Early life stage exposures to environmental contaminants can result in aberrant pancreatic ?-cell development, which may predispose an individual to diabetes. A common mode of toxicity shared by numerous, diverse environmental contaminants is the generation of reactive oxygen species (ROS) and oxidative stress. ROS and cellular redox potential play fundamental roles in normal embryonic development and cell signaling. Perturbation of these processes resulting from contaminant 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 oxidative stress, or the impact of toxicant exposures on pancreas development. The long-term goal of this research is to understand how embryos respond to oxidative stress, and how toxicant exposures contribute to the developmental origins of diabetes. The zebrafish (Danio rerio) is a well-established, widely used, and powerful model organism for studying vertebrate embryonic development in vivo. To investigate how changes in the developmental redox microenvironment affect toxicant sensitivity and pancreatic ?-cells at specific stages, we will us a fluorescent redox biosensor, redox imaging, and automated, time-lapse microscopy of transparent, transgenic zebrafish embryos exposed to environmental contaminants. This project will focus on environmentally relevant concentrations of persistent toxicants previously implicated in the etiology of diabetes (PCBs, phthalates, and the Teflon surfactant PFOS). We will examine the relationship between the most abundant antioxidant defense, glutathione (GSH), and the transcription factor Nrf2, that regulates the response to oxidative stress.
Our specific aims are: 1) elucidate the relationship between GSH and contaminant activation of Nrf2 during embryonic development and create an embryo redox map; 2) determine how an oxidant exposure history affects Nrf2 activation and toxicant sensitivity, 3) ascertain the roles of oxidative stress, GSH, and Nrf2 activation in deviant pancreatic ?-cell development, and identify critical sensitive windows of pancreas organogenesis. This research will lead to a mechanistic understanding of how early life chemical exposures and oxidative stress may damage the developing pancreas and predispose humans to diabetes and potentially other diseases. This work will also elucidate a poorly understood, but critical fundamental biological process- the role of the redox environment in embryonic development- and identify specific targets for mitigation and translational toxicology.

Public Health Relevance

People may be predisposed to diseases such as diabetes as a result of exposure to environmental contaminants during early life stages. Such exposures can cause oxidative stress, disrupt signaling pathways controlling embryo growth, and result in subtle structural or functional alterations to the insulin producing pancreatic ?-cells. This research will use the zebrafish embryo model to provide a mechanistic understanding of how embryonic exposure to such chemicals can damage the developing pancreas, and identify targets for mitigation and therapeutic interventions.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Systemic Injury by Environmental Exposure (SIEE)
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Schug, Thaddeus
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University of Massachusetts Amherst
Public Health & Prev Medicine
Schools of Public Health
United States
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Sant, Karilyn E; Timme-Laragy, Alicia R (2018) Zebrafish as a Model for Toxicological Perturbation of Yolk and Nutrition in the Early Embryo. Curr Environ Health Rep 5:125-133
Jacobs, Haydee M; Sant, Karilyn E; Basnet, Aviraj et al. (2018) Embryonic exposure to Mono(2-ethylhexyl) phthalate (MEHP) disrupts pancreatic organogenesis in zebrafish (Danio rerio). Chemosphere 195:498-507
Timme-Laragy, Alicia R; Hahn, Mark E; Hansen, Jason M et al. (2018) Redox stress and signaling during vertebrate embryonic development: Regulation and responses. Semin Cell Dev Biol 80:17-28
Brown, Sarah E; Sant, Karilyn E; Fleischman, Shana M et al. (2018) Pancreatic beta cells are a sensitive target of embryonic exposure to butylparaben in zebrafish (Danio rerio). Birth Defects Res 110:933-948
Sant, Karilyn E; Sinno, Paul P; Jacobs, Haydee M et al. (2018) Nrf2a modulates the embryonic antioxidant response to perfluorooctanesulfonic acid (PFOS) in the zebrafish, Danio rerio. Aquat Toxicol 198:92-102
Sant, Karilyn E; Jacobs, Haydee M; Borofski, Katrina A et al. (2017) Embryonic exposures to perfluorooctanesulfonic acid (PFOS) disrupt pancreatic organogenesis in the zebrafish, Danio rerio. Environ Pollut 220:807-817
Leung, Maxwell C K; Procter, Andrew C; Goldstone, Jared V et al. (2017) Applying evolutionary genetics to developmental toxicology and risk assessment. Reprod Toxicol 69:174-186
Sant, Karilyn E; Jacobs, Haydee M; Xu, Jiali et al. (2016) Assessment of Toxicological Perturbations and Variants of Pancreatic Islet Development in the Zebrafish Model. Toxics 4: