Maternal Methylation Research Articles

Maternal and paternal dietary quality, dietary inflammation status, and offspring DNA methylation

Abstract Background Altered nutritional conditions at early life stages may increase the risk of future disease in offspring. Recent evidence suggests that developmental programming may involve epigenetic mechanisms. However, few studies have evaluated the effect of parental dietary quality on offspring DNA methylation. We investigated the relationships between dietary quality and inflammatory potential of future parents and DNA methylation of their children at nine years. Methods We used data from the Lifeways Cross-Generation cohort, established between 2001 and 2003 in the Republic of Ireland. Maternal dietary intake during the first trimester and paternal diet of the 12 previous months were assessed with a food-frequency questionnaire. Dietary quality and inflammation were determined by the healthy eating index (HEI) 2015 score and the energy-adjusted dietary inflammation index (E-DII), respectively. The Illumina Infinium HumanMethylationEPIC (EPIC array) assessed methylation levels in saliva samples from 264 children. Dietary associations with DNA methylation at individual CpG sites were examined. Results After adjusting for multiple tests, maternal HEI-2015 scores were inversely associated with DNA methylation at 1 CpG site (cg21840035, p-value=5.5 × 10-8) located near the PLEKHM1 gene, whose functions involve regulation of bone development. An increase in paternal HEI score was related to lower methylation at one CpG site (cg22431767, p-value=4.1× 10-8) located near cell signaling gene LUZP1. No significant associations between maternal or paternal E-DII and DNA methylation at individual CpG sites were observed. Conclusions Parental dietary quality in the prenatal period may influence offspring childhood DNA methylation. A better understanding of the nutritional programming effects on epigenetic markers is essential to design public health strategies that could help women to achieve a healthier diet and optimize the health capital of children and future generations. Key messages Our findings suggest that both maternal and paternal dietary quality may have a long-term influence on the offspring epigenome, expand the current understanding of parental nutritional programming. Replication in other populations with contrasted dietary intake is warranted, with a view to informing public health recommendations to benefit the health of future generations.

Prenatal arsenic exposure, arsenic methylation efficiency, and neuropsychological development among preschool children in a Spanish birth cohort

BackgroundPrenatal arsenic (As) exposure could negatively affect child neuropsychological development, but the current evidence is inconclusive. ObjectivesTo explore the relationship between prenatal urinary total As (TAs) concentrations, the As species and the methylation efficiency, and child neuropsychological development in a Spanish birth cohort. We also studied the effect modification produced by sex and several nutrients and elements. Materials and methodsStudy subjects were 807 mother–child pairs participating in the INMA (Childhood and Environment) Project. Urinary TAs and its metabolites, monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), inorganic As (iAs) and arsenobetaine were measured in the first trimester of pregnancy. Methylation efficiency was determined through the percentages of the metabolites and using principal component analysis. Children's neuropsychological development was assessed at the age of 4–5 years using the McCarthy Scales of Children's Abilities (MSCA). Multivariable linear regression models were built to assess the association between TAs, the As species and the maternal methylation efficiency, and the neuropsychological scores. We explored effect modification by sex, iron status, maternal nutrients status (serum manganese and selenium, and urinary zinc), and maternal vitamins intake (folate, and vitamins B12 and B6). ResultsThe geometric mean (95%CI) of ∑As (sum of DMA, MMA and iAs) was 7.78 (7.41, 8.17) μg/g creatinine. MMA concentrations were inversely associated with the scores for the general, verbal, quantitative, memory, executive function and working memory scales (i.e. β [CI95%] = −1.37 [-2.33, −0.41] for the general scale). An inverse association between %MMA and the memory scores was found. Children whose mothers had lower manganese, zinc and ferritin concentrations obtained lower scores on several MSCA scales with decreasing As methylation efficiency. DiscussionAn inverse association was observed between MMA concentrations and children's neuropsychological development. Maternal levels of manganese, zinc and ferritin affected the association between As methylation efficiency and MSCA scores.

Epigenetic Modifications Associated with Maternal Anxiety during Pregnancy and Children's Behavioral Measures.

