Many halogenated, persistent, and bioaccumulative contaminants have been classified as endocrine disrupters, and in many cases these contaminants negatively impact thyroid regulation. Many of these contaminants share similar chemical structures with thyroid hormones, including aromatic linkages, halogenated substitutents and hydroxylation of the aromatic rings. These structural similarities may result in competitive binding with the thyroid regulating enzymes, diodinases (DIs), which convert the pro-hormone, thyroxine (T4), to the active hormone, triiodothyronine (T3), and/or to thyroid nuclear receptors. Very few studies have explored the impacts of these contaminants on tissue-specific hormone levels and Dl activity, and the potential consequences on development following early life exposure. Preliminary studies by the PI demonstrate that PBDEs decrease circulating thyroid hormones in fathead minnows, and inhibit Dl activity by more than 50% in vitro. Thus we propose that the mechanism, of thyroid toxicity involves impacts on deiodinase activity in tissues, affecting availability of T3 to bind to the thyroid nuclear receptors and activate transcriptional events critical to growth and development. The central hypothesis of this proposal is that exposure to halogenated contaminants (PBDEs and triclosan) alters thyroid homeostasis via impacts on Dl activity and by competition with thyroid nuclear receptors. We propose to investigate this hypothesis using zebrafish as a model.
The specific aims of this study are: 1. To examine structure-activity relationships between halogenated aromatic contaminants and inner and outer ring Dl activity in vitro;2. To examine the influence of chemical structure on binding and activation of thyroid hormone nuclear receptors;3. To examine impacts of PBDEs, chlorinated organophosphate compounds (e.g. chlorpyrifos), and BaP on Dl activity in the mixed neuronal/glial cell cultures used in the NBTA core;4. To examine the effects of both acute and chronic exposure to PBDEs and triclosan on tissue-specific Dl activity, thyroid hormone levels, and mRNA expression of thyroid genes in embryonic and larval stage zebrafish exposed in vivo;and 5.
Specific Aim 5 : To determine if early life exposure to PBDEs and triclosan affects development and behavior.

Public Health Relevance

This outlined study is directly relevant to the goals of the Superfund Program by invesfigafing early life exposures to halogenated, Superfund-related, chemicals and by investigating thyroid toxicity mechanisms of acfion. Outcomes from this project will have relevance to understanding developmental effects observed in both the biomedical and non-biomedical projects.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
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Special Emphasis Panel (ZES1-SET-V (04))
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Duke University
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Raftery, Tara D; Jayasundara, Nishad; Di Giulio, Richard T (2017) A bioenergetics assay for studying the effects of environmental stressors on mitochondrial function in vivo in zebrafish larvae. Comp Biochem Physiol C Toxicol Pharmacol 192:23-32
Mu, Jingli; Chernick, Melissa; Dong, Wu et al. (2017) Early life co-exposures to a real-world PAH mixture and hypoxia result in later life and next generation consequences in medaka (Oryzias latipes). Aquat Toxicol 190:162-173
Slotkin, Theodore A; Skavicus, Samantha; Card, Jennifer et al. (2017) In vitro models reveal differences in the developmental neurotoxicity of an environmental polycylic aromatic hydrocarbon mixture compared to benzo[a]pyrene: Neuronotypic PC12 Cells and embryonic neural stem cells. Toxicology 377:49-56
Luz, Anthony L; Godebo, Tewodros R; Smith, Latasha L et al. (2017) Deficiencies in mitochondrial dynamics sensitize Caenorhabditis elegans to arsenite and other mitochondrial toxicants by reducing mitochondrial adaptability. Toxicology 387:81-94
Hartman, Jessica H; Kozal, Jordan S; Di Giulio, Richard T et al. (2017) Zebrafish have an ethanol-inducible hepatic 4-nitrophenol hydroxylase that is not CYP2E1-like. Environ Toxicol Pharmacol 54:142-145
Meyer, Joel N; Chan, Sherine S L (2017) Sources, mechanisms, and consequences of chemical-induced mitochondrial toxicity. Toxicology 391:2-4
Slotkin, Theodore A; Skavicus, Samantha; Seidler, Frederic J (2017) Diazinon and parathion diverge in their effects on development of noradrenergic systems. Brain Res Bull 130:268-273
Lindberg, C D; Jayasundara, N; Kozal, J S et al. (2017) Resistance to polycyclic aromatic hydrocarbon toxicity and associated bioenergetic consequences in a population of Fundulus heteroclitus. Ecotoxicology 26:435-448
Abreu-Villa├ža, Yael; Levin, Edward D (2017) Developmental neurotoxicity of succeeding generations of insecticides. Environ Int 99:55-77
Jayasundara, Nishad; Fernando, Pani W; Osterberg, Joshua S et al. (2017) Cost of Tolerance: Physiological Consequences of Evolved Resistance to Inhabit a Polluted Environment in Teleost Fish Fundulus heteroclitus. Environ Sci Technol 51:8763-8772

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