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.
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.
|Oliveri, Anthony N; Ortiz, Erica; Levin, Edward D (2018) Developmental exposure to an organophosphate flame retardant alters later behavioral responses to dopamine antagonism in zebrafish larvae. Neurotoxicol Teratol 67:25-30|
|Slotkin, Theodore A; Skavicus, Samantha; Seidler, Frederic J (2018) Developmental neurotoxicity resulting from pharmacotherapy of preterm labor, modeled in vitro: Terbutaline and dexamethasone, separately and together. Toxicology 400-401:57-64|
|Lefèvre, Emilie; Bossa, Nathan; Gardner, Courtney M et al. (2018) Biochar and activated carbon act as promising amendments for promoting the microbial debromination of tetrabromobisphenol A. Water Res 128:102-110|
|Kollitz, Erin M; Kassotis, Christopher D; Hoffman, Kate et al. (2018) Chemical Mixtures Isolated from House Dust Disrupt Thyroid Receptor ? Signaling. Environ Sci Technol :|
|Hartman, Jessica H; Smith, Latasha L; Gordon, Kacy L et al. (2018) Swimming Exercise and Transient Food Deprivation in Caenorhabditis elegans Promote Mitochondrial Maintenance and Protect Against Chemical-Induced Mitotoxicity. Sci Rep 8:8359|
|Luz, Anthony L; Kassotis, Christopher D; Stapleton, Heather M et al. (2018) The high-production volume fungicide pyraclostrobin induces triglyceride accumulation associated with mitochondrial dysfunction, and promotes adipocyte differentiation independent of PPAR? activation, in 3T3-L1 cells. Toxicology 393:150-159|
|Day, D B; Xiang, J; Mo, J et al. (2018) Combined use of an electrostatic precipitator and a high-efficiency particulate air filter in building ventilation systems: Effects on cardiorespiratory health indicators in healthy adults. Indoor Air 28:360-372|
|Slotkin, Theodore A; Ko, Ashley; Seidler, Frederic J (2018) Does growth impairment underlie the adverse effects of dexamethasone on development of noradrenergic systems? Toxicology 408:11-21|
|Rock, Kylie D; Horman, Brian; Phillips, Allison L et al. (2018) EDC IMPACT: Molecular effects of developmental FM 550 exposure in Wistar rat placenta and fetal forebrain. Endocr Connect 7:305-324|
|Weinhouse, Caren; Truong, Lisa; Meyer, Joel N et al. (2018) Caenorhabditis elegans as an emerging model system in environmental epigenetics. Environ Mol Mutagen 59:560-575|
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