Epigenetic changes are associated with altered behavior and neuropsychiatric disorders and they modify the trajectory of aging. Maternal anxiety during pregnancy is a common environmental challenge for the fetus, causing changes in DNA methylation. Here, we determined the mediating role of DNA methylation and the moderating role of offspring sex on the association between maternal anxiety and children’s behavioral measures. In 83 mother–child dyads, maternal anxiety was assessed in each trimester of pregnancy when the child was four years of age. Children’s behavioral measures and children’s buccal DNA methylation levels (NR3C1, IGF2/H19 ICR, and LINE1) were examined. Higher maternal anxiety during the third trimester was associated with more methylation levels of the NR3C1. Moderating effects of sex on the association between maternal anxiety and methylation were found for IGF2/H19 and LINE1 CpGs. Mediation analysis showed that methylation of NR3C1 could buffer the effects of maternal anxiety on children’s behavioral measures, but this effect did not remain significant after controlling for covariates. In conclusion, our data support an association between maternal anxiety during pregnancy and DNA methylation. The results also underscore the importance of sex differences and timing effects. However, DNA methylation as underlying mechanism of the effect of maternal anxiety during pregnancy on offspring’s behavioral measures was not supported.

Whole-Genome Methylation Analysis Revealed ART-Specific DNA Methylation Pattern of Neuro- and Immune-System Pathways in Chinese Human Neonates.

The DNA methylation of human offspring can change due to the use of assisted reproductive technology (ART). In order to find the differentially methylated regions (DMRs) in ART newborns, cord blood maternal cell contamination and parent DNA methylation background, which will add noise to the real difference, must be removed. We analyzed newborns’ heel blood from six families to identify the DMRs between ART and natural pregnancy newborns, and the genetic model of methylation was explored, meanwhile we analyzed 32 samples of umbilical cord blood of infants born with ART and those of normal pregnancy to confirm which differences are consistent with cord blood data. The DNA methylation level was lower in ART-assisted offspring at the whole genome-wide level. Differentially methylated sites, DMRs, and cord blood differentially expressed genes were enriched in the important pathways of the immune system and nervous system, the genetic patterns of DNA methylation could be changed in the ART group. A total of three imprinted genes and 28 housekeeping genes which were involved in the nervous and immune systems were significant different between the two groups, six of them were detected both in heel blood and cord blood. We concluded that there is an ART-specific DNA methylation pattern involved in neuro- and immune-system pathways of human ART neonates, providing an epigenetic basis for the potential long-term health risks in ART-conceived neonates.

1455Leveraging multi-omic negative controls for effect estimation in molecular epidemiologic studies: A simulation study

Abstract Background Exploratory null-hypothesis significance testing (e.g. GWAS, EWAS) form the backbone of molecular epidemiology, however methods to identify true causal signals are underdeveloped. Via plasmode simulation, I evaluate two approaches to quantitatively control for shared unmeasured confounding and recover unbiased effects using complementary epigenomes and biologically-informed structural assumptions. Methods I adapt proposed negative control-based estimators, the control outcome calibration approach (COCA) and proximal g-computation (PG) to case studies in perinatal molecular epidemiology. COCA may be employed when maternal epigenome has no direct effects on phenotype and proxy shared unmeasured confounders and PG further with suitable genetic instruments (e.g. mQTLs). Baseline covariates were extracted from 777 mother-child pairs in a birth cohort with maternal blood and fetal cord DNA methylation array data. Treatment and outcome values were simulated in 2000 bootstraps. Bootstrapped, ordinary (COCA) and 2-stage (PG) least squares were fitted to estimate treatment effects and standard errors under various common settings of missing confounders (e.g. paternal data). Doubly-robust, machine learning estimators were explored. Results COCA and PG performed well in simplistic data generating processes. However, in real-world cohort simulations, COCA performed acceptably only in settings with strong proxy confounders, but otherwise poorly (median bias 610%; coverage 29%). PG performed slightly better. Alternatively, simple covariate adjustment for maternal methylation outperformed (median bias 22%; 71% coverage) COCA, PG, and machine learning estimators. Discussion Molecular epidemiology provides key opportunity to leverage biological knowledge against unmeasured confounding. Negative control calibration or adjustments may help under limited scenarios where assumptions are fulfilled, but should be tested with suitable simulations. Key messages Quantitative approaches for unmeasured confounding in molecular epidemiology are a critical gap. Negative control calibration or adjustment may help under limiting scenarios. Proposed estimators should be tested in simulation settings that closely mimic target data.

