# Altering the Balance of Adipogenic and Osteogenic Regulatory Pathways from Early Life Exposure to HPCs and AOPEs

> **NIH NIH P42** · DUKE UNIVERSITY · 2020 · $178,015

## Abstract

Project Summary/Abstract
Duke’s Superfund research center examines the problem of early life exposure to hazardous chemicals and
later life consequences. Over the last funding period, Project 2 investigated the effects of halogenated phenolic
chemicals (HPCs, e.g. bromophenols, OH-BDEs) on pathways regulated by thyroid hormones and examined
effects on development in later life stages. We found that 6-OH-BDE 47 was the most acutely toxic HPC
investigated (LC50=130 nM) in early life stage exposures to zebrafish, resulting in delayed development, loss
of pigmentation, and skeletal deformities which was mediated at least in part by down regulation of thyroid
hormone receptor beta (TRβ). TR receptors in conjunction with multiple nuclear receptors (PPARy, VDR, ER)
facilitate a highly coordinated and orchestrated series of events governing the commitment and differentiation
of mesenchymal stem cells to multiple mesenchymal lineages including osteoblasts (bone cells), chondrocytes
(cartilage cells), adipocytes (fat cells) and others. A theme that is emerging in this field is that early life toxicant
exposures may alter gene regulatory networks that coordinate the balance of mesenchymal stem cell
commitment towards adipogenic and osteochondral lineages. Here we expand upon our previous findings that
exposure to select HPCs and AOPEs can lead to defined skeletal malformations through modification of highly
regulated osteochondral and adipogenic transcriptional programs. We anticipate that the effects of HPCs and
APEs on skeletal and adipogenic development may be occurring through TR and PPAR mediated pathways
that converge on similar phenotypes. Here we test the hypothesis that early life exposure to HPCs and APEs
result in adverse effects on both osteochondral and adipogenic development through dysregulation of TR and
PPAR signaling pathways. We propose to investigate this hypothesis using human cell cultures (in vitro) and
the zebrafish model (in vivo). Specifically we will evaluate nuclear receptor structure-function, use cell cultures
to investigate effects of these chemicals on proliferation and differentiation of mesenchymal stem cells, and
ultimately use the zebrafish as in vivo model to quantify effects on craniofacial and skeletal development and
adiposity. Results from this project will help us elucidate cross-talk and compensatory responses of chemicals
that disrupt both TR and PPAR signaling pathways. They will also provide a hierarchical framework from the
level of protein to cell to whole organism through which we will link mechanistic insights for HPC exposures
with acute developmental toxicities observed in a small aquarium fish model of human disease. Furthermore
we hope to identify key chemical structures that might impart greater bioactivity. We anticipate our approach
will facilitate a broader conceptual understanding of putative adverse outcome pathways for HPCs and help
inform human and environmental risk assessments.

## Key facts

- **NIH application ID:** 9942437
- **Project number:** 5P42ES010356-18
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** HEATHER M STAPLETON
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $178,015
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942437

## Citation

> US National Institutes of Health, RePORTER application 9942437, Altering the Balance of Adipogenic and Osteogenic Regulatory Pathways from Early Life Exposure to HPCs and AOPEs (5P42ES010356-18). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9942437. Licensed CC0.

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