Environmental exposures such as maternal adiposity mark the placental epigenome which modulates placental function. Pregnancies in obese mothers generate an adverse intrauterine environment, via their inflammatory milieu and metabolic derangements that programs the offspring in a sexually dimorphic manner for obesity, diabetes and metabolic disease in adult life. Understanding the role of the intrauterine environment on epigenetic regulation of placental function is needed to prevent the intergenerational transmission of disease. Epigenetic information is conveyed via the interaction of mitotically heritable patterns of DNA methylation and chromatin structure. Using a genome-scale DNA methylation array we find 18 genes with significantly increased methylation, and 3 genes with significantly decreased methylation, in the region from - 100 to +100bp of their transcription start sites in placentas of obese compared to normal body weight women. One gene with increased methylation encodes for ten eleven translocation 3 (TET3), a member of a ketoglutarate and iron-dependent dioxygenase enzyme superfamily, that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), and can be regulated by the metabolic environment. 5mC and 5hmC may epigenetically control expression of distinct sets of genes. Increased placental TET3 promoter methylation may decrease TET3 expression, reduce demethylation activity and be linked to the overall increase in promoter methylation with obesity. We will test two hypotheses: a. increasing maternal adiposity during pregnancy increases global DNA methylation, the balance of methylation to hydroxymethylation at certain gene promoters and alters the transcriptional profile in placenta and b. TET3 expression can be epigenetically regulated in the placenta by hypoxic, inflammatory, redox or metabolic stress. The impact of this highly innovative study will be the effect on overall population health of our increased knowledge of the epigenetic regulation of placental function by maternal adiposity, its relationship to the developmental programming of obesity and metabolic syndrome and the therapeutic opportunities revealed.

Public Health Relevance

Environmental exposures including maternal adiposity may mark the placental epigenome which then modulates placental gene expression and function. Pregnancies in obese mothers generate an adverse intrauterine environment that may program the offspring in a sexually dimorphic manner for obesity, diabetes and metabolic disease in adult life. We will use a genome scale method to determine placental DNA methylation and define the mechanism whereby maternal obesity epigenetically regulates placental function to recognize therapeutic opportunity.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21HD076266-03
Application #
9276325
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Ilekis, John V
Project Start
2013-08-01
Project End
2017-07-31
Budget Start
2016-01-27
Budget End
2017-07-31
Support Year
3
Fiscal Year
2014
Total Cost
$44,038
Indirect Cost
$15,442
Name
Oregon Health and Science University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Mitsuya, Kohzoh; Parker, Ashley N; Liu, Lu et al. (2017) Alterations in the placental methylome with maternal obesity and evidence for metabolic regulation. PLoS One 12:e0186115