Early-pregnancy maternal body mass index is associated with common DNA methylation markers in cord blood and placenta: a paired-tissue epigenome-wide association study

ABSTRACT Women entering pregnancy with elevated body mass index (BMI) face greater risk of adverse outcomes during pregnancy, delivery, and for their offspring later in life, potentially via epigenetics. If epigenetic programming occurs early during in utero development, the differential marks should be detectable in multiple tissues despite the known unique epigenetic profile in each. We used early-pregnancy BMI as reflection of maternal metabolic milieu exposure in peri-conception and early-pregnancy period. We analysed DNA methylation in paired cord blood and placenta samples among 437 newborns from Gen3G, a pre-birth prospective cohort of primarily European descent. We measured DNA methylation in both tissues across the genome in >720,000 CpG sites using the Illumina MethylationEPIC array. At each site, we used linear mixed models (LMMs) with an unstructured variance-covariance matrix to test for an association between maternal early-pregnancy BMI and DNA methylation in both tissues (modelled as M-values). We adjusted for tissue-specific covariates, offspring sex, gestational age at delivery, and maternal smoking and age. Women had a mean (SD) BMI of 25.4 (5.7) kg/m2 measured at first trimester visit (mean=9.9 weeks). Early-pregnancy BMI was associated with differential DNA methylation levels in paired-tissue analyses at two sites: cg10593758 (β=0.0126, SE=0.0025; P=4.07e-7), annotated to CRHBP, and cg0762168 (β=−0.0094, SE=0.0018; P=2.78e-7), annotated to CCDC97. Application of LMMs in DNA methylation data from distinct fetal-origin tissues allowed us to identify CpG sites at which early-pregnancy BMI may have an epigenetic ‘programming’ effect on overall fetus development. One site (CRHBP) may play a role in hypothalamic-pituitary-adrenal axis regulation.

Placental DNA methylation marks are associated with maternal depressive symptoms during early pregnancy

Maternal depressive symptoms during pregnancy are a significant risk factor for adverse developmental and health outcomes of the offspring. The molecular mechanisms mediating the long-term effects of this exposure are not well understood. Previous studies have found association between prenatal exposure to maternal psychological distress and placental DNA methylation of candidate genes, which can influence placental barrier function and development of the fetus. Our objective in this study was to determine epigenome wide association of maternal depressive symptoms in early pregnancy with the placental DNA methylation. For this purpose we examined DNA methylomes of 92 placental samples by using reduced representation bisulfite sequencing. The placental samples were collected after deliveries of 39 girls and 59 boys, whose mothers had Edinburgh Postnatal Depression Score ranging from 0 to 19 at gestational week 14. According to our results maternal depressive symptoms are associated with DNA methylation of 2833 CpG sites, which are particularly over-represented in genic enhancers. The genes overlapping or nearest to these sites are functionally enriched for development of neurons and show expression enrichment in several regions of developing brain. The genomic regions harboring the DNA methylation marks are enriched for single nucleotide polymorphisms associated with mental disease trait class. Potential cellular signaling cascades mediating the effects include inflammatory and hormonal pathways. As a conclusion our results suggest that maternal depressive symptoms during early pregnancy are associated with DNA methylation marks in placenta in genes, which are important for the development and long-term health of the brain. Whether similar marks can be detected in exposed children remains to be elucidated in further studies.

Maternal Folic Acid Intake and Methylation Status of Genes Associated with Ventricular Septal Defects in Children: Case-Control Study.

