# Activation of Nrf2 during embryonic development - mechanisms and consequences

> **NIH NIH R01** · UNIVERSITY OF MASSACHUSETTS AMHERST · 2022 · $488,597

## Abstract

Abstract
Early life stage exposures to toxicants can result in islet malformations, which may predispose individuals to
diabetes. The glutathione redox microenvironment plays fundamental roles in embryonic development and cell
signaling, perturbation of which can result in functional or structural alterations that only become apparent with
subsequent stress or age. Surprisingly little is known about how embryos respond to oxidative stress, or the
impact of toxicant exposures on pancreatic β-cell development. This project takes a multi-level approach using
state-of-the-art techniques to elucidate the complex pathophysiological mechanisms by which exposures to
Per-and-polyfluoroalkyl substances (PFAS) that cause oxidative stress derail islet development, and the
consequences for β-cell function. We test the central hypothesis that deviations from the GSH redox
microenvironment and aberrant activation of the transcription factor Nrf2- at the wrong place and the wrong
time- impair β-cell development and function. There are three overarching goals of this project: 1) to deepen
our understanding of the role of Nrf2 activation in embryonic β-cells and islet development; 2) ascertain the
impact of PFAS on insulin biosynthesis; and 3) identify β-cell fragility and bioindicators of later-life metabolic
impacts that can be translated to human health. We will use transgenic zebrafish, confocal microscopy and
immunofluorescence, redox proteomics and insulin misfolding assays, and cultured β-cells to investigate
exposures to two common PFAS (PFOS, PFHxS), and a legacy aqueous film-forming foam (AFFF). This work
will have a sustained and powerful impact on the fields of developmental toxicology, redox biology, and the
developmental origins of health and disease and provides critical advances towards developing science-based
PFAS guidelines, targets for clinical interventions, and public health policies.

## Key facts

- **NIH application ID:** 10467508
- **Project number:** 2R01ES025748-06
- **Recipient organization:** UNIVERSITY OF MASSACHUSETTS AMHERST
- **Principal Investigator:** Alicia R Timme-Laragy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $488,597
- **Award type:** 2
- **Project period:** 2016-06-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10467508

## Citation

> US National Institutes of Health, RePORTER application 10467508, Activation of Nrf2 during embryonic development - mechanisms and consequences (2R01ES025748-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10467508. Licensed CC0.

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