Grant Abstract: Activation of Nrf2 during embryonic development: mechanisms and consequences

Grant Number: 5R01ES025748-04
PI Name: Timme-Laragy
Project Title: Activation of Nrf2 during embryonic development: mechanisms and consequences

Abstract: 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.

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