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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R03ES032889&format=word)
| Principal Investigator: Bisesi, Joseph H | |
|---|---|
| Institute Receiving Award | University Of Florida |
| Location | Gainesville, FL |
| Grant Number | R03ES032889 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 17 Mar 2021 to 29 Feb 2024 |
| DESCRIPTION (provided by applicant): | Project Summary Polybrominated diphenyl ethers (BDEs) were used as flame retardants until they were phased out in the USA several years ago due to concerns about their environmental persistence and toxicity. However, continued human exposure to BDEs is well established and is linked to neurodevelopmental deficits and disruption of circulating thyroid hormones. While most studies have focused on interactions of these contaminants with thyroids receptors involved in reproductive and metabolic functions, little attention has been paid to mechanisms involving thyroid hormone biosynthesis pathways. In light of the epidemiological associations between BDE exposure and circulating thyroid hormone levels, and the lack of studies that examine the mechanistic drivers of this phenomenon, the overall scientific premise of this proposal is that exposure to OH-BDEs disrupts the negative feedback inhibition of thyroid hormone biosynthesis. Modulation of this important biosynthesis pathway may be the missing link to explain the epidemiological associations between BDEs in the blood and hypothyroidism. We posit that there are two understudied mechanisms through which BDEs and their metabolites may modulate circulating thyroid hormones. The first mechanism will examine OH-BDE metabolites interactions with the thyroid hormone receptor beta 2 (TRβ2), a thyroid receptor isoform found exclusively in the hypothalamus and pituitary where it is involved in feedback inhibition of thyroid hormone synthesis. The second mechanism will examine indirect modulation of thyroid receptor function by OH-BDE-via epigenetic mechanisms, specifically miRNAs. We propose two highly independent but related specific aims to address these knowledge gaps. These studies are designed to test hypotheses related to OH-BDE regulation of upstream hypothalamic feedback loops that control circulating levels of thyroid hormone. Specific aim 1 will test the hypothesis that OH- BDEs will antagonize the hypothalamic and pituitary specific thyroid receptor, TRβ2, ultimately decreasing thyrotropin-releasing hormone (TRH) in hypothalamic neuronal cells. These hypotheses will be tested using thyroid hormone receptor reporter assays and a hypothalamus cell line. Specific aim 2 will test the hypothesis that thyroid hormone receptor expression is repressed in the hypothalamus by miRNA regulators in the presence of OH-BDEs. This hypothesis will be tested by measuring miRNA regulators of TRs in hypothalamic cells in relation to TRs expression and TRH. If hypothalamic miRNA regulators of TRs correlate to changes in synthesized TRH, we will conclude that miRNAs are key regulators by which OH-BDEs impose negative effects on the thyroid system. Completion of these aims will lend mechanistic insight into the observed thyroid effects associated with exposure to brominated flame retardants. These assays are adaptable to other thyroid hormone disruptors and this mechanism may be significant in regulating circulating levels of thyroid hormones following environmental chemical exposures. Results from these studies will lend important evidence to support future in vivo research proposals focused on these mechanisms. |
| Science Code(s)/Area of Science(s) |
Primary: 50 - Endocrine System Secondary: 03 - Carcinogenesis/Cell Transformation |
| Publications | No publications associated with this grant |
| Program Officer | Thaddeus Schug |