Developmental toxicants and congenital pancreas malformations

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Project Summary Early life stage exposures to xenobiotics can result in aberrant pancreatic development, which may predispose an individual to pancreatitis and metabolic dysfunction. A common mode of toxicity shared by numerous compounds is the generation of reactive oxygen species (ROS) and redox stress. ROS and cellular redox potential play fundamental roles in normal embryonic development and cell signaling. Perturbation of these processes resulting from xenobiotic exposure can alter cell fate decisions, resulting in functional or structural alterations that only become apparent with subsequent stress or age. However, surprisingly little is known about how embryos respond to redox stress, or the impact of xenobiotic exposures on pancreas development. Congenital pancreas malformations in humans are estimated to occur in approximately ten percent of the population and are associated with obesity, pancreatitis, Type 1 and Type 2 diabetes mellitus. The causes of these malformations are not well understood, and cannot be fully explained by genetic polymorphisms, suggesting a strong exogenous component. We have found that early life exposures to PFAS compounds and pro-oxidants results in a short exocrine pancreas. This grant takes a systems-level approach in transgenic zebrafish (Danio rerio) embryos to investigate a potential mechanism of oxidative stress in this deformity, and seeks to establish the functional outcomes of the truncated exocrine pancreas phenotype. Zebrafish are a well- established, widely used, and powerful model organism for studying vertebrate embryonic development in vivo. This work will facilitate advancement of a mechanistic understanding of how early-life xenobiotic exposures and redox stress can damage the developing pancreas and predispose humans to metabolic diseases.