DNA methylation in cord blood as mediator of the association between prenatal arsenic exposure and gestational age

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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Replicated umbilical cord blood DNA methylation loci associated with gestational age at birth

Epigenetics ◽

10.1080/15592294.2020.1767277 ◽

2020 ◽

Vol 15 (11) ◽

pp. 1243-1258 ◽

Cited By ~ 1

Author(s):

Timothy P. York ◽

Shawn J. Latendresse ◽

Colleen Jackson-Cook ◽

Dana M. Lapato ◽

Sara Moyer ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Gestational Age ◽

Gestational Age At Birth ◽

Age At Birth

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Prenatal lead exposure and cord blood DNA methylation in PROGRESS: an epigenome-wide association study

Environmental Epigenetics ◽

10.1093/eep/dvaa014 ◽

2020 ◽

Vol 6 (1) ◽

Author(s):

Jonathan A Heiss ◽

Martha M Téllez-Rojo ◽

Guadalupe Estrada-Gutiérrez ◽

Lourdes Schnaas ◽

Chitra Amarasiriwardena ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Gestational Age ◽

Lead Exposure ◽

Inductively Coupled Plasma ◽

Maternal Education ◽

Association Studies ◽

Mode Of Delivery ◽

Underlying Mechanisms ◽

Prenatal Lead Exposure

Abstract The effects of prenatal lead exposure on child development include impaired growth and cognitive function. DNA methylation might be involved in the underlying mechanisms and previous epigenome-wide association studies reported associations between lead exposure during pregnancy and cord blood methylation levels. However, it is unclear during which developmental stage lead exposure is most harmful. Cord blood methylation levels were assayed in 420 children from a Mexican pre-birth cohort using the Illumina Infinium MethylationEPIC microarray. Lead concentrations were measured in umbilical cord blood as well as in blood samples from the mothers collected at 2nd and 3rd trimester and delivery using inductively coupled plasma-mass spectrometry. In addition, maternal bone lead levels were measured in tibia and patella using X-ray fluorescence. Comprehensive quality control and preprocessing of microarray data was followed by an unbiased restriction to methylation sites with substantial variance. Methylation levels at 202 111 cytosine-phosphate-guanine sites were regressed on each exposure adjusting for child sex, leukocyte composition, batch variables, gestational age, birthweight-for-gestational-age, maternal age, maternal education and mode of delivery. We find no association between prenatal lead exposure and cord blood methylation. This null result is strengthened by a sensitivity analysis showing that in the same dataset known biomarkers for birthweight-for-gestational-age can be recovered and the fact that phenotypic associations with lead exposure have been described in the same cohort.

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Differential DNA methylation profile in infants born small-for-gestational-age: association with markers of adiposity and insulin resistance from birth to age 24 months

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001402 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001402

Author(s):

Marta Diaz ◽

Edurne Garde ◽

Abel Lopez-Bermejo ◽

Francis de Zegher ◽

Lourdes Ibañez

Keyword(s):

Insulin Resistance ◽

Dna Methylation ◽

Body Composition ◽

Cord Blood ◽

Gestational Age ◽

Small For Gestational Age ◽

Diabetes Risk ◽

Metabolic Dysfunction ◽

A Genome ◽

Methylation Profiling

IntroductionPrenatal growth restraint followed by rapid postnatal weight gain increases lifelong diabetes risk. Epigenetic dysregulation in critical windows could exert long-term effects on metabolism and confer such risk.Research design and methodsWe conducted a genome-wide DNA methylation profiling in peripheral blood from infants born appropriate-for-gestational-age (AGA, n=30) or small-for-gestational-age (SGA, n=21, with postnatal catch-up) at age 12 months, to identify new genes that may predispose to metabolic dysfunction. Candidate genes were validated by bisulfite pyrosequencing in the entire cohort. All infants were followed since birth; cord blood methylation profiling was previously reported. Endocrine-metabolic variables and body composition (dual-energy X-ray absorptiometry) were assessed at birth and at 12 and 24 months.ResultsGPR120 (cg14582356, cg01272400, cg23654127, cg03629447), NKX6.1 (cg22598426, cg07688460, cg17444738, cg12076463, cg10457539), CPT1A (cg14073497, cg00941258, cg12778395) and IGFBP 4 (cg15471812) genes were hypermethylated (GPR120, NKX6.1 were also hypermethylated in cord blood), whereas CHGA (cg13332653, cg15480367, cg05700406), FABP5 (cg00696973, cg10563714, cg16128701), CTRP1 (cg19231170, cg19472078, cg0164309, cg07162665, cg17758081, cg18996910, cg06709009), GAS6 (N/A), ONECUT1 (cg14217069, cg02061705, cg26158897, cg06657050, cg15446043) and SLC2A8 (cg20758474, cg19021975, cg11312566, cg12281690, cg04016166, cg03804985) genes were hypomethylated in SGA infants. These genes were related to β-cell development and function, inflammation, and glucose and lipid metabolism and associated with body mass index, body composition, and markers of insulin resistance at 12 and 24 months.ConclusionIn conclusion, at 12 months, abnormal methylation of GPR120 and NKX6.1 persists and new epigenetic marks further involved in adipogenesis and energy homeostasis arise in SGA infants. These abnormalities may contribute to metabolic dysfunction and diabetes risk later in life.

