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

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

Environmental Epigenetics ◽

10.1093/eep/dvaa021 ◽

2020 ◽

Vol 6 (1) ◽

Author(s):

Carolyn F McCabe ◽

Vasantha Padmanabhan ◽

Dana C Dolinoy ◽

Steven E Domino ◽

Tamara R Jones ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Disease Risk ◽

Estimation Algorithm ◽

First Trimester ◽

Type I ◽

Environmental Toxicants ◽

Cell Type ◽

Bisphenol S ◽

Blood Leukocytes

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

ISEE Conference Abstracts ◽

10.1289/isee.2021.o-lt-091 ◽

2021 ◽

Vol 2021 (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 ◽

Association Study ◽

Metal Exposure

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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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Maternal levels of endocrine disrupting chemicals in the first trimester of pregnancy are associated with infant cord blood DNA methylation

Epigenetics ◽

10.1080/15592294.2018.1448680 ◽

2018 ◽

Vol 13 (3) ◽

pp. 301-309 ◽

Cited By ~ 20

Author(s):

Luke Montrose ◽

Vasantha Padmanabhan ◽

Jaclyn M. Goodrich ◽

Steven E. Domino ◽

Marjorie C. Treadwell ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Endocrine Disrupting Chemicals ◽

First Trimester ◽

Endocrine Disrupting ◽

First Trimester Of Pregnancy

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Maternal Vitamin D and Newborn Telomere Length

Nutrients ◽

10.3390/nu13062012 ◽

2021 ◽

Vol 13 (6) ◽

pp. 2012

Author(s):

Lisa Daneels ◽

Dries S. Martens ◽

Soumia Arredouani ◽

Jaak Billen ◽

Gudrun Koppen ◽

...

Keyword(s):

Vitamin D ◽

Cord Blood ◽

Telomere Length ◽

First Trimester ◽

Maternal Serum ◽

Adverse Outcomes ◽

Dietary Vitamin ◽

Maternal Vitamin ◽

Vitamin D Intake ◽

Diet Supplements

Nutrition is important during pregnancy for offspring health. Gestational vitamin D intake may prevent several adverse outcomes and might have an influence on offspring telomere length (TL). In this study, we want to assess the association between maternal vitamin D intake during pregnancy and newborn TL, as reflected by cord blood TL. We studied mother–child pairs enrolled in the Maternal Nutrition and Offspring’s Epigenome (MANOE) cohort, Leuven, Belgium. To calculate the dietary vitamin D intake, 108 women were asked to keep track of their diet using the seven-day estimated diet record (EDR) method. TL was assessed in 108 cord blood using a quantitative real-time PCR method. In each trimester of pregnancy, maternal serum 25-hydroxyvitamin D (25-OHD) concentration was measured. We observed a positive association (β = 0.009, p-value = 0.036) between newborn average relative TL and maternal vitamin D intake (diet + supplement) during the first trimester. In contrast, we found no association between average relative TL of the newborn and mean maternal serum 25-OHD concentrations during pregnancy. To conclude, vitamin D intake (diet + supplements), specifically during the first trimester of pregnancy, is an important factor associated with TL at birth.

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Birthweight DNA methylation signatures in infant saliva

Clinical Epigenetics ◽

10.1186/s13148-021-01053-1 ◽

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.

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Associations of circulating folate, vitamin B12 and homocysteine concentrations in early pregnancy and cord blood with epigenetic gestational age: the Generation R Study

Clinical Epigenetics ◽

10.1186/s13148-021-01065-x ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Giulietta S. Monasso ◽

Leanne K. Küpers ◽

Vincent W. V. Jaddoe ◽

Sandra G. Heil ◽

Janine F. Felix

Keyword(s):

Dna Methylation ◽

Vitamin B12 ◽

Cord Blood ◽

Gestational Age ◽

Fetal Development ◽

Maternal Plasma ◽

Plasma Homocysteine ◽

Training Population ◽

Epigenetic Aging ◽

Pregnancy Dating

Abstract Background Circulating folate, vitamin B12 and homocysteine concentrations during fetal development have been associated with health outcomes in childhood. Changes in fetal DNA methylation may be an underlying mechanism. This may be reflected in altered epigenetic aging of the fetus, as compared to chronological aging. The difference between gestational age derived in clinical practice and gestational age predicted from neonatal DNA methylation data is referred to as gestational age acceleration. Differences in circulating folate, vitamin B12 and homocysteine concentrations during fetal development may be associated with gestational age acceleration. Results Up to 1346 newborns participating in the Generation R Study, a population-based prospective cohort study, had both cord blood DNA methylation data available and information on plasma folate, serum total and active B12 and plasma homocysteine concentrations, measured in early pregnancy and/or in cord blood. A subgroup of 380 newborns had mothers with optimal pregnancy dating based on a regular menstrual cycle and a known date of last menstrual period. For comparison, gestational age acceleration was calculated based the method of both Bohlin and Knight. In the total study population, which was more similar to Bohlin’s training population, one standard deviation score (SDS) higher maternal plasma homocysteine concentrations was nominally associated with positive gestational age acceleration [0.07 weeks, 95% confidence interval (CI) 0.02, 0.13] by Bohlin’s method. In the subgroup with pregnancy dating based on last menstrual period, the method that was also used in Knight’s training population, one SDS higher cord serum total and active B12 concentrations were nominally associated with negative gestational age acceleration [(− 0.16 weeks, 95% CI − 0.30, − 0.02) and (− 0.15 weeks, 95% CI − 0.29, − 0.01), respectively] by Knight’s method. Conclusions We found some evidence to support associations of higher maternal plasma homocysteine concentrations with positive gestational age acceleration, suggesting faster epigenetic than clinical gestational aging. Cord serum vitamin B12 concentrations may be associated with negative gestational age acceleration, indicating slower epigenetic than clinical gestational aging. Future studies could examine whether altered fetal epigenetic aging underlies the associations of circulating homocysteine and vitamin B12 blood concentrations during fetal development with long-term health outcomes.

