As childhood obesity prevalence escalates in developed countries, etiologic studies of obesity have focused on the interaction between genetic variants and modifiable risk factors that encompass energy balance, estimated as caloric intake less caloric expenditure. A compelling alternative explanation is that environmentally induced deregulation of epigenetic mechanisms that guide expression of genes involved in energy balance may culminate in gene expression profiles that predispose to an obese phenotype. Because imprinted genes are regulated by epigenetic mechanisms, and because they are normally expressed from only one parental chromosome, they are particularly susceptible to genetic and/or epigenetic deregulation. Indeed, aberrant DNA methylation at imprint regulatory elements of the paternally expressed growth factor, IGF2, have been associ- ated with increased risk of obesity and overgrowth disorders. DLK1 is elevated in the circulation of obese hu- mans, and both DLK1 and NNAT are involved in adipogenesis. An obesity model in mice was generated through disruption of imprinted Gnasxl. Mechanisms associated with imprint deregulation are only now being unraveled. Feeding female mice a methyl group donor-rich diet during pregnancy triggers altered methylation of the Agouti locus in pups, which subsequently modulates risk of obesity and diabetes. There is a higher pro- pensity for persistent childhood obesity in children born to mothers who smoke during pregnancy, and our data support that IGF2 is epigenetically altered and upregulated in neonates born to smoking mothers. Our central hypothesis is that early exposures increase the risk of epigenetic deregulation of imprinted gene regulatory elements, resulting in altered expression of growth regulatory genes and subsequent rapid weight gain in the offspring, fueling the childhood obesity epidemic.
Our aims are to: (1) Determine if altered methylation of im- printed gene regulatory regions controlling 12 imprinted genes at birth is associated with increased risk of rapid weight gain and obesity in children at age 1, 3 and at 5 years;(2) Determine if in utero exposures to a maternal methyl group donor-rich diet and/or cigarette smoke is associated with increased risk of aberrant DNA methyla- tion at imprinted gene regulatory regions and risk of obesity in children at these ages;(3) Determine if the child's diet (ages 3 and 5 years) is associated with alterations in methylation profiles at these imprint regulatory elements. Genome-wide methylation profiles for ~14,500 genes will also be generated at ages 1 and 5 years to assess the role of methylation in rapid growth and obesity. We will follow 690 participants in our Newborn Epigenetics STudy (NEST) and assess diet, collect anthropometric measurements and buccal cells. We will combine NEST periconceptional, prenatal, parturition and age one year data with data proposed for collection at ages 3 and 5 years to evaluate these exposures in relation to epigenetic changes at imprint regu- latory elements and obesity. Understanding the role of epigenetics in the genesis of childhood obesity will ulti- mately lead to new ways of preventing obesity and associated human diseases.

Public Health Relevance

Public Health Statement of Relevance This longitudinal epidemiology project will study how prenatal and early childhood nutrition affect the function of genes believed to play role in the development of obesity and obesity-related chronic disease. Because nutrition-related patterns of gene deregulation are potentially reversible, identifying nutritional and other risk factors associated with abnormal gene functioning may lead to therapeutic and public health interventions for childhood obesity and for adult onset, obesity-related chronic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK085173-04
Application #
8460569
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Silva, Corinne M
Project Start
2010-07-27
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$484,778
Indirect Cost
$168,281
Name
Duke University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Felix, Janine F; Joubert, Bonnie R; Baccarelli, Andrea A et al. (2018) Cohort Profile: Pregnancy And Childhood Epigenetics (PACE) Consortium. Int J Epidemiol 47:22-23u
Li, Yue; Xie, Changchun; Murphy, Susan K et al. (2016) Lead Exposure during Early Human Development and DNA Methylation of Imprinted Gene Regulatory Elements in Adulthood. Environ Health Perspect 124:666-73
Joubert, Bonnie R; Felix, Janine F; Yousefi, Paul et al. (2016) DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis. Am J Hum Genet 98:680-96
Fuemmeler, Bernard F; Lee, Chien-Ti; Soubry, Adelheid et al. (2016) DNA Methylation of Regulatory Regions of Imprinted Genes at Birth and Its Relation to Infant Temperament. Genet Epigenet 8:59-67
Fuemmeler, Bernard F; Wang, Lin; Iversen, Edwin S et al. (2016) Association between Prepregnancy Body Mass Index and Gestational Weight Gain with Size, Tempo, and Velocity of Infant Growth: Analysis of the Newborn Epigenetic Study Cohort. Child Obes 12:210-8
Nye, Monica D; King, Katherine E; Darrah, Thomas H et al. (2016) Maternal blood lead concentrations, DNA methylation ofMEG3DMR regulating the DLK1/MEG3 imprinted domain and early growth in a multiethnic cohort. Environ Epigenet 2:
Benjamin Neelon, Sara E; Stroo, Marissa; Mayhew, Meghan et al. (2015) Correlation between maternal and infant cortisol varies by breastfeeding status. Infant Behav Dev 40:252-8
Soubry, A; Murphy, S K; Wang, F et al. (2015) Newborns of obese parents have altered DNA methylation patterns at imprinted genes. Int J Obes (Lond) 39:650-7
Nye, Monica D; Hoyo, Cathrine; Murphy, Susan K (2015) In vitro lead exposure changes DNA methylation and expression of IGF2 and PEG1/MEST. Toxicol In Vitro 29:544-50
Soubry, Adelheid; Hoyo, Cathrine; Jirtle, Randy L et al. (2014) A paternal environmental legacy: evidence for epigenetic inheritance through the male germ line. Bioessays 36:359-71

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