pb biomarkers using separate linear regression models, controlling for sex and estimated UCB cell-type proportions. We identified 3 DMPs associated with maternal T1 BLL, 2 with T3 BLL, and 2 with tibia bone Pb. We identified one DMR within PDGFRL associated with T1 BLL, one located at chr6:30095136-30095295 with T3 BLL, and one within TRHR with tibia bone Pb (adjusted P-value < .05). Pathway analysis identified 15 overrepresented gene pathways for differential methylation that overlapped among all 3 trimesters with the largest overlap between T1 and T2 (adjusted P-value < .05). Pathways of interest include nodal signaling pathway and neurological system processes. These data provide evidence for differential methylation by prenatal Pb exposure that may be trimester-specific.

scholarly journals Socioeconomic status and DNA methylation from birth through mid-childhood: a prospective study in Project Viva

Epigenomics ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1413-1427 ◽  
Author(s):  
Zachary M Laubach ◽  
Wei Perng ◽  
Andres Cardenas ◽  
Sheryl L Rifas-Shiman ◽  
Emily Oken ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Socioeconomic Status ◽  
Cord Blood ◽  
Cpg Sites ◽  
Infinium Humanmethylation450 Beadchip ◽  
Genome Wide ◽  
Peripheral Leukocytes ◽  
A Prospective Study ◽  
The Relationship ◽  
Neighborhood Level

Aim: We investigated associations of prenatal socioeconomic status (SES) with DNA methylation at birth, and to explore persistence of associations into early (∼3 years) and mid-childhood (∼7 years) among 609 mother–child pairs in a Boston-area prebirth cohort. Materials & methods: First, we created a prenatal SES index comprising individual- and neighborhood-level metrics and examined associations of low (lowest 10%) versus high (upper 90%) SES with genome-wide DNA methylation in cord blood via the Infinium HumanMethylation450 BeadChip. Next, we evaluated persistence of associations detected in cord blood with DNA methylation of the same CpG sites measured in peripheral leukocytes in early- and mid-childhood. Results & conclusion: Low prenatal SES was associated with methylation at CpG sites near ACSF3, TNRC6C-AS1, MTMR4 and LRRN4. The relationship with LRRN4 persisted into early childhood.

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

2017 ◽  
Vol 16 (1) ◽  
Author(s):  
Akhilesh Kaushal ◽  
Hongmei Zhang ◽  
Wilfried J. J. Karmaus ◽  
Todd M. Everson ◽  
Carmen J. Marsit ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Arsenic Exposure ◽  
Later Life ◽  
In Utero ◽  
Genome Wide

scholarly journals Birthweight DNA Methylation Signatures in Infant Saliva 

2020 ◽  
Author(s):  
Chiara Moccia ◽  
Maja Popovic ◽  
Elena Isaevska ◽  
Valentina Fiano ◽  
Morena Trevisan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Gestational Age ◽  
Low Birthweight ◽  
Continuous Variable ◽  
Linear Regression Models ◽  
Association Analyses ◽  
Cpg Sites ◽  
Adverse Health Outcomes ◽  
Methylation Variation

Abstract Background Low birthweight has been repeatedly associated with long-term adverse health outcomes and many non-communicable diseases. Our aim was to investigate whether cord blood birthweight-associated CpG sites identified by the PACE Consortium replicate in infant saliva, and to explore saliva-specific DNA methylation signatures of birthweight. Methods DNA methylation was assessed using Infinium HumanMethylation450K array in 141 saliva samples collected from children of the NINFEA birth cohort at an average age of 10.8 (range 7-17) months. The association analyses between birthweight and DNA methylation variations were carried out using robust linear regression models both in replication and exploratory EWAS analyses.Results None of the cord blood birthweight-associated CpGs identified by the PACE Consortium was replicated in infant saliva. In saliva EWAS analyses, birthweight as continuous variable was associated with DNA methylation variation in 44 CpG sites, while being born small for gestational age (SGA, lower 10th percentile of birthweight for gestational age according to WHO reference charts) was associated with DNA methylation variation in 44 CpGs (all false discovery rate p-values<0.05), with only one overlapping CpG between the two analyses. Despite no overlap with PACE results at the CpG level, two of the top saliva birthweight CpGs mapped at genes identified also by the PACE consortium (MACROD1 and RPTOR).Conclusion Our study provides an indication of the birthweight and SGA epigenetic salivary signatures in children around 10 months of age. DNA methylation signatures in cord blood may not be comparable with saliva DNA methylation signatures at about 10 months of age, suggesting that the birthweight epigenetic marks are likely time and tissue specific.

