Toxicant disruption of receptor-mediated endocytosis in oogenesis and later life metabolic dysfunction

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Summary 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 perfluorinated compounds (PFCs) disrupted MERC expression and altered oocyte nutrient quantity and composition. Further, these preconception PFC exposures impaired pancreatic organogenesis, decreasing insulin-producing islet area in the resulting embryos. In the nematode (Caenorhabditis elegans), preconception exposed eggs developed elevated triglyceride levels as adults, suggestive of metabolic dysfunction. The goal of this study is to gain a mechanistic understanding of the process by which preconception PFC exposures impair oocyte nutrient deposition, induce nutritional stress and predispose individuals to metabolic dysfunction later in life. We will use 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 first aim of this study will elucidate the mechanisms by which these maternal preconception exposures disrupt MERC function, and impair nutrient deposition in the oocyte. The second aim will assess how these exposures affect embryonic nutrition and development of the pancreas—a master regulator of glucose homeostasis and digestion. The third aim will delineate the truncation of the healthspan by assessing metabolic dysfunction later in life. Overall, this project will identify a mechanism by which maternal preconception exposures can reduce oocyte quality and impair metabolic function throughout the life course. 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.