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Plasma mineral (selenium, zinc or copper) concentrations in the general pregnant population, adjusted for supplement intake, in relation to thyroid function

British Journal Of Nutrition ◽

10.1017/s000711452000255x ◽

2020 ◽

Vol 125 (1) ◽

pp. 71-78

Author(s):

Victor Pop ◽

Johannes Krabbe ◽

Wolfgang Maret ◽

Margaret Rayman

Keyword(s):

Thyroid Function ◽

Reference Range ◽

First Trimester ◽

Future Research ◽

Thyroid Peroxidase ◽

Reference Ranges ◽

Lower Plasma ◽

The Mean ◽

The Impact ◽

Supplement Intake

AbstractThe present study reports on first-trimester reference ranges of plasma mineral Se/Zn/Cu concentration in relation to free thyroxine (FT4), thyrotropin (TSH) and thyroid peroxidase antibodies (TPO-Ab), assessed at 12 weeks’ gestation in 2041 pregnant women, including 544 women not taking supplements containing Se/Zn/Cu. The reference range (2·5th–97·5th percentiles) in these 544 women was 0·72–1·25 µmol/l for Se, 17·15–35·98 µmol/l for Cu and 9·57–16·41 µmol/l for Zn. These women had significantly lower mean plasma Se concentration (0·94 (sd 0·12) µmol/l) than those (n 1479) taking Se/Zn/Cu supplements (1·03 (sd 0·14) µmol/l; P < 0·001), while the mean Cu (26·25 µmol/l) and Zn (12·55 µmol/l) concentrations were almost identical in these sub-groups. Women with hypothyroxinaemia (FT4 below reference range with normal TSH) had significantly lower plasma Zn concentrations than euthyroid women. After adjusting for covariates including supplement intake, plasma Se (negatively), Zn and Cu (positively) concentrations were significantly related to logFT4; Se and Cu (but not Zn) were positively and significantly related to logTSH. Women taking additional Se/Zn/Cu supplements were 1·46 (95 % CI 1·09, 2·04) times less likely to have elevated titres of TPO-Ab at 12 weeks of gestation. We conclude that first-trimester Se reference ranges are influenced by Se-supplement intake, while Cu and Zn ranges are not. Plasma mineral Se/Zn/Cu concentrations are associated with thyroid FT4 and TSH concentrations. Se/Zn/Cu supplement intake affects TPO-Ab status. Future research should focus on the impact of trace mineral status during gestation on thyroid function.

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Human Leukocyte Antigen and Red Blood Cells Impact Umbilical Cord Blood CD34+ Cell Viability after Thawing

International Journal of Molecular Sciences ◽

10.3390/ijms20194875 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4875 ◽

Cited By ~ 1

Author(s):

Vanegas ◽

Galindo ◽

Páez-Gutiérrez ◽

González-Acero ◽

Medina-Valderrama ◽

...

Keyword(s):

Human Leukocyte Antigen ◽

Cell Viability ◽

Cord Blood ◽

Red Blood Cells ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Blood Cells ◽

Human Leukocyte ◽

Hla Typing ◽

Leukocyte Antigen

Hematopoietic progenitor cell (HPC) transplantation is a treatment option for malignant and nonmalignant diseases. Umbilical cord blood (UCB) is an important HPC source, mainly for pediatric patients. It has been demonstrated that human leukocyte antigen (HLA) matching and cell dose are the most important features impacting clinical outcomes. However, UCB matching is performed using low resolution HLA typing and it has been demonstrated that the unnoticed mismatches negatively impact the transplant. Since we found differences in CD34+ viability after thawing of UCB units matched for two different patients (p = 0.05), we presumed a possible association between CD34+ cell viability and HLA. We performed a multivariate linear model (n = 67), comprising pre-cryopreservation variables and high resolution HLA genotypes separately. We found that pre-cryopreservation red blood cells (RBC), granulocytes, and viable CD34+ cell count significantly impacted CD34+ viability after thawing, along with HLA-B or -C (R2 = 0.95, p = 0.01; R2 = 0.56, p = 0.007, respectively). Although HLA-B*40:02 may have a negative impact on CD34+ cell viability, RBC depletion significantly improves it.

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