Environmental and Genetic Perturbations During Development Shape Multi-Organ Health Outcomes

Abstract

The developmental origin of health and disease hypothesis (DOHaD) postulates that environmental and genetic factors present during prenatal and perinatal stages alter development and fundamentally influence adolescent and adult health. Adverse or stressful intrauterine events repeatedly associate with poor health outcomes, including psychiatric disease, neurobehavioral abnormalities, metabolic disease, and cardiovascular disorders. Prenatal alcohol exposure (PAE) is a common developmental stressor that can result in fetal alcohol spectrum disorder (FASD). At least 10% of pregnancies involve alcohol exposure, and recent estimates suggest that 2.5 - 5% of babies born from North America and Europe, and greater than 10% of those from South Africa, have FASD. Affected patients can present with behavioral and cognitive alterations, nerve and brain abnormalities, birth defects in organs such as the heart and kidney, and craniofacial anomalies. The teratogenic effects of EtOH are thought to have a lifelong impact on affected individuals; however, the consequences of PAE on adult metabolic health outcomes have yet to be characterized. Furthermore, the cellular and molecular mechanisms underlying EtOH’s teratogenicity are poorly understood. In Chapter 2, I investigate metabolic health outcomes in FASD. I demonstrate that adults with FASD have an increased incidence of metabolic abnormalities, including type 2 diabetes, low HDL, high triglycerides, and female-specific overweight and obesity, and recapitulate these findings in zebrafish model of embryonic alcohol exposure (EAE). Furthermore, I identify several consequences of EAE that may contribute to these phenotypes, including a reduction in adult swimming activity, diet-responsive transcriptional changes, and alterations in visceral adipocyte and hepatic development. In Chapter 3, I identify the proteasome as a critical target of EAE and demonstrate that EtOH-induced disruptions to the ubiquitin proteasome system (UPS) may contribute to neurodevelopmental disorder, craniofacial malformation, and endoderm defects following EAE. Finally, in Chapter 4, I interrogate the role of nuclear receptor nr5a2 in endoderm formation and demonstrate that it is required for hepatopancreas development. Taken together, this dissertation demonstrates the life-long impact of environmental and genetic perturbations during development, and provides clinically relevant insight into the metabolic health outcomes and molecular underpinnings of FASD.