Before the placenta becomes fully functional late in the first trimester, the human embryo's primary source of nutrients is the yolk?a cache of maternally-deposited lipids and proteins. The deposition of yolk into the oocyte is governed by receptor-mediated endocytosis, namely by a receptor complex called MERC. Preliminary studies in zebrafish (Danio rerio) have shown that maternal exposures to per and polyfluorinatedalkyl compounds (PFAS) disrupted MERC expression and altered oocyte nutrient quantity and composition. Further, these preconception PFAS exposures impaired pancreatic organogenesis, decreasing insulin-producing islet area in the resulting embryos. The goal of this study is to gain a mechanistic understanding of the process by which preconception PFAS exposures impair oocyte nutrient deposition, induce nutritional stress and predispose individuals to metabolic dysfunction later in life. Additionally, we will assess the potential for a nutritional supplement, alpha lipoic acid, to mitigate the adverse effects on the oocyte and early life development. The R01 uses an evolutionary, three-model approach combining the strengths of the zebrafish, nematode, and fruitfly (Drosophila melanogaster) models (e.g. transparent, high numbers of progeny, short generation time, and transgenic and mutant lines) to assess the nutritional and metabolic consequences of preconception exposures to two persistent perfluorinated compounds: the legacy toxicant perfluorooctanesulfonic acid, and its emerging replacement chemical perfluorobutanesulfonic acid. The administrative supplement expands this to look at the potential of the dietary supplement alpha-lipoic acid to ameliorate maternal transfer of PFOS into oocytes and subsequent offspring growth and pancreas development. We will use the zebrafish and the fruitfly for the work in the supplement. Overall, this project will identify a mechanism by which maternal preconception exposures can reduce oocyte quality and impair metabolic function throughout the life course, and identify a potential solution to protect human health. This project addresses NIEHS goals to 1) identify key ?sensitive? windows during which exposures may contribute to the Developmental Origins of Health and Disease paradigm, and 2) discover hazards posed by emerging contaminants.
This project will investigate how maternal exposures to perfluorinated chemicals prior to conception disrupt the deposition of nutrients and toxicants into the oocyte, and predispose offspring to metabolic dysfunction later in life. We will use three model organisms (zebrafish, worms, and flies) which are widely used models for studying metabolic dysfunction in humans, and differentiate whether the altered lipid content in the egg or maternal loading of toxicants into the egg is responsible for the later metabolic phenotypes and truncation of the healthspan. In this supplement to this project, we will assess whether a nutritional supplement- alpha lipoic acid- can mitigate the adverse effects on oocyte nutrition and offspring health.
|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:|