Background: DNA methylation is the best epigenetic mechanism for explaining the interactions between nutrients and genes involved in intrauterine growth and development programming. A possible contributor of methylation abnormalities to congenital heart disease is the folate methylation regulatory pathway; however, the mechanisms and methylation patterns of VSD-associated genes are not fully understood. Objective: To determine if maternal dietary intake of folic acid (FA) is related to the methylation status (MS) of VSD-associated genes (AXIN1, MTHFR, TBX1, and TBX20). Methods: Prospective case–control study; 48 mothers and their children were evaluated. The mothers’ dietary variables were collected through a food frequency questionnaire focusing on FA and the consumption of supplements with FA. The MS of promoters of genes was determined in the children. Results: The intake of FA supplements was significantly higher in the control mothers. In terms of maternal folic acid consumption, significant differences were found in the first trimester of pregnancy. Significant differences were observed in the MS of MTHFR and AXIN1 genes in VSD and control children. A correlation between maternal FA supplementation and MS of AXIN1 and TBX20 genes was found in control and VSD children, respectively. Conclusions: A lower MS of AXIN1 genes and a higher MS of TBX20 genes is associated with FA maternal supplementation.

Epigenome-Wide Association Study Reveals Methylation Loci Associated With Offspring Gestational Diabetes Mellitus Exposure and Maternal Methylome.

OBJECTIVEGestational diabetes mellitus (GDM) is associated with an increased risk of obesity and insulin resistance in offspring later in life, which might be explained by epigenetic changes in response to maternal hyperglycemic exposure.RESEARCH DESIGN AND METHODSWe explored the association between GDM exposure and maternal blood and newborn cord blood methylation in 536 mother-offspring pairs from the prospective FinnGeDi cohort using Illumina MethylationEPIC 850K BeadChip arrays. We assessed two hypotheses. First, we tested for shared maternal and offspring epigenetic effects resulting from GDM exposure. Second, we tested whether GDM exposure and maternal methylation had an epigenetic effect on the offspring.RESULTSWe did not find any epigenetic marks (differentially methylated CpG probes) with shared and consistent effects between mothers and offspring. After including maternal methylation in the model, we identified a single significant (false discovery rate 1.38 × 10−2) CpG at the cg22790973 probe (TFCP2) associated with GDM. We identified seven additional FDR-significant interactions of maternal methylation and GDM status, with the strongest association at the same cg22790973 probe (TFCP2), as well as cg03456133, cg24440941 (H3C6), cg20002843 (LOC127841), cg19107264, and cg11493553 located within the UBE3C gene and cg17065901 in FAM13A, both susceptibility genes for type 2 diabetes and BMI, and cg23355087 within the DLGAP2 gene, known to be involved in insulin resistance during pregnancy.CONCLUSIONSOur study reveals the potential complexity of the epigenetic transmission between mothers with GDM and their offspring, likely determined by not only GDM exposure but also other factors indicated by maternal epigenetic status, such as maternal metabolic history.

Prenatal Bisphenol a Exposure, DNA Methylation, and Low Birth Weight: A Pilot Study in Taiwan.

Prenatal exposure to bisphenol A (BPA) may increase the risk of abnormal birth outcomes, and DNA methylation might mediate these adverse effects. This study aimed to investigate the effects of maternal BPA exposure on maternal and fetal DNA methylation levels and explore whether epigenetic changes are related to the associations between BPA and low birth weight. We collected urine and blood samples originating from 162 mother-infant pairs in a Taiwanese cohort study. We measured DNA methylation using the Illumina Infinium HumanMethylation 450 BeadChip in 34 maternal blood samples with high and low BPA levels based on the 75th percentile level (9.5 μg/g creatinine). Eighty-seven CpGs with the most differentially methylated probes possibly interacting with BPA exposure or birth weight were selected using two multiple regression models. Ingenuity pathway analysis (IPA) was utilized to narrow down 18 candidate CpGs related to disease categories, including developmental disorders, skeletal and muscular disorders, skeletal and muscular system development, metabolic diseases, and lipid metabolism. We then validated these genes by pyrosequencing, and 8 CpGs met the primer design score requirements in 82 cord blood samples. The associations among low birth weight, BPA exposure, and DNA methylation were analyzed. Exposure to BPA was associated with low birth weight. Analysis of the epigenome-wide findings did not show significant associations between BPA and DNA methylation in cord blood of the 8 CpGs. However, the adjusted odds ratio for the dehydrogenase/reductase member 9 (DHRS9) gene, at the 2nd CG site, in the hypermethylated group was significantly associated with low birth weight. These results support a role of BPA, and possibly DHRS9 methylation, in fetal growth. However, additional studies with larger sample sizes are warranted.

