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.
|Brown, D R; Bailey, J M; Oliveri, A N et al. (2016) Developmental exposure to a complex PAH mixture causes persistent behavioral effects in naive Fundulus heteroclitus (killifish) but not in a population of PAH-adapted killifish. Neurotoxicol Teratol 53:55-63|
|Luz, Anthony L; Godebo, Tewodros R; Bhatt, Dhaval P et al. (2016) From the Cover: Arsenite Uncouples Mitochondrial Respiration and Induces a Warburg-like Effect in Caenorhabditis elegans. Toxicol Sci 152:349-62|
|Lefevre, Emilie; Bossa, Nathan; Wiesner, Mark R et al. (2016) A review of the environmental implications of in situ remediation by nanoscale zero valent iron (nZVI): Behavior, transport and impacts on microbial communities. Sci Total Environ 565:889-901|
|Czaplicki, L M; Cooper, E; Ferguson, P L et al. (2016) A New Perspective on Sustainable Soil Remediation-Case Study Suggests Novel Fungal Genera Could Facilitate in situ Biodegradation of Hazardous Contaminants. Remediation (N Y) 26:59-72|
|Chernick, Melissa; Ware, Megan; Albright, Elizabeth et al. (2016) Parental dietary seleno-L-methionine exposure and resultant offspring developmental toxicity. Aquat Toxicol 170:187-98|
|Cooper, Ellen M; Kroeger, Gretchen; Davis, Katherine et al. (2016) Results from Screening Polyurethane Foam Based Consumer Products for Flame Retardant Chemicals: Assessing Impacts on the Change in the Furniture Flammability Standards. Environ Sci Technol 50:10653-10660|
|Riley, Amanda K; Chernick, Melissa; Brown, Daniel R et al. (2016) Hepatic Responses of Juvenile Fundulus heteroclitus from Pollution-adapted and Nonadapted Populations Exposed to Elizabeth River Sediment Extract. Toxicol Pathol 44:738-48|
|Santa-Gonzalez, Gloria A; Gomez-Molina, Andrea; Arcos-Burgos, Mauricio et al. (2016) Distinctive adaptive response to repeated exposure to hydrogen peroxide associated with upregulation of DNA repair genes and cell cycle arrest. Redox Biol 9:124-133|
|Petro, Ann; Sexton, Hannah G; Miranda, Caroline et al. (2016) Persisting neurobehavioral effects of developmental copper exposure in wildtype and metallothionein 1 and 2 knockout mice. BMC Pharmacol Toxicol 17:55|
|Abreu-VillaÃ§a, Yael; Levin, Edward D (2016) Developmental neurotoxicity of succeeding generations of insecticides. Environ Int :|
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