PROJECT SUMMARY The Developmental Origins of Health and Disease model, that the early life environment has widespread consequences for later health, has been applied primarily to the role of prenatal stressors on offspring outcomes. Despite compelling new evidence that vulnerable exposure windows occur prior to conception, very little is known about the impact of preconception stress exposure on pregnancy health, the fetal environment, or on offspring neurodevelopment. In response to RFA-OD-16-004 ‘Environmental Influences on Child Health Outcomes (ECHO) Pediatric Cohorts’ (UG3/UH3), we propose to test the hypothesis that preconception environmental stress exposure will predict deficits in offspring neurodevelopment via alterations in maternal capacity to regulate stress during pregnancy. Furthermore, we contend that preconception nutrition status will attenuate the negative effects of preconception stress exposure on offspring outcomes. The proposed study will build on the Pittsburgh Girls Study (PGS), a longitudinal study of 2,450 urban-living young women for whom the timing and chronicity of multiple stress exposures (e.g. housing and family stress, exposure to violence) has been prospectively and robustly measured for the past 16 years spanning childhood through early adulthood. The majority of PGS participants are from populations that are under-represented in research: African-Americans and women from low-income environments. Biomarkers of preconception stress exposure (i.e. immune and cardiometabolic function) and nutrition (i.e., vitamin D, fatty acids, iron, protein and folic acid) will be assessed in early adulthood. PGS participants who become pregnant over the period of award (N ≈ 800) will complete three psychophysiological assessments of stress regulation (e.g. intensity and recovery of cortisol response) during pregnancy, and placental function will be assessed. Offspring neurodevelopment will be assessed at 6, 15, 24 and 36 months with multi-modal measures (e.g., neural and behavioral measures of executive function and stress reactivity). The first study aim is to elucidate the prospective associations between preconception stress exposure and deficits in offspring neurodevelopment. The second aim is to determine the extent to which prenatal stress regulation mediates this association. Our UG3 feasibility aims will be carried out within the PGS infrastructure, thereby ensuring that methods established will translate seamlessly to the proposed study. Our interdisciplinary team has expertise in every aspect of the proposed study and includes long-standing, productive collaborations between investigators at the Universities of Pittsburgh and Chicago, institutions that are extremely well-suited to support the proposed study. Achieving the stated aims of the proposed study will contribute to the identification of prerequisites for optimal child health. Furthermore, our prospective design for measuring prenatal stress regulation and off...