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

检查甲状腺激素合成反馈回路作为溴化阻燃剂代谢物的异生素靶标

• 批准号: 10373054
• 负责人: Joseph H Bisesi
• 金额: $ 7.45万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-17 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373054
• 关键词: Address; Affinity; Anabolism; Attention; Biological Assay; Blood; Body Fluids; Cell Line; Cells; Chemicals; Conflict (Psychology); Consumption; Data; Environment; Epidemiology; Epigenetic Process; Exposure to; Feedback; Flame Retardants; Functional disorder; Future; Hormones; House Dust; Hypothalamic structure; Hypothyroidism; Impairment; Knowledge; Light; Link; Literature; Measurable; Measures; Messenger RNA; Metabolic; Metabolite Interaction; MicroRNAs; Natural Products; Nature; Neurodevelopmental Deficit; Neurons; Pathway interactions; Pattern; Phase; Pituitary Gland; Plasmids; Play; Process; Production; Protein Isoforms; Receptors, Adrenergic, beta-1; Regulation; Reporter; Reporting; Research; Research Proposals; Role; Seafood; Source; System; Testing; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormone Receptor beta 2; Thyroid Hormones; Thyrotropin-Releasing Hormone; Toxic effect; Xenobiotics; desensitization; design; environmental chemical exposure; epidemiology study; experimental study; exposed human population; exposure route; hormone biosynthesis; in silico; in vivo; insight; marine organism; novel; polybrominated diphenyl ether; receptor; receptor expression; receptor function; reproductive; response

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.

项目摘要 多溴联苯醚（BDEs）被用作阻燃剂，直到在美国被淘汰 几年前，由于担心其环境持久性和毒性。不过，续 人类接触溴化二苯醚的情况已得到充分证实，并与神经发育缺陷和 循环甲状腺激素虽然大多数研究都集中在这些污染物与 甲状腺素受体参与生殖和代谢功能，但其作用机制研究较少 涉及甲状腺激素生物合成途径。鉴于溴化二苯醚与其他化学品之间的流行病学联系， 暴露和循环甲状腺激素水平，以及缺乏研究，检查机械驱动程序， 鉴于这一现象，这一提议的总体科学前提是，接触羟基溴化二苯醚会扰乱 甲状腺激素生物合成的负反馈抑制。调节这一重要的生物合成 在解释血液中的溴化二苯醚和 甲状腺功能减退症。我们认为，有两个未充分研究的机制，通过这些机制，溴化二苯醚及其 代谢物可调节循环甲状腺激素。第一个机制将检查羟溴二苯醚代谢物 与甲状腺激素受体β 2（TRβ2）的相互作用，TR β 2是一种甲状腺受体亚型，仅在 下丘脑和垂体，在那里它参与甲状腺激素合成的反馈抑制。第二 将通过表观遗传学机制研究羟基溴二苯醚对甲状腺受体功能的间接调节， 特别是miRNAs。我们提出了两个高度独立但相关的具体目标，以解决这些知识 差距。这些研究旨在检验与下丘脑上游的OH-BDE调节有关的假设， 控制甲状腺激素循环水平的反馈回路。具体目标1将检验OH- 溴化二苯醚将拮抗下丘脑和垂体特异性甲状腺受体TRβ2， 促甲状腺激素释放激素（TRH）在下丘脑神经元细胞。这些假设将通过以下方式进行检验： 甲状腺激素受体报告基因测定和下丘脑细胞系。具体目标2将检验假设 甲状腺激素受体的表达在下丘脑中受到miRNA调节剂的抑制， OH-BDEs。这一假设将通过测量下丘脑细胞中TRs的miRNA调节剂来检验， TRs表达与TRH的关系。如果TRs的下丘脑miRNA调节因子与 我们将得出结论，miRNAs是OH-BDEs施加负面影响的关键调节因子 对甲状腺系统的影响这些目标的完成将使我们对观察到的甲状腺效应有更深入的了解 与接触溴化阻燃剂有关。这些测定方法适用于其他甲状腺激素 干扰物，这种机制可能在调节甲状腺激素循环水平方面具有重要意义， 环境化学品暴露。这些研究的结果将为支持未来的研究提供重要证据。 体内研究的建议集中在这些机制。