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

> **NIH NIH R01** · UNIVERSITY OF MASSACHUSETTS AMHERST · 2021 · $384,737

## Abstract

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.

## Key facts

- **NIH application ID:** 10246504
- **Project number:** 5R01ES028201-05
- **Recipient organization:** UNIVERSITY OF MASSACHUSETTS AMHERST
- **Principal Investigator:** Alicia R Timme-Laragy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,737
- **Award type:** 5
- **Project period:** 2017-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246504

## Citation

> US National Institutes of Health, RePORTER application 10246504, Toxicant disruption of receptor-mediated endocytosis in oogenesis and later life metabolic dysfunction (5R01ES028201-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10246504. Licensed CC0.

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