scholarly journals DNA methylation mediates the effect of maternal smoking on offspring birthweight: a birth cohort study of multi-ethnic US mother–newborn pairs

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Richard Xu ◽  
Xiumei Hong ◽  
Boyang Zhang ◽  
Wanyu Huang ◽  
Wenpin Hou ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Health Outcomes ◽  
Cord Blood ◽  
Birth Cohort ◽  
Fetal Growth ◽  
Maternal Smoking ◽  
Cpg Sites ◽  
Smoking Exposure ◽  
Lower Birthweight

Abstract Background Maternal smoking affects more than half a million pregnancies each year in the US and is known to result in fetal growth restriction as measured by lower birthweight and its associated long-term consequences. Maternal smoking also has been linked to altered fetal DNA methylation (DNAm). However, what remains largely unexplored is whether these DNAm alterations are merely markers of smoking exposure or if they also have implications for health outcomes. This study tested the hypothesis that fetal DNAm mediates the effect of maternal smoking on newborn birthweight. Methods This study included mother–newborn pairs from a US predominantly urban, low-income multi-ethnic birth cohort. DNAm in cord blood were determined using the Illumina Infinium MethylationEPIC BeadChip. After standard quality control and normalization procedures, an epigenome-wide association study (EWAS) of maternal smoking was performed using linear regression models, controlling for maternal age, education, race, parity, pre-pregnancy body mass index, alcohol consumption, gestational age, maternal pregestational/gestational diabetes, child sex, cord blood cell compositions and batch effects. To quantify the degree to which cord DNAm mediates the smoking-birthweight association, the VanderWeele-Vansteelandt approach for single mediator and structural equational model for multiple mediators were used, adjusting for pertinent covariates. Results The study included 954 mother–newborn pairs. Among mothers, 165 (17.3%) ever smoked before or during pregnancy. Newborns with smoking exposure had on average 258 g lower birthweight than newborns without exposure (P < 0.001). Using a false discovery rate (FDR) < 0.05 as the significance cutoff, the EWAS identified 38 differentially methylated CpG sites associated with maternal smoking. Of those, 17 CpG sites were mapped to previously reported genes: GFI1, AHRR, CYP1A1, and CNTNAP2; 8 of those, located in the first three genes, were Bonferroni significantly associated with newborn birthweight and mediated the smoking-birthweight association. The combined mediation effect of the three genes explained 67.8% of the smoking-birthweight association. Conclusions Our study not only lends further support that maternal smoking alters fetal DNAm in a multiethnic population, but also suggests that fetal DNAm substantially mediates the maternal smoking–birthweight association. Our findings, if further validated, indicate that DNAm modification is likely an important pathway by which maternal smoking impairs fetal growth and, perhaps, even long-term health outcomes.

scholarly journals Epigenetic signatures of smoking associate with cognitive function, brain structure, and mental and physical health outcomes in the Lothian Birth Cohort 1936

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Janie Corley ◽  
Simon R. Cox ◽  
Sarah E. Harris ◽  
Maria Valdéz Hernandez ◽  
Susana Muñoz Maniega ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cognitive Function ◽  
Health Outcomes ◽  
Physical Health ◽  
Birth Cohort ◽  
Smoking Status ◽  
Brain Mri ◽  
Smoking Exposure ◽  
Eta Squared ◽  
Lothian Birth Cohort

