title: Newborns of obese parents have altered DNA methylation patterns at imprinted genes.
abstract: 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 ⩾30 kg m(-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 (β=-2.57; s.e.=0.95; P=0.008), PEG3 (β=-1.71; s.e.=0.61; P=0.005) and NNAT (β=-3.59; s.e.=1.76; P=0.04) DMRs. Changes related to maternal obesity detected at other loci were as follows: β-coefficient was +2.58 (s.e.=1.00; P=0.01) at the PLAGL1 DMR and -3.42 (s.e.=1.69; P=0.04) at the MEG3 DMR.
  
  
  CONCLUSIONS
  We found altered methylation outcomes at multiple imprint regulatory regions in children born to obese parents, compared with children born to non-obese parents. In spite of the small sample size, our data suggest a preconceptional influence of parental life-style or overnutrition on the (re)programming of imprint marks during gametogenesis and early development. More specifically, the significant and independent association between paternal obesity and the offspring's methylation status suggests the susceptibility of the developing sperm for environmental insults. The acquired imprint instability may be carried onto the next generation and increase the risk for chronic diseases in adulthood.
authors.affiliation: 1] Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA [2] Epidemiology Research Group, Department of Public Health and Primary Care, Faculty of Medicine, KULeuven, Leuven, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Soubry
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Murphy
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
authors.forename: F
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Obstetrics and Gynecology, Division of Clinical and Epidemiologic Research and Cancer Prevention, Duke University Medical Center, Durham, NC, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Vidal
authors.affiliation: Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: B F
authors.initials: BF
authors.lastname: Fuemmeler
authors.affiliation: Carolinas Cord Blood Bank, Robertson Cell and Translational Therapy Program, Duke Translational Research Institute, Duke University Medical Center, Durham, NC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kurtzberg
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal and Fetal Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: A
authors.initials: A
authors.lastname: Murtha
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Jirtle
authors.affiliation: 1] Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA [2] Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Schildkraut
authors.affiliation: Department of Obstetrics and Gynecology, Division of Clinical and Epidemiologic Research and Cancer Prevention, Duke University Medical Center, Durham, NC, USA.
authors.forename: C
authors.initials: C
authors.lastname: Hoyo
mesh_terms: D000328:Adult; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D004781:Environmental Exposure; D005260:Female; D005312:Fetal Blood / Q000378:metabolism*; D018392:Genomic Imprinting; D006801:Humans; D007231:Infant, Newborn; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D010290:Parents; D011247:Pregnancy; D011506:Proteins / Q000235:genetics; D016601:RNA-Binding Proteins; D015203:Reproducibility of Results; D049031:Sarcoglycans / Q000235:genetics; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D014470:Umbilical Cord / Q000166:cytology / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; C490237:NNAT protein, human; D009419:Nerve Tissue Proteins; C432965:PEG10 protein, human; C490820:PEG3 protein, human; C106464:PLAGL1 protein, human; D011506:Proteins; D016601:RNA-Binding Proteins; C526572:SGCE protein, human; D049031:Sarcoglycans; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C103637:mesoderm specific transcript protein; D007335:Insulin-Like Growth Factor II