Pregnancy Induces an Immunological Memory Characterized by Maternal Immune Alterations Through Specific Genes Methylation.

During pregnancy, the maternal immune system undergoes major adaptive modifications that are necessary for the acceptance and protection of the fetus. It has been postulated that these modifications are temporary and limited to the time of pregnancy. Growing evidence suggests that pregnancy has a long-term impact on maternal health, especially among women with pregnancy complications, such as preeclampsia (PE). In addition, the presence of multiple immunological-associated changes in women that remain long after delivery has been reported. To explain these long-term modifications, we hypothesized that pregnancy induces long-term immunological memory with effects on maternal well-being. To test this hypothesis, we evaluated the immunological phenotype of circulating immune cells in women at least 1 year after a normal pregnancy and after pregnancy complicated by PE. Using multiparameter flow cytometry (FCM) and whole-genome bisulfite sequencing (WGBS), we demonstrate that pregnancy has a long-term effect on the maternal immune cell populations and that this effect differs between normal pregnancy and pregnancy complicated by PE; furthermore, these modifications are due to changes in the maternal methylation status of genes that are associated with T cell and NK cell differentiation and function. We propose the existence of an “immunological memory of pregnancy (IMOP)” as an evolutionary advantage for the success of future pregnancies and the proper adaptation to the microchimeric status established during pregnancy. Our findings demonstrate that the type of immune cell populations modified during pregnancy may have an impact on subsequent pregnancy and future maternal health.

Maternal Caffeine Intake and DNA Methylation in Newborn Cord Blood

ObjectivesPrior research has suggested that epigenetic mechanisms may underly associations between maternal caffeine intake and adverse childhood metabolic outcomes. We examined preconception and early pregnancy maternal caffeine exposure with DNA methylation (DNAm) patterns in the cord blood of 378 neonates. MethodsDNAm was profiled by the Infinium MethylationEPIC BeadChip in women enrolled in the EAGeR Trial. Maternal serum was collected 1–2 cycles preconception and at 8 weeks gestation as was self-reported caffeinated beverage intake through standardized questionnaires or daily diaries. Serum caffeine, paraxanthine, and theobromine were measured by liquid chromatography mass spectrometry. We performed multivariable robust linear regression to assess associations between maternal caffeine and methylation β-values and Ingenuity Pathway Analysis to evaluate biologic implications. ResultsPreconceptionally, 65%, 21% and 7% reported any soda, coffee or tea intake, respectively with the majority consuming on average ≤ 1 serving/day. Preconception self-reported intake compared to no intake was associated with DNAm at cg09002832 near GLIS3 (false discovery rate [FDR] p = 0.036). No associations with self-reported intake were found during pregnancy. Preconception serum markers were not associated with individual CpG sites (FDR > 5%), though pregnancy theobromine (tertile 2 vs 1) was associated with DNAm at cg09460369 near RAB2A (FDR p = 0.012). Overlapping pathways for the top 100 CpG sites identified in the preconception intake and pregnancy theobromine analyses elucidated cell cycle and lipid metabolism processes. ConclusionsFew differences in DNAm were identified in association with maternal caffeine intake in this low consumption population. DNAm changes from preconception caffeine or pregnancy theobromine exposure may be linked to signaling networks involving lipid metabolism, but further research among women with higher caffeine and theobromine exposure is warranted. Funding SourcesEpidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

Folate and vitamin B12 status: associations with maternal glucose and neonatal DNA methylation sites related to dysglycaemia, in pregnant women with obesity.

