Although the impact of prenatal alcohol exposure (PAE) on early development has been well established, the Developmental Origins of Health and Disease (DOHaD) hypothesis suggests there may be longer- term consequences that increase the risk for adult diseases or disorders. Previously, it has been difficult to isolate the effects of PAE from those associated with other life experiences in affected individuals so that, often, the role of PAE may be overlooked. In fact, viewed from this context, PAE may be considered the first in a series of adverse exposures that result, eventually, in a higher risk for negative outcomes in this vulnerable population. Programing of fetal systems by PAE may alter the developmental trajectory and result in a sensitized organism that is vulnerable to later life challenges. The endocrine and immune systems have been found to be highly susceptible to programming by early life events, and together are thought to play key roles in linking early life adverse exposures with long-term health and functional outcomes. Thus, programming of these systems may be one mechanism by which PAE impacts adult health and neurobehavioral outcomes. In our ongoing CIFASD4 research negative impacts of PAE on physical and mental health outcomes in midlife were observed and attributable to both PAE and to associated early life adversity and social factors. Also noted were long-lasting, adverse changes in immune function, with inflammation starting in infancy and lasting into adulthood, suggesting an increased inflammatory burden over the life course. In the proposed study, we will test a “multiple hit” hypothesis that PAE results in a vulnerable organism that may be further impacted by social adversity and lack of resources/coping skills, resulting in immune and endocrine dysregulation that in turn, may be key drivers of early-onset health and neurobehavioral problems over the life course. 360 individuals representing a diverse sample of affected individuals from three sites, Atlanta, Seattle, and Canada, will participate in a quasi-experimental study of PAE effects in midlife. In addition to measuring PAE/FASD and environmental conditions, we will use state-of-the-art methodologies to identify biomarkers (inflammatory, angiogenesis, vascular injury, metabolic, and neurodegenerative markers, transcriptional profiling of individual cells, and telomere length) of early-onset functional deficits including both physical and mental health. Specifically, within the context of the negative effects of social adversity and the positive influences of social resources and coping skills, we will evaluate: Aim 1. the role of immune and endocrine dysregulation in physical and mental health outcomes in adults with FASD/PAE; Aim 2 the impact of PAE and the possible role of PAE-induced immune and endocrine dysregulation on neurocognitive performance and markers of early-onset functional deficits in adults with FASD/PAE in comparison to age-matched controls and...