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Duke University

Superfund Research Program

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

Project Leader: Heather M. Stapleton
Co-Investigators: P. Lee Ferguson, Seth W. Kullman (North Carolina State University)
Grant Number: P42ES010356
Funding Period: 2017-2022

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Project Summary (2017-2022)

The Duke University Superfund Research Program (SRP) Center examines the problem of early life exposure to hazardous chemicals and later life consequences. Researchers previously investigated the effects of halogenated phenolic chemicals (HPCs, e.g., bromophenols, hydroxylated brominated diphenyl ethers - OH-BDEs) on pathways regulated by thyroid hormones and examined effects on development in later life stages. The researchers 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 (bone/cartilage) cell lineages.

In this project, the researchers expand upon their previous findings that exposure to select HPCs and aryl organophosphate esters (AOPEs) can lead to defined skeletal malformations through modification of highly regulated osteochondral and adipogenic transcriptional programs. The Duke SRP Center researchers 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 they 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 peroxisome proliferator-activated receptor (PPAR) signaling pathways. The researchers are investigating this hypothesis using human cell cultures (in vitro) and the zebrafish model (in vivo). Specifically, they use cell cultures to investigate effects of these chemicals on proliferation and differentiation of mesenchymal stem cells, and ultimately use the zebrafish as an 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. Their results will also provide a hierarchical framework from the level of protein to cell to whole organism through which they link mechanistic insights for HPC exposures with acute developmental toxicities observed in a small aquarium fish model of human disease. Furthermore, they hope to identify key chemical structures that might impart greater bioactivity. The researchers anticipate their approach will facilitate a broader conceptual understanding of putative adverse outcome pathways for HPCs and help inform human and environmental risk assessments.

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