There is strong evidence that the environment experienced in utero contributes to cardiovascular, metabolic, immunologic, and nervous system health during both childhood and adulthood. Defining children at-risk early in life is critical to improving health outcomes;biomarkers of exposure and outcome are powerful tools to use in risk identification and offer an opportunity to inform the mechanisms involved in the developmental origins of disease. Emerging evidence, from our own laboratories and others, suggests that the placenta, as a master regulator of the intrauterine environment and of fetal development, plays a critical role in the developmental origins of health and disease. Thus, the placenta is an ideal tissue in which to identify functional biomarkers that mediate fetal programming of health. In published and preliminary studies we have demonstrated that exposures, such as arsenic, can alter the patterns of DNA methylation and of gene expression in primary human placental tissue, and we have demonstrated that such alterations are associated with fetal growth and newborn neurobehavioral measures.
We aim here to develop novel biomarkers of exposure and outcome by examining the hypothesis that environmental exposures encountered by a pregnant woman impact the epigenetic and gene expression profiles of the infant's placenta and these functional alterations are associated with poor-health outcomes in the children. We will employ the existing resources of the ongoing New Hampshire Birth Cohort Study, and its established biorepository of placental tissues, to allow sensitive and robust assessment of gene expression and genomewide DNA methylation in combination with infant and maternal biomarkers of arsenic exposure. We propose to use state-of-the-art genomic technologies to identify and validate novel profiles of DNA methylation and gene expression susceptible to environmental exposure in human placenta and to examine their association with newborn outcomes including growth, infection and neurodevelopment being assessed in Projects 1 and 2 of the Program. These examinations will provide critical insight into the mechanisms of the developmental origins of lifelong health, highlight novel pathways affected by exposures that drive children's health, and identify novel biomarkers which can be used to find at the earliest points of life, children at-risk so necessary interventions can be employed soon enough to prevent future disease.

Public Health Relevance

The placenta serves as a key functional organ in defining the environment encountered by a developing fetus. Understanding and defining molecular alterations to the placenta associated with exposure and with adverse outcomes will allow for early identification of at-risk children and will provide insight onto novel pathways to target for targeted preventative approaches.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01ES022832-02
Application #
8665937
Study Section
Special Emphasis Panel (ZES1)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Type
DUNS #
City
Hanover
State
NH
Country
United States
Zip Code
03755
Appleton, Allison A; Lester, Barry M; Armstrong, David A et al. (2015) Examining the joint contribution of placental NR3C1 and HSD11B2 methylation for infant neurobehavior. Psychoneuroendocrinology 52:32-42
Armstrong, David A; Lesseur, Corina; Conradt, Elisabeth et al. (2014) Global and gene-specific DNA methylation across multiple tissues in early infancy: implications for children's health research. FASEB J 28:2088-97
Davis, Matthew A; Gilbert-Diamond, Diane; Karagas, Margaret R et al. (2014) A dietary-wide association study (DWAS) of environmental metal exposure in US children and adults. PLoS One 9:e104768
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Paquette, Alison G; Marsit, Carmen J (2014) The developmental basis of epigenetic regulation of HTR2A and psychiatric outcomes. J Cell Biochem 115:2065-72
Lesseur, Corina; Armstrong, David A; Paquette, Alison G et al. (2014) Maternal obesity and gestational diabetes are associated with placental leptin DNA methylation. Am J Obstet Gynecol 211:654.e1-9
Davis, Matthew A; Li, Zhigang; Gilbert-Diamond, Diane et al. (2014) Infant toenails as a biomarker of in utero arsenic exposure. J Expo Sci Environ Epidemiol 24:467-73
Lesseur, Corina; Paquette, Alison G; Marsit, Carmen J (2014) Epigenetic Regulation of Infant Neurobehavioral Outcomes. Med Epigenet 2:71-79
Lesseur, Corina; Armstrong, David A; Murphy, Megan A et al. (2014) Sex-specific associations between placental leptin promoter DNA methylation and infant neurobehavior. Psychoneuroendocrinology 40:1-9

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