The goal of this proposal is to extend the scope of our on-going studies to test specific hypotheses regarding the effects of maternal-placental-fetal stress biology during intrauterine life on the human newborn and infant telomere biology system. The elucidation of biological mechanisms underlying the effects of the intrauterine environment on subsequent health and disease risk outcomes (fetal/developmental programming) is an area of active interest and intense investigation. We advance the hypothesis that telomere biology may represent an important and novel mechanism underlying the observed effects of disparate suboptimal intrauterine exposures on subsequent health and disease risk phenotypes of interest. We propose to focus on two key telomere biology-related outcomes - leukocyte telomere length at birth and at 12 months age, and mitogen-stimulated leukocyte telomerase expression at birth, and on the effects of a major biological pathway in human gestation - stress-related maternal-placental-fetal (MPF) endocrine, immune/inflammatory and oxidative state - that may mediate the effects of a diverse set of suboptimal conditions on the developing fetus. We will conduct a prospective, longitudinal, follow-up study in a representative, population-based cohort of N=120 newborns from birth (T1) and over the early postnatal growth phase until 12 months age (T2). A unique strength of our proposal is the availability in our "parent" projects (RO1 HD-060628, RO1 HD-065825) of a cohort of newborns and infants who are extensively characterized over the course of intrauterine and postnatal life with the measures required in the present study. Another notable feature includes our trans-disciplinary team of investigators with a collaboration record and extensive, published expertise in maternal-placental-fetal stress biology (Pathik Wadhwa, Sonja Entringer), telomere biology (Elizabeth Blackburn, Elissa Epel, Jue Lin), immunology (Edward Nelson), and obstetrics/neonatology (Deborah Wing, Hyagriv Simhan). We will address the following Specific Aims: 1) To test the hypothesis that exposure to elevated intrauterine biological stress predicts a) newborn leukocyte telomere length (LTL) and b) change in LTL from birth till 12 months age. 2) To test the hypothesis that exposure to elevated intrauterine biological stress predicts newborn leukocyte telomerase activity. 3) After identifying which measures of intrauterine stress biology (and at which specific time points in gestation) predict newborn and infant LTL and telomerase activity, we will address exploratory questions of their determinants using the available comprehensive data collected in the on-going "parent" projects. The significance and impact of this study derives from the importance of achieving at a better understanding of underlying processes (mechanisms) that alter risk or vulnerability for subsequent health and disease risk outcomes. This study will collect novel data (serial measures of newborn and infant telomere biology) and address hypotheses that set the stage for translational research. We submit that this proposed study represents an appropriate expansion of the scientific scope of the parent project.

Public Health Relevance

This proposal addresses the question whether exposure to excess biological stress during intrauterine life may program the newborn and infant telomere biology system in a manner that accelerates cellular dysfunction, aging and disease susceptibility. A substantial body of evidence suggests that the intrauterine and early postnatal life environment may play a critical role in determining health and susceptibility for a range of complex, common disorders that confer a major, global burden of disease (i.e., the concept of fetal or developmental programming of health and disease). The elucidation of biological mechanisms underlying these observed effects is an area of active interest and intense investigation. We suggest telomere biology may represent an important and novel underlying mechanism for the observed effects. Our proposed study will quantify the effects of prenatal biological stress on newborn and infant leukocyte telomere length and newborn telomerase activity. By using biological (maternal-placental-fetal endocrine, immune and oxidative) stress measures that are known to reflect a variety of possible intrauterine perturbations, we suggest our approach will be more effective in capturing fetal exposure to a broader set of factors than other studies that have focused primarily on size at birth or maternal under- or overnutrition during pregnancy. By examining changes in telomere length over time, our study will clarify whether the mechanisms that underlie the effects of exposure to adverse intrauterine conditions relate to telomere attrition rate in early life. By concurrently assessing telomerase activity afte mitogen stimulation in cord blood at birth, we will be able to quantify the consequences of intrauterine perturbation-related changes on the maximal capacity of cells to produce telomerase. Thus, the scientific significance of this research is that it will clarify the mechaniss that underlie individual vulnerability for in utero stress-related health outcomes. The public health impact is that the information gained from this study will contribute knowledge that is required to ultimately develop and test interventions to prevent, minimize or reverse the risk for a range of complex, common aging-related disorders that confer a major, global burden of disease as a consequence of the exposures during intrauterine life, and thereby promote better health for our children and future generations.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
3R01HD060628-04S1A1
Application #
8514381
Study Section
Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
Program Officer
Reddy, Uma M
Project Start
2009-01-01
Project End
2015-01-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$317,921
Indirect Cost
$111,311
Name
University of California Irvine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Graham, Alice M; Buss, Claudia; Rasmussen, Jerod M et al. (2016) Implications of newborn amygdala connectivity for fear and cognitive development at 6-months-of-age. Dev Cogn Neurosci 18:12-25
Short, Sarah J; Stalder, Tobias; Marceau, Kristine et al. (2016) Correspondence between hair cortisol concentrations and 30-day integrated daily salivary and weekly urinary cortisol measures. Psychoneuroendocrinology 71:12-8
Moog, Nora K; Buss, Claudia; Entringer, Sonja et al. (2016) Maternal Exposure to Childhood Trauma Is Associated During Pregnancy With Placental-Fetal Stress Physiology. Biol Psychiatry 79:831-9
Moog, N K; Entringer, S; Heim, C et al. (2015) Influence of maternal thyroid hormones during gestation on fetal brain development. Neuroscience :
Entringer, Sonja; Epel, Elissa S; Lin, Jue et al. (2015) Maternal Folate Concentration in Early Pregnancy and Newborn Telomere Length. Ann Nutr Metab 66:202-8
Entringer, Sonja; Buss, Claudia; Wadhwa, Pathik D (2015) Prenatal stress, development, health and disease risk: A psychobiological perspective-2015 Curt Richter Award Paper. Psychoneuroendocrinology 62:366-75
Lindsay, Karen L; Hellmuth, Christian; Uhl, Olaf et al. (2015) Longitudinal Metabolomic Profiling of Amino Acids and Lipids across Healthy Pregnancy. PLoS One 10:e0145794
Fox, Molly; Entringer, Sonja; Buss, Claudia et al. (2015) Intergenerational transmission of the effects of acculturation on health in Hispanic Americans: a fetal programming perspective. Am J Public Health 105 Suppl 3:S409-23
Entringer, Sonja; Epel, Elissa S; Lin, Jue et al. (2015) Maternal estriol concentrations in early gestation predict infant telomere length. J Clin Endocrinol Metab 100:267-73
Shalev, Idan; Entringer, Sonja; Wadhwa, Pathik D et al. (2013) Stress and telomere biology: a lifespan perspective. Psychoneuroendocrinology 38:1835-42

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