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 (TR?). 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.
Halogenated phenolic compounds (HPCs) and aryl organophosphate esters (AOPEs) are hazardous chemicals of high interest to the Superfund program and their stakeholders. The US population receives chronic exposure to both of these chemicals, particularly AOPEs (e.g. triphenyl phosphate, TPP) and polybrominated diphenyl ethers (PBDEs), which are metabolized to HPCs. They are ubiquitously detected in human tissues, with higher levels reported in young children relative to adults. Furthermore, they are considered to be endocrine disruptors and interfere with thyroid hormone regulation. This proposed research will help identify the mechanisms by which they interfere with thyroid hormone regulation and alter growth and skeletal development.
Showing the most recent 10 out of 291 publications
