Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort (original) (raw)
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Newborns of obese parents have altered DNA methylation patterns at imprinted genes
2013
BACKGROUND: Several epidemiologic studies have demonstrated associations between periconceptional environmental exposures and health status of the offspring in later life. Although these environmentally related effects have been attributed to epigenetic changes, such as DNA methylation shifts at imprinted genes, little is known about the potential effects of maternal and paternal preconceptional overnutrition or obesity. OBJECTIVE: We examined parental preconceptional obesity in relation to DNA methylation profiles at multiple human imprinted genes important in normal growth and development, such as: maternally expressed gene 3 (MEG3), mesoderm-specific transcript (MEST), paternally expressed gene 3 (PEG3), pleiomorphic adenoma gene-like 1 (PLAGL1), epsilon sarcoglycan and paternally expressed gene 10 (SGCE/PEG10) and neuronatin (NNAT). METHODS: We measured methylation percentages at the differentially methylated regions (DMRs) by bisulfite pyrosequencing in DNA extracted from umbilical cord blood leukocytes of 92 newborns. Preconceptional obesity, defined as BMI X30 kg m À 2 , was ascertained through standardized questionnaires. RESULTS: After adjusting for potential confounders and cluster effects, paternal obesity was significantly associated with lower methylation levels at the MEST
Obesity-related DNA methylation at imprinted genes in human sperm: Results from the TIEGER study
Clinical epigenetics, 2016
Epigenetic reprogramming in mammalian gametes resets methylation marks that regulate monoallelic expression of imprinted genes. In males, this involves erasure of the maternal methylation marks and establishment of paternal-specific methylation to appropriately guide normal development. The degree to which exogenous factors influence the fidelity of methylation reprogramming is unknown. We previously found an association between paternal obesity and altered DNA methylation in umbilical cord blood, suggesting that the father's endocrine, nutritional, or lifestyle status could potentiate intergenerational heritable epigenetic abnormalities. In these analyses, we examine the relationship between male overweight/obesity and DNA methylation status of imprinted gene regulatory regions in the gametes. Linear regression models were used to compare sperm DNA methylation percentages, quantified by bisulfite pyrosequencing, at 12 differentially methylated regions (DMRs) from 23 overweight/...
Cancer Causes & Control, 2012
Purpose Altered methylation at Insulin-like Growth Factor 2 (IGF2) regulatory regions has previously been associated with obesity, and several malignancies including colon, esophageal, and prostate adenocarcinomas, presumably via changes in expression and/or loss of imprinting, but the functional significance of these DNA methylation marks have not been demonstrated in humans. We examined associations among DNA methylation at IGF2 differentially methylated regions (DMRs), circulating IGF2 protein concentrations in umbilical cord blood (UCB) and birth weight in newborns. Methods Questionnaire data were obtained from 300 pregnant women recruited between 2005 and 2009. UCB DNA methylation was measured by bisulfite pyrosequencing. UCB plasma concentrations of soluble IGF2 were measured by ELISA assays. Generalized linear regression models were used to examine the relationship between DMR methylation and IGF2 levels. Results Lower IGF2 DMR methylation was associated with elevated plasma IGF2 protein concentrations (b = -9.87, p \ 0.01); an association that was stronger in infants born to obese women (pre-pregnancy BMI [ 30 kg/m 2 , b = -20.21, p \ 0.0001). Elevated IGF2 concentrations were associated with higher birth weight (p \ 0.0001) after adjusting for maternal race/ethnicity, pre-pregnancy BMI, cigarette smoking, gestational diabetes, and infant sex. These patterns of association were not apparent at the H19 DMR.
