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 #
5R01ES022223-02
Application #
8726395
Study Section
Neurological, Aging and Musculoskeletal Epidemiology Study Section (NAME)
Program Officer
Mcallister, Kimberly A
Project Start
2013-09-01
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Hanover
State
NH
Country
United States
Zip Code
03755
Paquette, Alison G; Houseman, E Andres; Green, Benjamin B et al. (2016) Regions of variable DNA methylation in human placenta associated with newborn neurobehavior. Epigenetics 11:603-13
Green, Benjamin B; Houseman, E Andres; Johnson, Kevin C et al. (2016) Hydroxymethylation is uniquely distributed within term placenta, and is associated with gene expression. FASEB J 30:2874-84
Andersson, Niklas W; Li, Qian; Mills, Carrie W et al. (2016) Influence of prenatal maternal stress on umbilical cord blood cytokine levels. Arch Womens Ment Health 19:761-7
Appleton, Allison A; Murphy, Megan A; Koestler, Devin C et al. (2016) Prenatal Programming of Infant Neurobehaviour in a Healthy Population. Paediatr Perinat Epidemiol 30:367-75
Kingsley, Samantha L; Eliot, Melissa N; Whitsel, Eric A et al. (2016) Maternal residential proximity to major roadways, birth weight, and placental DNA methylation. Environ Int 92-93:43-9
Thompson, Jeffrey A; Marsit, Carmen J (2016) A METHYLATION-TO-EXPRESSION FEATURE MODEL FOR GENERATING ACCURATE PROGNOSTIC RISK SCORES AND IDENTIFYING DISEASE TARGETS IN CLEAR CELL KIDNEY CANCER. Pac Symp Biocomput 22:509-520
Marsit, Carmen J (2016) Placental Epigenetics in Children's Environmental Health. Semin Reprod Med 34:36-41
Marsit, Carmen J (2015) Influence of environmental exposure on human epigenetic regulation. J Exp Biol 218:71-9
Paquette, Alison G; Lester, Barry M; Lesseur, Corina et al. (2015) Placental epigenetic patterning of glucocorticoid response genes is associated with infant neurodevelopment. Epigenomics 7:767-79
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

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