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 多溴二苯基醚（BDES）用作阻燃剂，直到在美国逐步淘汰它们 几年前，由于担心它们的环境持久性和毒性。但是，继续 人类对BDE的暴露是良好的，并且与神经发育缺陷有关 循环甲状腺激素。尽管大多数研究都集中在这些污染物与 涉及生殖和代谢功能的甲状腺受体，对机制的关注很少 涉及甲状腺同种生物合成途径。鉴于BDE之间的流行病学关联 暴露和循环甲状腺激素水平以及缺乏研究的研究 这种现象，该提议的总体科学前提是，暴露于OH-BDES会破坏 甲状腺激素生物合成的负反馈抑制。调节这种重要的生物合成 途径可能是解释血液中BDE和 甲状腺功能减退症。我们指出，有两种理解的机制 代谢产物可能调节循环甲状腺激素。第一个机制将检查OH-BDE代谢物 与甲状腺同源受体β2（TRβ2）的相互作用，甲状腺受体同工型仅在 下丘脑和孤立参与甲状腺雌激素合成的反馈抑制。第二个 机制将通过OH-BDE-VIA表观遗传机制检查甲状腺受体功能的间接调节， mirnas。我们提出了两个高度独立但相关的特定目的，以解决这些知识 空白。这些研究旨在测试与上游下游下游调节有关的假设 反馈环控制甲状腺激素的循环水平。特定目标1将检验以下假设。 BDE将拮抗下丘脑和特异性甲状腺受体TRβ2，最终降低 下丘脑神经元细胞中促甲状腺蛋白释放的马酮（TRH）。这些假设将使用 甲状腺马酮受体报告基因分析和下丘脑细胞系。具体目标2将检验假设 在存在下，miRNA调节剂在下丘脑中反映了甲状腺马酮受体的表达 OH-BDES。该假设将通过测量下丘脑细胞中TR的miRNA调节剂进行检验 与TRS表达和TRH有关。如果TRS的下丘脑miRNA调节剂与变化相关 合成的TRH，我们将包括miRNA是OH-BDE造成负面影响的关键调节剂 在甲状腺系统上。这些目标的完成将使机械洞察到观察到的甲状腺效应 与暴露于溴化的阻燃剂有关。这些测定可适应其他甲状腺激素 破坏者和这种机制可能在调节甲状腺激素的循环水平上很重要 环境化学暴露。这些研究的结果将提供重要的证据，以支持未来 Vivo研究提案的重点是这些机制。