ABSTRACT Exposure to social disadvantage is the most salient determinant of population health disparities. Although sub- stantial progress had been made in understanding how social disadvantage becomes biologically embedded, crucial knowledge gaps remain. Biological embedding has been described primarily at the level of differentiated cell types and tissues. Based on the consideration that a) social disadvantage’s long-term effects extend well beyond the lifespan of differentiated cells, whose replenishment occurs only from stem/progenitor cells, and b) can be perpetuated across generations, we advance the novel hypothesis that the origins of health disparities may extend all the way down to the level of stem cells, and specifically to the effects of maternal social disadvantage exposure on offspring stem cells during embryonic/fetal life. Our proposed study will focus on disparities between Hispanic, non-Hispanic Black, and non-Hispanic White mothers and their newborns in obesity and metabolic phenotypes; on mesenchymal progenitor/stromal cells (MSCs) and MSC- derived adipocytes as the stem and differentiated cells of interest; on mitochondrial function, adipogenic propensity/activity and insulin sensitivity as the key intracellular processes of importance; on newborn adipose tissue mass and glucose-insulin regulation as the outcomes of significance; and on maternal-fetal gestational biology as the proximate transmission pathway. We will conduct this study in a cohort of N=240 child-mother dyads; isolate and culture fetal MSCs from newborn cord tissue; perform high-resolution cellular experiments; and characterize neonatal phenotypes in vitro in MSC-derived adipoctyes, and in vivo using whole body densitometry. Aim 1 will test the hypothesis that maternal exposure to social disadvantage is associated with newborn mesenchymal stem cell characteristics, i.e., reduced mitochondrial efficiency, increased adipogenic propensity, and reduced insulin sensitivity. Aim 2 will test the hypothesis that variation in ma- ternal and fetal gestational biology (composite measures of endocrine, immune/inflammatory, and metabolic ligands) mediates the effects of social disadvantage on newborn mesenchymal stem cells. Aim 3 will establish the clinical significance of variation in MSC characteristics for neonatal obesity-related phenotypes at the a) cellular level (MSC- derived adipocyte size and fat content; mitochondrial function; adipogenic activity), and b) whole-body level (percent fat mass and systemic insulin sensitivity). Aim 4 (exploratory) will elucidate potentially modifiable maternal psychosocial and behavioral factors that relate to the specific components of social disadvantage that are associated with new- born MSC biology. Aim 5 will establish a shared repository (biobank) of MSC, cord blood, cord and placental tissue samples for future studies of molecular mechanisms (gene expression profiles, epigenetic characteristics) and in vitro cell differenti...