Abstract Recent advances in genome-wide DNA methylation (DNAm) profiling for smoking behaviour have given rise to a new, molecular biomarker of smoking exposure. It is unclear whether a smoking-associated DNAm (epigenetic) score has predictive value for ageing-related health outcomes which is independent of contributions from self-reported (phenotypic) smoking measures. Blood DNA methylation levels were measured in 895 adults aged 70 years in the Lothian Birth Cohort 1936 (LBC1936) study using the Illumina 450K assay. A DNA methylation score based on 230 CpGs was used as a proxy for smoking exposure. Associations between smoking variables and health outcomes at age 70 were modelled using general linear modelling (ANCOVA) and logistic regression. Additional analyses of smoking with brain MRI measures at age 73 (n = 532) were performed. Smoking-DNAm scores were positively associated with self-reported smoking status (P < 0.001, eta-squared ɳ2 = 0.63) and smoking pack years (r = 0.69, P < 0.001). Higher smoking DNAm scores were associated with variables related to poorer cognitive function, structural brain integrity, physical health, and psychosocial health. Compared with phenotypic smoking, the methylation marker provided stronger associations with all of the cognitive function scores, especially visuospatial ability (P < 0.001, partial eta-squared ɳp2 = 0.022) and processing speed (P < 0.001, ɳp2 = 0.030); inflammatory markers (all P < 0.001, ranges from ɳp2 = 0.021 to 0.030); dietary patterns (healthy diet (P < 0.001, ɳp2 = 0.052) and traditional diet (P < 0.001, ɳp2 = 0.032); stroke (P = 0.006, OR 1.48, 95% CI 1.12, 1.96); mortality (P < 0.001, OR 1.59, 95% CI 1.42, 1.79), and at age 73; with MRI volumetric measures (all P < 0.001, ranges from ɳp2 = 0.030 to 0.052). Additionally, education was the most important life-course predictor of lifetime smoking tested. Our results suggest that a smoking-associated methylation biomarker typically explains a greater proportion of the variance in some smoking-related morbidities in older adults, than phenotypic measures of smoking exposure, with some of the accounted-for variance being independent of phenotypic smoking status.

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 Placental DNA methylation signatures of maternal smoking during pregnancy and potential impacts on fetal growth

2019 ◽  
Author(s):  
Todd M. Everson ◽  
Marta Vives-Usano ◽  
Emie Seyve ◽  
Andres Cardenas ◽  
Marina Lacasaña ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Birth Outcomes ◽  
Fetal Growth ◽  
Maternal Smoking ◽  
Meta Analysis ◽  
Growth Factor Signaling ◽  
Hormone Activity ◽  
Smoking During Pregnancy ◽  
Placental Function ◽  
Maternal Smoking During Pregnancy

AbstractMaternal smoking during pregnancy (MSDP) contributes to poor birth outcomes, in part through disrupted placental functions, which may be reflected in the placental epigenome. We meta-analyzed the associations between MSDP and placental DNA methylation (DNAm) and between DNAm and birth outcomes within the Pregnancy And Childhood Epigenetics (PACE) consortium (7 studies, N=1700, 344 with any MSDP). We identified 1224 CpGs that were associated with MSDP, of which 341 associated with birth outcomes and 141 associated with gene expression. Only 6 of these CpGs were consistent with the findings from a prior meta-analysis of cord blood DNAm, demonstrating substantial tissue-specific responses to MSDP. The placental MSDP associated CpGs were enriched for growth-factor signaling, hormone activity, inflammation, and vascularization, which play important roles in placental function. We demonstrate links between placental DNAm, MSDP and poor birth outcomes, which may better inform the mechanisms through which MSDP impacts placental function and fetal growth.

scholarly journals Epigenome-wide association study of maternal hemoglobin A1c in pregnancy and cord blood DNA methylation

Epigenomics ◽  
2021 ◽  
Author(s):  
Diana L Juvinao-Quintero ◽  
Anne P Starling ◽  
Andres Cardenas ◽  
Camille E Powe ◽  
Patrice Perron ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Hemoglobin A1c ◽  
Mendelian Randomization ◽  
Statistical Significance ◽  
Perinatal Outcomes ◽  
Gestational Hyperglycemia ◽  
Adverse Perinatal Outcomes ◽  
Hba1c Levels

Background: Gestational hyperglycemia is associated with adverse perinatal outcomes and long-term offspring metabolic programming, likely through dysregulation of DNA methylation (DNAm). Materials & methods: We tested associations between maternal HbA1c and cord blood DNAm among 412 mother–child pairs in the genetics of glucose regulation in gestation and growth (Gen3G) and implemented Mendelian randomization to infer causality. We sought replication in an independent sample from Healthy Start. Results: Higher second trimester HbA1c levels were associated with lower DNAm at cg21645848 (p = 3.9 × 10-11) near URGCP. Mendelian randomization and replication analyses showed same direction of effect between HbA1c and DNAm at cg21645848, but did not reach statistical significance. Conclusion: We found that higher maternal glycemia reflected by HbA1c is associated with cord blood DNAm at URGCP, a gene related with inflammatory pathways.