scholarly journals 5-Hydroxymethylcytosine in cord blood and associations of DNA methylation with sex in newborns

Mutagenesis ◽  
2019 ◽  
Vol 34 (4) ◽  
pp. 315-322
Author(s):  
Olivia Solomon ◽  
Julia L Macisaac ◽  
Gwen Tindula ◽  
Michael S Kobor ◽  
Brenda Eskenazi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Health Assessment ◽  
Differential Methylation ◽  
Size Difference ◽  
Cpg Sites ◽  
Genome Wide ◽  
Two Measures ◽  
Low Levels ◽  
Effect Size Difference

Abstract DNA methylation has been widely studied for associations with exposures and health outcomes. Both 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic marks that may function differently to impact gene expression; however, the most commonly used technology to assess methylation for population studies in blood use are the Illumina 450K and EPIC BeadChips, for which the traditional bisulfite conversion does not differentiate 5mC and 5hmC marks. We used a modified protocol originally developed by Stewart et al. to analyse oxidative bisulfite-converted and conventional bisulfite-converted DNA for the same subject in parallel by the EPIC chip, allowing us to isolate the two measures. We measured 5mC and 5hmC in cord blood of 41 newborn participants of the Center for Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort and investigated differential methylation of 5mC + 5hmC, isolated 5mC and isolated 5hmC with sex at birth as an example of a biological variable previously associated with DNA methylation. Results showed low levels of 5hmC throughout the epigenome in the cord blood samples in comparison to 5mC. The concordance of autosomal hits between 5mC + 5hmC and exclusive 5mC analyses were low (25%); however, overlap was larger with increased effect size difference. There were 43 autosomal cytosine nucleotide followed by a guanine nucleotide (CpG) sites where 5hmC was associated with sex, 21 of which were unique to 5hmC after adjustment for cell composition. 5hmC only accounts for a small portion of overall methylation in cord blood; however, it has the potential to impact interpretation of combined 5hmC + 5mC studies in cord blood, especially given that effect sizes of differential methylation analyses are often small. Several significant CpG sites were unique to 5hmC, suggesting some functions distinct from 5mC. More studies of genome-wide 5hmC in children are warranted.

scholarly journals A Genome-Wide Integrative Association Study of DNA Methylation and Gene Expression Data and Later Life Cognitive Functioning in Monozygotic Twins

2020 ◽  
Vol 14 ◽  
Author(s):  
Mette Soerensen ◽  
Dominika Marzena Hozakowska-Roszkowska ◽  
Marianne Nygaard ◽  
Martin J. Larsen ◽  
Veit Schwämmle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cognitive Functioning ◽  
Association Study ◽  
Gene Expression Data ◽  
Monozygotic Twins ◽  
Later Life ◽  
Expression Data ◽  
Genome Wide ◽  
A Genome

Abstract MP42: Adherence To Healthy Dietary Patterns In Pregnancy And Placental Dna Methylation- An Epigenome Wide Association Study