Recent studies implicate maternal gestational diabetes mellitus (GDM) in differential methylation of infant DNA. Folate and vitamin B12 play a role in DNA methylation, and these vitamins may also influence GDM risk. The aims of this study were to determine folate and vitamin B12 status in obese pregnant women and investigate associations between folate and vitamin B12 status, maternal dysglycaemia and neonatal DNA methylation at cytosine-phosphate-guanine sites previously observed to be associated with dysglycaemia. Obese pregnant women who participated in the UK Pregnancies Better Eating and Activity Trial were included. Serum folate and vitamin B12 were measured at the oral glucose tolerance test (OGTT) visit. Cord blood DNA methylation was assessed using the Infinium MethylationEPIC BeadChip. Regression models with adjustment for confounders were used to examine associations. Of the 951 women included, 356 (37.4%) were vitamin B12 deficient, and 44 (4.6%) were folate deficient. Two-hundred and seventy-one women (28%) developed GDM. Folate and vitamin B12 concentrations were not associated with neonatal DNA methylation. Higher folate was positively associated with 1-h plasma glucose after OGTT (β = 0.031, 95% CI 0.001-0.061, p = 0.045). There was no relationship between vitamin B12 and glucose concentrations post OGTT or between folate or vitamin B12 and GDM. In summary, we found no evidence to link folate and vitamin B12 status with the differential methylation of neonatal DNA previously observed in association with dysglycaemia. We add to the evidence that folate status may be related to maternal glucose homoeostasis although replication in other maternal cohorts is required for validation.

DNA Methylation in Babies Born to Nonsmoking Mothers Exposed to Secondhand Smoke during Pregnancy: An Epigenome-Wide Association Study.

Background:Maternal smoking during pregnancy is related to altered DNA methylation in infant umbilical cord blood. The extent to which low levels of smoke exposure among nonsmoking pregnant women relates to offspring DNA methylation is unknown.Objective:This study sought to evaluate relationships between maternal prenatal plasma cotinine levels and DNA methylation in umbilical cord blood in newborns using the Infinium HumanMethylation 450K BeadChip.Methods:Participants from the Newborn Epigenetics Study cohort who reported not smoking during pregnancy had verified low levels of cotinine from maternal prenatal plasma (0 to ), and offspring epigenetic data from umbilical cord blood were included in this study (). Multivariable linear regression models were fit to the data, controlling for cell proportions, age, race, education, and parity. Estimates represent changes in response to any unit increase in exposure. Results:Multivariable linear regression models yielded 29,049 CpGs that were differentially methylated in relation to increases in cotinine at a 5% false discovery rate. Top CpGs were within or near genes involved in neuronal functioning (PRKG1, DLGAP2, BSG), carcinogenesis (FHIT, HSPC157) and inflammation (AGER). Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggest cotinine was related to methylation of gene pathways controlling neuronal signaling, metabolic regulation, cell signaling and regulation, and cancer. Further, enhancers associated with transcription start sites were enriched in altered CpGs. Using an independent sample from the same study population (), bisulfite pyrosequencing was performed with infant cord blood DNA for two genes within our top 20 hits (AGER and PRKG1). Results from pyrosequencing replicated epigenome results for PRKG1 (cg17079497, , , ) but not for AGER (cg09199225; , , ).Discussion:Secondhand smoke exposure among nonsmoking women may alter DNA methylation in regions involved in development, carcinogenesis, and neuronal functioning. These novel findings suggest that even low levels of smoke exposure during pregnancy may be sufficient to alter DNA methylation in distinct sites of mixed umbilical cord blood leukocytes in pathways that are known to be altered in cord blood from pregnant active smokers. https://doi.org/10.1289/EHP8099

Effect of prenatal exposure to phthalates on epigenome-wide DNA methylations in cord blood and implications for fetal growth: The Hokkaido Study on Environment and Children's Health

