# Examining thyroid hormone synthesis feedback loops as xenobiotic target for brominated flame retardant metabolites

> **NIH NIH R03** · UNIVERSITY OF FLORIDA · 2021 · $74,540

## Abstract

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 lev...

## Key facts

- **NIH application ID:** 10193280
- **Project number:** 1R03ES032889-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Joseph H Bisesi
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $74,540
- **Award type:** 1
- **Project period:** 2021-03-17 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10193280

## Citation

> US National Institutes of Health, RePORTER application 10193280, Examining thyroid hormone synthesis feedback loops as xenobiotic target for brominated flame retardant metabolites (1R03ES032889-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10193280. Licensed CC0.

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