Diabetes and Metabolic Syndrome: Clinical Research and Reviews, 2017
This review examined whether maternal and paternal periconceptional nutrition effects an offspring's likelihood of developing chronic metabolic related conditions due to epigenetic imprinting. Methods: A literature search was conducted in multiple science databases and limited to studies published after 2012, in English language and peer reviewed. The data from selected articles were extracted and a qualitative approach was employed due to heterogeneity of results. Results: Newborns from obese fathers showed altered methylation overall and significant hypomethylation at the Insulin-like Growth Factor 2 (IGF2) gene. High maternal pre-pregnancy body mass index (BMI) was associated with altered offspring DNA methylation levels and gestational diabetes mellitus induced significantly increased methylation levels in offspring. Gestational weight gain was not associated with differentially methylated cord blood. Birth weight was higher in offspring exposed to famine in early gestation. Offspring born post maternal bariatric surgery showed a lower percentage of body fat and improved fasting insulin levels compared to siblings born pre-maternal bariatric surgery. Conclusions: The available evidence suggests that poor maternal and paternal periconceptional nutrition can increase the risk of metabolic syndrome in offspring, through epigenetic imprinting. Potential parents should be advised that maintaining a healthy diet and BMI is likely to reduce the risk of metabolic syndrome in offspring.
Clinical epigenetics, 2018
This study assessed the associations between nine differentially methylated regions (DMRs) of imprinted genes in DNA derived from umbilical cord blood leukocytes in males and females and (1) birth weight for gestational age score, (2) weight-for-length (WFL) score at 1 year, and (3) body mass index (BMI) score at 3 years. We conducted multiple linear regression in = 567 infants at birth, = 288 children at 1 year, and = 294 children at 3 years from the Newborn Epigenetics Study (NEST). We stratified by sex and adjusted for race/ethnicity, maternal education, maternal pre-pregnancy BMI, prenatal smoking, maternal age, gestational age, and paternal race. We also conducted analysis restricting to infants not born small for gestational age. We found an association between higher methylation of the sequences regulating paternally expressed gene 10 () and anthropometric scores at 1 year ( = 0.84; 95% CI = 0.34, 1.33; = 0.001) and 3 years ( = 1.03; 95% CI = 0.37, 1.69; value = 0.003) in...
DNA methylation of the IGF2/H19 imprinting control region and adiposity distribution in young adults
Clinical Epigenetics, 2012
Background: The insulin-like growth factor 2 (IGF2) and H19 imprinted genes control growth and body composition. Adverse in-utero environments have been associated with obesity-related diseases and linked with altered DNA methylation at the IGF2/H19 locus. Postnatally, methylation at the IGF2/H19 imprinting control region (ICR) has been linked with cerebellum weight. We aimed to investigate whether decreased IGF2/H19 ICR methylation is associated with decreased birth and childhood anthropometry and increased contemporaneous adiposity. DNA methylation in peripheral blood (n = 315) at 17 years old was measured at 12 cytosine-phosphate-guanine sites (CpGs), analysed as Sequenom MassARRAY EpiTYPER units within the IGF2/H19 ICR. Birth size, childhood head circumference (HC) at six time-points and anthropometry at age 17 years were measured. DNA methylation was investigated for its association with anthropometry using linear regression.
Epigenomics, 2013
Aim: We examined the association between birth weight and methylation in the imprinted IGF/H19 loci, the nonimprinted gene NR3C1 and repetitive element DNA (LINE-1 and Alu). Materials & methods: We collected umbilical cord venous blood from 219 infants born in Mexico City (Mexico) as part of a prospective birth cohort study and analyzed DNA methylation using pyrosequencing. Results: Birth weight was not associated with DNA methylation of the regions studied. One of the CpG dinucleotides in the IGF2 imprinting control region (ICR)1 includes a potential C–T SNP. Among individuals with an absence of methylation at this site, probably due to a paternally inherited T allele, birth weight was associated with mean methylation status of both IGF2 ICR1 and ICR2. However, this association would not have survived adjustment for multiple testing. Conclusion: While we did not detect an association between DNA methylation and birth weight, our study suggests a potential gene–epigene interaction b...