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.

项目总结