Circulation ◽  
2021 ◽  
Vol 143 (Suppl_1) ◽  
Author(s):  
Cuilin Zhang ◽  
Jing Wu ◽  
Marion Ouidir ◽  
Stefanie Hinkle ◽  
Fasil Ayele
Keyword(s):  
Dna Methylation ◽  
Dietary Patterns ◽  
First Trimester ◽  
Healthy Eating Index ◽  
Nervous System Development ◽  
Dietary Quality ◽  
Analysis Tool ◽  
Linear Regression Models ◽  
Cpg Sites ◽  
In Pregnancy

Background: Accumulating evidence support the intergenerational impacts of diet in pregnancy. The underlying mechanisms, however, remain unclear. Placental epigenetic mechanisms may be involved although data from human epidemiological studies are sparse. We aimed to investigate associations of dietary quality in pregnancy with epigenome-wide placental DNA methylation in a multiracial pregnancy cohort. Methods: DNA methylation was measured using the Illumina Infinium Human Methylation450 Beadchip on placentas obtained at delivery from 301 pregnant women who participated in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort. Dietary information during periconception and early first trimester was collected using food frequency questionnaires, and diet in the second and third trimester was collected using a 24-hour dietary recall during four study visits. Scores for adherence to three healthy dietary patterns, alternate Healthy Eating Index (aHEI), alternate Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH), were calculated. For associations of each dietary pattern score with methylation, we conducted analyses using robust linear regression models after the adjustment for age, pre-pregnancy body mass index, race/ethnicity, physical activity, total energy intakes, and population stratification. Genes annotating the top significant CpG sites (false discovery rate (FDR) adjusted P<0.05) were queried for enrichment of functional pathways using the Ingenuity Pathway Analysis tool. Results: Adherence to aHEI was significantly associated with methylation of 8 CpG sites, with the most significant association manifested in cg16724319- MDH1B (P=1.9x10 -10 ). Adherence to aMED was related to methylation of 14 CpG sites, with the most significant association manifested in cg07835181- CLCN7 (P=1.7x10 -11 ). DASH was significantly related to 33 CpG sites, with the most significant association manifested in cg26292547- REV3L (P=4.4x10 -10 ). Further, genes annotating the significant CpG sites were enriched in pathways related to cardiovascular and nervous system development and function, cancer, organismal injury and abnormalities, and reproductive system diseases. Conclusion: Findings from the epigenome wide study suggest that overall dietary quality in pregnancy is associated with placental DNA methylation changes at different loci potentially related to cardiovascular, neurological, reproductive, and cancer phenotypes.

scholarly journals Structural insights into CpG-specific DNA methylation by human DNA methyltransferase 3B

2020 ◽  
Vol 48 (7) ◽  
pp. 3949-3961 ◽  
Author(s):  
Chien-Chu Lin ◽  
Yi-Ping Chen ◽  
Wei-Zen Yang ◽  
James C K Shen ◽  
Hanna S Yuan
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Cytosine Methylation ◽  
Catalytic Domain ◽  
De Novo ◽  
Water Channel ◽  
Dna Methyltransferases ◽  
Structural Basis ◽  
Cpg Sites ◽  
Methylation Patterns

Abstract DNA methyltransferases are primary enzymes for cytosine methylation at CpG sites of epigenetic gene regulation in mammals. De novo methyltransferases DNMT3A and DNMT3B create DNA methylation patterns during development, but how they differentially implement genomic DNA methylation patterns is poorly understood. Here, we report crystal structures of the catalytic domain of human DNMT3B–3L complex, noncovalently bound with and without DNA of different sequences. Human DNMT3B uses two flexible loops to enclose DNA and employs its catalytic loop to flip out the cytosine base. As opposed to DNMT3A, DNMT3B specifically recognizes DNA with CpGpG sites via residues Asn779 and Lys777 in its more stable and well-ordered target recognition domain loop to facilitate processive methylation of tandemly repeated CpG sites. We also identify a proton wire water channel for the final deprotonation step, revealing the complete working mechanism for cytosine methylation by DNMT3B and providing the structural basis for DNMT3B mutation-induced hypomethylation in immunodeficiency, centromere instability and facial anomalies syndrome.

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