Prenatal exposure to phthalates negatively affects the offspring's health. In particular, epigenetic alterations, such as DNA methylation, may connect phthalate exposure with health outcomes. Here, we evaluated the association of di-2-ethylhexyl phthalate (DEHP) exposure in utero with cord blood epigenome-wide DNA methylation in 203 mother-child pairs enrolled in the Hokkaido Study on Environment and Children's Health, using the Illumina HumanMethylation450 BeadChip. Epigenome-wide association analysis demonstrated the predominant positive associations between the levels of the primary metabolite of DEHP, mono(2-ethylhexyl) phthalate (MEHP), in maternal blood and DNA methylation levels in cord blood. The genes annotated to the CpGs positively associated with MEHP levels were enriched for pathways related to metabolism, the endocrine system, and signal transduction. Among them, methylation levels of CpGs involved in metabolism were inversely associated with the offspring's ponderal index (PI). Further, clustering and mediation analyses suggested that multiple increased methylation changes may jointly mediate the association of DEHP exposure in utero with the offspring's PI at birth. Although further studies are required to assess the impact of these changes, this study suggests that differential DNA methylation may link phthalate exposure in utero to fetal growth and further imply that DNA methylation has predictive value for the offspring's obesity.

Maternal blood metal concentrations and whole blood DNA methylation during pregnancy in the Early Autism Risk Longitudinal Investigation (EARLI)

ABSTRACT The maternal epigenome may be responsive to prenatal metals exposures. We tested whether metals are associated with concurrent differential maternal whole blood DNA methylation. In the Early Autism Risk Longitudinal Investigation cohort, we measured first or second trimester maternal blood metals concentrations (cadmium, lead, mercury, manganese, and selenium) using inductively coupled plasma mass spectrometry. DNA methylation in maternal whole blood was measured on the Illumina 450 K array. A subset sample of 97 women had both measures available for analysis, all of whom did not report smoking during pregnancy. Linear regression was used to test for site-specific associations between individual metals and DNA methylation, adjusting for cell type composition and confounding variables. Discovery gene ontology analysis was conducted on the top 1,000 sites associated with each metal. We observed hypermethylation at 11 DNA methylation sites associated with lead (FDR False Discovery Rate q-value <0.1), near the genes CYP24A1, ASCL2, FAT1, SNX31, NKX6-2, LRC4C, BMP7, HOXC11, PCDH7, ZSCAN18, and VIPR2. Lead-associated sites were enriched (FDR q-value <0.1) for the pathways cell adhesion, nervous system development, and calcium ion binding. Manganese was associated with hypermethylation at four DNA methylation sites (FDR q-value <0.1), one of which was near the gene ARID2. Manganese-associated sites were enriched for cellular metabolism pathways (FDR q-value<0.1). Effect estimates for DNA methylation sites associated (p < 0.05) with cadmium, lead, and manganese were highly correlated (Pearson ρ > 0.86). DNA methylation sites associated with lead and manganese may be potential biomarkers of exposure or implicate downstream gene pathways.

Fat mass and obesity-associated (FTO) gene epigenetic modifications in gestational diabetes: new insights and possible pathophysiological connections

AimsGestational diabetes mellitus (GDM) can lead to short- and long-term complications for the child. Epigenetic alterations could contribute to explaining the metabolic disturbances associated with foetal programming. Although the role of the FTO gene remains unclear, it affects metabolic phenotypes probably mediated by epigenetic mechanisms. The aim of this study was to assess whether placental DNA epigenetic modifications at FTO promoter-associated cysteine–phosphate–guanine (CpG) sites are correlated with GDM. A secondary aim was to evaluate the association between the placental FTO DNA methylation and the maternal metabolic traits in women with and without GDM.MethodsSocio-demographic characteristics, clinical parameters at the third trimester of pregnancy, Mediterranean diet adherence, and physical activity were assessed in 33 GDM women and 27 controls. Clinical information about the newborns was registered at birth. The FTO rs9939609 (T > A) was genotyped.ResultsNo association between FTO DNA methylation and GDM was found. DNA methylation on the maternal side at the CpG1 was associated with maternal smoking in GDM (p = 0.034), and DNA methylation at the CpG3 was correlated with smoking or former smoking in controls (p = 0.023). A higher level of TGs was correlated with higher foetal placental DNA methylation at the CpG2 (p = 0.036) in GDM. An inverse association between HDL-C and maternal placental DNA methylation at the CpG3 in controls (p = 0.045) was found. An association between FTO rs9939609 and neonatal birthweight (p = 0.033) was detected.ConclusionsIn the awareness that the obesity pathophysiology is complex, the study adds a piece to this intricate mosaic.

