There is growing evidence that lifelong health, including mental health, is particularly shaped by the environment experienced during the in-utero developmental period. The intrauterine environment is influenced by a complex variety of factors, including maternal lifestyle, environmental exposures, socioeconomic status, and psychosocial aspects, making risk determination based on identification of these factors difficult and inaccurate. Yet, defining children at-risk early is utterly critical to improving future mental health outcomes. Due to the unique regulatory features of imprinted genes and their sensitivity to environmental exposures, genomic imprinting has been proposed as an ideal integrated measure of the intrauterine environment for use in epidemiologic studies of the developmental origins of health and disease. As imprinted genes in the placenta can impact the function of this critical organ in directing fetal development and programming, there is also strong evidence to support establishing and validating the link between alterations in imprinting and newborn neurodevelopmental outcomes. Compelled by strong rationale and by emerging evidence, including work from our laboratories linking placenta imprinted gene expression to infant neurodevelopment, this project aims to develop an imprinting-based biomarker that can prospectively predict neurobehavioral outcomes, which ultimately can be used for immediate identification of infants at-risk in order for early intervention to be initiated/implemented. We have developed a multi-stage research plan to first utilize the comprehensive resources of the ongoing Rhode Island Child Health Study (RICHS), which employs the validated and prospectively predictive NICU Network Neurobehavioral Scales (NNNS) as a phenotypic measure of newborn neurobehavior in a birth cohort of 900 newborn infants, to define a biomarker panel associated with key neurobehavioral measures. We will then demonstrate the validity and generalizability of this biomarker using an established but independent resource, the New Hampshire Birth Cohort Study (NHBCS), which uses similar data collection procedures as RICHS. In addition, although the environment is extraordinarily complex, we have decided to focus on fetal exposure to metals, specifically those which are widely considered neurotoxins or those considered protective, as a paradigm to build a comprehensive model to examine the inter-relationships among in utero trace metals exposure, genomic imprinting, and newborn neurobehavioral outcomes. Identification of an imprinting signature associated with abnormal neurodevelopment or environmental exposure would have significant clinical and public health implications by pinpointing certain environmental risk factors for neurobehavioral defects or serve as a basis for early diagnostic tools thus providing an opportunity for early intervention.

Public Health Relevance

This project aims to identify an epigenetic biomarker in an accessible tissue at birth that predicts altered neurodevelopmental trajectories. Such a biomarker may have significant clinical and public health impact, providing an opportunity for early interventions for at-risk children, and potentially identifying novel paths for prevention an treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES022223-01A1
Application #
8576697
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Mcallister, Kimberly A
Project Start
2013-09-01
Project End
2018-04-30
Budget Start
2013-09-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$853,106
Indirect Cost
$151,477
Name
Dartmouth College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041027822
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
Lesseur, Corina; Paquette, Alison G; Marsit, Carmen J (2014) Epigenetic Regulation of Infant Neurobehavioral Outcomes. Med Epigenet 2:71-79
Paquette, Alison G; Lester, Barry M; Koestler, Devin C et al. (2014) Placental FKBP5 genetic and epigenetic variation is associated with infant neurobehavioral outcomes in the RICHS cohort. PLoS One 9:e104913
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
Kappil, Maya; Chen, Jia (2014) Environmental exposures in utero and microRNA. Curr Opin Pediatr 26:243-51
Lester, Barry M; Conradt, Elisabeth; Marsit, Carmen J (2014) Are epigenetic changes in the intrauterine environment related to newborn neurobehavior? Epigenomics 6:175-8
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