Social Disadvantage and Fetal Programming of Newborn-Infant Telomere Biology

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 DESCRIPTION (provided by applicant): Population health disparities are evident from the earliest stages of the life, persist over the life span, and are perpetuated across generations. Their most salient determinant is exposure to social disadvantage. Research has elucidated how social disadvantage gets biologically embedded to impact disease risk over the life span, but little is known about how its effects are transmitted across generations. Our application addresses this important gap. We propose to investigate the process of intergenerational (mother-to-child) transmission of social disadvantage, with a focus on newborn and infant telomere biology as the primary outcome, the intrauterine period as the transmission time window, and maternal-placental-fetal (MPF) stress biology as the proximate transmission pathway. Telomere dynamics play a fundamental, causal role in the maintenance of genomic and cellular integrity, and telomere dysfunction represents perhaps the most salient antecedent cellular phenotype of disease risk for common, age-related disorders. Animal and human studies converge to support the critical importance of the initial (early life) setting of telomere length (TL) and telomerase activity (TA) for future health and disease risk, but little is currentl known about the determinants of this initial setting. Published and preliminary data by us and others provides biological plausibility for the novel concept that the initial setting of the telomre system is plastic and substantially influenced by developmental conditions. We hypothesize that, at the cellular level, the origins of health disparities may trace back, in part, to the effets of maternal social disadvantage on the on the initial setting of her child's telomere length and telomerase expression capacity, mediated by the "programming" actions of maternal-placental-fetal (MPF) endocrine, immune and oxidative stress biology. We propose to test this hypothesis in a prospective, longitudinal cohort study of N=1,000 child-mother dyads with serial measures across gestation and birth through the first year of life. Because race/ethnicity and socioeconomic status (SES) represent the principal proxy measures of social disadvantage, and because racial/ethnic differences in health are most pronounced between Non-Hispanic Blacks (hereinafter `Black') and Non-Hispanic Whites (hereinafter `White'), our proposed study population will include approximately equal numbers of Black and White mothers and their offspring. A unique strength of this population is the substantial variation in SES not only across but also within the two racial/ethnic groups, which will enable us to extricate their independent and combined (interaction) effects. We also will evaluate whether effects vary by the sex of the child. Specific Aims: A1: To test the hypothesis that maternal social disadvantage is prospectively associated with newborn and infant telomere biology. A2: To test the hypothesis that maternal-placental-fetal (MPF) stress biology mediates the effects of social disadvantage on newborn and infant telomere biology. A3: Identify and quantify the maternal psychological, behavioral and biophysical characteristics that are associated with social disadvantage and may account for its impact on newborn and infant telomere biology. The significance and impact of this study derives from the importance of better understanding the determinants and mechanisms underlying age-related disease risk in minority, disadvantaged populations (NIA Reversibility Initiative 2012) to inform translational research on early identification and intervention.