Children With Disruptive Mood Dysregulation Disorder and Psychopathological Risk in Their Mothers: The Function of Global DNA Methylation.

Epigenetic mechanisms, in particular DNA methylation, have been implicated in the etiopathogenesis of psychopathologies in adulthood. The significance of this mechanism in child psychopathologies, however, is much less recognized. Here, we examined whether global DNA methylation alteration was associated with the presence of disruptive mood dysregulation disorder (DMDD) in children. Moreover, in light of the relevance of the interplay between children and parents for the onset and maintaining of psychopathology during development, we measured the association between psychological symptoms, attachment styles, and global DNA methylation levels in healthy and DMDD mother-child dyads (mothers: N = 126, age = 38.3 ± 2.5 years; children: N = 150, age = 8.2 ± 0.9 years, gender ratio [f/m] = 72/78). We did not observe any significant differences in global DNA methylation levels in DMDD children when compared with healthy peers, and children's symptoms did not correlate with variations in this parameter. The mothers showed different levels of psychological symptomatology. Notably, mothers with high psychological symptomatology showed the lowest levels of global DNA methylation. Maternal global DNA methylation levels were associated with maternal hostility, interpersonal sensitivity, psychoticism, and general severity index. Moreover, we found an effect of maternal mental health on the severity of children's symptoms, independently from both maternal and child DNA methylation levels. Despite here DNA methylation does not appear to be involved in the maternal inheritance of vulnerability to depression, this biological link could still arise in later stages of the child's development.

Maternal DNA Methylation During Pregnancy: a Review.

Multiple environmental, behavioral, and hereditary factors affect pregnancy. Recent studies suggest that epigenetic modifications, such as DNA methylation (DNAm), affect both maternal and fetal health during the period of gestation. Some of the pregnancy-related risk factors can influence maternal DNAm, thus predisposing both the mother and the neonate to clinical adversities with long-lasting consequences. DNAm alterations in the promoter and enhancer regions modulate gene expression changes which play vital physiological role. In this review, we have discussed the recent advances in our understanding of maternal DNA methylation changes during pregnancy and its associated complications such as gestational diabetes and anemia, adverse pregnancy outcomes like preterm birth, and preeclampsia. We have also highlighted some major gaps and limitations in the area which if addressed might improve our understanding of pregnancy and its associated adverse clinical conditions, ultimately leading to healthy pregnancies and reduction of public health burden.

Characterization of the effects of age and childhood maltreatment on ELOVL2 DNA methylation.

DNA methylation of the elongation of very long chain fatty acids protein 2 (ELOVL2) was suggested as a biomarker of biological aging, while childhood maltreatment (CM) has been associated with accelerated biological aging. We investigated the association of age and CM experiences with ELOVL2 methylation in peripheral blood mononuclear cells (PBMC). Furthermore, we investigated ELOVL2 methylation in the umbilical cord blood mononuclear cells (UBMC) of newborns of mothers with and without CM. PBMC and UBMC were isolated from 113 mother-newborn dyads and genomic DNA was extracted. Mothers with and without CM experiences were recruited directly postpartum. Mass array spectrometry and pyrosequencing were used for methylation analyses of ELOVL2 intron 1, and exon 1 and 5' end, respectively. ELOVL2 5' end and intron 1 methylation increased with higher age but were not associated with CM experiences. On the contrary, overall ELOVL2 exon 1 methylation increased with higher CM, but these changes were minimal and did not increase with age. Maternal CM experiences and neonatal methylation of ELOVL2 intron 1 or exon 1 were not significantly correlated. Our study suggests region-specific effects of chronological age and experienced CM on ELOVL2 methylation and shows that the epigenetic biomarker for age within the ELOVL2 gene does not show accelerated biological aging years after CM exposure.