Project 2: Thyroid Metabolism Disruption Key in Toxicant-Induced Developmental Im

Duke University, Durham NC

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Abstract

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.