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Cord blood DNA methylation of DNMT3A mediates the association between in utero arsenic exposure and birth outcomes: Results from a prospective birth cohort in Bangladesh

Environmental Research ◽

10.1016/j.envres.2020.109134 ◽

2020 ◽

Vol 183 ◽

pp. 109134

Author(s):

Anne K. Bozack ◽

Andres Cardenas ◽

John Geldhof ◽

Quazi Quamruzzaman ◽

Mahmuder Rahman ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Birth Cohort ◽

Birth Outcomes ◽

Arsenic Exposure ◽

In Utero ◽

Prospective Birth Cohort

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Influence Of Prenatal Mercury And Arsenic Exposure In Utero On Dna Methylation In Umbilical Cord Blood

ISEE Conference Abstracts ◽

10.1289/isee.2015.2015-703 ◽

2015 ◽

Vol 2015 (1) ◽

pp. 703

Author(s):

Andres Cardenas ◽

Devin C. Koestler ◽

E. Andres Houseman ◽

Brian P. Jackson ◽

Molly L. Kile ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Arsenic Exposure ◽

In Utero

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

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174414000221 ◽

2014 ◽

Vol 5 (4) ◽

pp. 288-298 ◽

Cited By ~ 91

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.

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Epigenome-wide contributions to individual differences in childhood phenotypes: A GREML approach

10.1101/2021.06.24.21259449 ◽

2021 ◽

Author(s):

Alexander Neumann ◽

Jean-Baptiste Pingault ◽

Janine F. Felix ◽

Vincent W. V. Jaddoe ◽

Henning Tiemeier ◽

...

Keyword(s):

Dna Methylation ◽

Birth Weight ◽

Cord Blood ◽

Gestational Age ◽

Cross Validation ◽

Epigenetic Mechanism ◽

School Age ◽

Adhd Symptoms ◽

Cpg Sites ◽

Variance Explained

Background: DNA methylation is an epigenetic mechanism involved in human development. Numerous epigenome-wide association studies (EWAS) have investigated the associations of DNA methylation at single CpG sites with childhood outcomes. However, the overall contribution of DNA methylation across the genome (R2Methylation) towards childhood phenotypes is unknown. An estimate of R2Methylation would provide context regarding the importance of DNA methylation explaining variance in health outcomes. Methods: We estimated the variance explained by epigenome-wide cord blood methylation (R2Methylation) for five childhood phenotypes: gestational age, birth weight, and body mass index (BMI), IQ and ADHD symptoms at school age. We adapted a genome-based restricted maximum likelihood (GREML) approach with cross-validation (CV) to DNA methylation data and applied it in two population-based birth cohorts: ALSPAC (n=775) and Generation R (n=1382). Results: Using information from >470,000 autosomal probes we estimated that DNA methylation at birth explains 45% (SDCV = 0.07) of gestational age variance and 16% (SDCV = 0.05) of birth weight variance. The R2Methylation estimates for BMI, IQ and ADHD symptoms at school age estimates were near 0% across almost all cross-validation iterations. Conclusions: The results suggest that cord blood methylation explains a moderate to large degree of variance in gestational age and birth weight, in line with the success of previous EWAS in identifying numerous CpG sites associated with these phenotypes. In contrast, we could not obtain a reliable estimate for school-age BMI, IQ and ADHD symptoms. This may reflect a null bias due to insufficient sample size to detect variance explained in more weakly associated phenotypes, although the true R2Methylation for these phenotypes is likely below that of gestational age and birth weight when using DNA methylation at birth.

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