scholarly journals Ramadan Fasting during Pregnancy and Health Outcomes in Offspring: A Systematic Review

Nutrients ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 3450
Author(s):  
Violet N. L. Oosterwijk ◽  
Joyce M. Molenaar ◽  
Lily A. van Bilsen ◽  
Jessica C. Kiefte-de Jong
Keyword(s):  
Health Outcomes ◽  
Fetal Growth ◽  
Islamic Law ◽  
Quality Score ◽  
Cochrane Library ◽  
Long Term Effects ◽  
High Quality ◽  
Ramadan Fasting ◽  
Negative Effect

Ramadan is one of the five pillars of Islam, during which fasting is obligatory for all healthy individuals. Although pregnant women are exempt from this Islamic law, the majority nevertheless choose to fast. This review aims to identify the effects of Ramadan fasting on the offspring of Muslim mothers, particularly on fetal growth, birth indices, cognitive effects and long-term effects. A systematic literature search was conducted until March 2020 in Web of Science, Pubmed, Cochrane Library, Embase and Google Scholar. Studies were evaluated based on a pre-defined quality score ranging from 0 (low quality) to 10 (high quality), and 43 articles were included. The study quality ranged from 2 to 9 with a mean quality score of 5.4. Only 3 studies had a high quality score (>7), of which one found a lower birth weight among fasting women. Few medium quality studies found a significant negative effect on fetal growth or birth indices. The quality of articles that investigated cognitive and long-term effects was poor. The association between Ramadan fasting and health outcomes of offspring is not supported by strong evidence. To further elucidate the effects of Ramadan fasting, larger prospective and retrospective studies with novel designs are needed.

scholarly journals DNA methylation links prenatal smoking exposure to later life health outcomes in offspring

2018 ◽  
Author(s):  
Petri Wiklund ◽  
Ville Karhunen ◽  
Rebecca C Richmond ◽  
Alina Rodriguez ◽  
Maneka De Silva ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Health Outcomes ◽  
Maternal Smoking ◽  
Psychiatric Morbidity ◽  
Later Life ◽  
Prenatal Smoking ◽  
Smoking During Pregnancy ◽  
Mediation Analyses ◽  
Increased Risk ◽  
Prenatal Maternal Smoking

AbstractMaternal smoking during pregnancy is associated with adverse offspring health outcomes across their life course. We hypothesize that DNA methylation is a potential mediator of this relationship. To test this, we examined the association of prenatal maternal smoking with DNA methylation in 2,821 individuals (age 16 to 48 years) from five prospective birth cohort studies and perform Mendelian randomization and mediation analyses to assess, whether methylation markers have causal effects on disease outcomes in the offspring. We identify 69 differentially methylated CpGs in 36 genomic regions (P < 1×10−7), and show that DNA methylation may represent a biological mechanism through which maternal smoking is associated with increased risk of psychiatric morbidity in the exposed offspring.

scholarly journals DNA methylation patterns of β-globin cluster in β-thalassemia patients

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiuqin Bao ◽  
Yangjin Zuo ◽  
Diyu Chen ◽  
Cunyou Zhao
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Methylation Level ◽  
Epigenetic Modification ◽  
Fetal Hemoglobin ◽  
Cpg Sites ◽  
Hbf Level ◽  
Globin Promoter ◽  
Methylation Patterns ◽  
Normal Controls

