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.

Public Health Relevance

This project will investigate how maternal exposures to perfluorinated chemicals prior to conception disrupt the deposition of nutrients (lipids, protein, glucose) 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. We will examine redox disruptions affecting the expression and function of proteins that comprise the Multifunctional Endocytotic Receptor Complex that mediates this process, 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
3R01ES028201-03S1
Application #
10008145
Study Section
Special Emphasis Panel (ZES1)
Program Officer
Schug, Thaddeus
Project Start
2017-09-06
Project End
2020-05-31
Budget Start
2019-09-06
Budget End
2020-05-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Massachusetts Amherst
Department
Biostatistics & Other Math Sci
Type
Schools of Public Health
DUNS #
153926712
City
Hadley
State
MA
Country
United States
Zip Code
01035
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
Qi, Weipeng; Clark, John M; Timme-Laragy, Alicia R et al. (2018) Perfluorobutanesulfonic acid (PFBS) potentiates adipogenesis of 3T3-L1 adipocytes. Food Chem Toxicol 120:340-345
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