Abstract Background Reactivation of fetal hemoglobin (HbF, α2γ2) holds a therapeutic target for β-thalassemia and sickle cell disease. Although many HbF regulators have been identified, the methylation patterns in β-globin cluster driving the fetal-to-adult hemoglobin switch remains to be determined. Results Here, we evaluated DNA methylation patterns of the β-globin cluster from peripheral bloods of 105 β0/β0 thalassemia patients and 44 normal controls. We also recruited 15 bone marrows and 4 cord blood samples for further evaluation. We identified that the CpG sites in the locus control region (LCR) DNase I hypersensitive site 4 and 3 (HS4-3) regions, and γ- and β-globin promoters displayed hypomethylation in β0/β0-thalassemia patients, especially for the patients with high HbF level, as compared with normal controls. Furthermore, hypomethylations in most of CpG sites of the HS4-3 core regions were also observed in bone marrows (BM) of β0/β0-patients compared with normal controls; and methylation level of γ-globin promoter -50 and + 17 CpG sites showed lower methylation level in patients with high HbF level compared with those with low HbF level and a negative correlation with HbF level among β0-thalassemia patients. Finally, γ-globin promoter + 17 and + 50 CpG sites also displayed significant hypomethylation in cord blood (CB) tissues compared with BM tissues from normal controls. Conclusions Our findings revealed methylation patterns in β-globin cluster associated with β0 thalassemia disease and γ-globin expression, contributed to understand the epigenetic modification in β0 thalassemia patients and provided candidate targets for the therapies of β-hemoglobinopathies.

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 A Comparison of Vitamin E Status and Associated Pregnancy Outcomes in Maternal–Infant Dyads between a Nigerian and a United States Population

Nutrients ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 1300
Author(s):  
Caleb Cave ◽  
Corrine Hanson ◽  
Marina Schumacher ◽  
Elizabeth Lyden ◽  
Jeremy Furtado ◽  
...  
Keyword(s):  
United States ◽  
Vitamin E ◽  
Health Outcomes ◽  
Cord Blood ◽  
Fetal Growth ◽  
Pregnancy Outcomes ◽  
Mode Of Delivery ◽  
The Us ◽  
Adverse Pregnancy ◽  
Vitamin E Status

Oxidative stress is associated with adverse pregnancy outcomes, and vitamin E has powerful anti-oxidant properties with the potential to impact health outcomes. Tocopherol isomers of vitamin E differ in their ability to modulate inflammation and vary in concentration in diets containing high proportions of processed versus unprocessed foods. The purpose of this study was to compare vitamin E status and associated pregnancy outcomes (mode of delivery, chorioamnionitis, APGARs (measure of appearance, pulse, grimace, activity, respiration), gestational age at delivery, and fetal growth) between maternal–infant dyads in a developed and a developing nation to identify potentially modifiable differences that may impact pregnancy and neonatal outcomes and provide a way to improve maternal and neonatal health. Plasma tocopherol levels were evaluated in 189 Midwestern United States (US) mother–infant pairs and 99 Central Nigerian mother–infant pairs. Maternal and infant concentrations of α-, γ-, and δ-tocopherol were measured using HPLC with diode-array detection. Descriptive statistics were calculated and tocopherol concentrations were associated with clinical outcomes such as mode of delivery, chorioamnionitis, APGARS, and fetal growth. Alpha- and γ-tocopherol levels were higher in the US mothers, (alpha: 12,357.9 (175.23–34,687.75) vs. 8333.1 (1576.59–16,248.40) (mcg/L); p < 0.001) (gamma: 340.7 (224.59–4385.95) vs. 357.5 (66.36–1775.31) (mcg/L); p < 0.001), while δ-tocopherol levels were higher in the Nigerian mothers (delta: 261.7 (24.70–1324.71) vs. 368.9 (43.06–1886.47) (mcg/L); p < 0.001). US infants had higher γ-tocopherol levels than Nigerian infants (203.1 (42.53–1953.23) vs. 113.8 (0.00–823.00) (mcg/L); p < 0.001), while both the Nigerian mothers and infants had higher α:γ-tocopherol ratios (8.5 vs. 26.2, and 8.9 vs. 18.8, respectively; p < 0.001). Our results in both populations show associations between increased circulating γ-tocopherol and negative outcomes like Caesarian sections, in contrast to the associations with positive outcomes such as vaginal delivery seen with increased α:γ-tocopherol ratios. Growth was positively associated with α- and γ-tocopherols in cord blood in the US population, and with cord blood δ-tocopherols in the Nigerian population. Tocopherol levels likely impact health outcomes in pregnancy in a complicated metabolism across the maternal–fetal axis that appears to be potentially influenced by culture and available diet.

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