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The Colorful Diversity of Thyroid Hormone Metabolites.

ABSTRACT: Since the discovery of L-thyroxine, the main secretory product of the thyroid gland, and its major metabolite T3, which exerts the majority of thyroid hormone action via ligand-dependent modulation of the function of T3 receptors in nuclei, mitochondria, and other subcellular compartments, various other T4-derived endogenous metabolites have been identified in blood and tissues of humans, animals, and early protochordates. This review addresses major historical milestones and experimental findings resulting in the discovery of the key enzymes of thyroid hormone metabolism, the three selenoprotein deiodinases, as well as the decarboxylases and amine oxidases involved in formation and degradation of recently identified endogenous thyroid hormone metabolites, i.e. 3-iodothyronamine and 3-thyroacetic acid. The concerted action of deiodinases 2 and 3 in regulation of local T3 availability is discussed. Special attention is given to the role of the thyromimetic "hot" metabolite 3,5-T2 and the "cool" 3-iodothyronamine, especially after administration of pharmacological doses of these endogenous thyroid hormone metabolites in various animal experimental models. In addition, available information on the biological roles of the two major acetic acid derivatives of thyroid hormones, i.e. Tetrac and Triac, as well as sulfated metabolites of thyroid hormones is reviewed. This review addresses the consequences of the existence of this broad spectrum of endogenous thyroid hormone metabolites, the "thyronome," beyond the classical thyroid hormone profile comprising T4, T3, and rT3 for appropriate analytical coverage and clinical diagnostics using mass spectrometry versus immunoassays for determination of total and free concentrations of thyroid hormone metabolites in blood and tissues.

SUBMITTER: Kohrle J

PROVIDER: S-EPMC6587369 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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The Colorful Diversity of Thyroid Hormone Metabolites.

Köhrle Josef J

European thyroid journal 20190521 3

Since the discovery of L-thyroxine, the main secretory product of the thyroid gland, and its major metabolite T3, which exerts the majority of thyroid hormone action via ligand-dependent modulation of the function of T3 receptors in nuclei, mitochondria, and other subcellular compartments, various other T4-derived endogenous metabolites have been identified in blood and tissues of humans, animals, and early protochordates. This review addresses major historical milestones and experimental findin ...[more]

PMID: 31259154

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Project description:BACKGROUND:Maintaining thyroid homeostasis during pregnancy is essential for normal fetal growth and development. Growing evidence suggests that phthalates interfere with normal thyroid function. Few human studies have investigated the degree to which phthalates may affect thyroid hormone levels in particularly susceptible populations such as pregnant women. OBJECTIVES:We examined the associations between repeated measures of urinary phthalate metabolites and plasma thyroid hormone levels in samples collected at up to four time points per subject in pregnancy. Additionally, we investigated the potential windows of susceptibility to thyroid hormone disturbances related to study visit of sample collection. METHODS:Data were obtained from pregnant women (n = 439) participating in a nested case-control study of preterm birth with 116 cases and 323 controls. We measured 9 phthalate metabolite concentrations in urine samples collected at up to four study visits per subject during pregnancy (median = 10, 18, 26, and 35 weeks of gestation, respectively). We also measured a panel of thyroid function markers in plasma collected at the same four time points per subject during pregnancy. RESULTS:Although our results were generally null, in repeated measures analyses we observed that phthalate metabolites were largely inversely associated with thyrotropin and positively associated with free and total thyroid hormones. Cross-sectional analyses by study visit revealed that the magnitude and/or direction of these relationships varied by timing of exposure during gestation. CONCLUSIONS:These results support previous reports showing the potential for environmental phthalate exposure to alter circulating levels of thyroid hormones in pregnant women. Citation: Johns LE, Ferguson KK, McElrath TF, Mukherjee B, Meeker JD. 2016. Associations between repeated measures of maternal urinary phthalate metabolites and thyroid hormone parameters during pregnancy. Environ Health Perspect 124:1808-1815;?http://dx.doi.org/10.1289/EHP170.

Project description:BackgroundThyroid hormone receptors (TRs) are critical endocrine receptors that regulate a multitude of processes in adult and developing organisms, and thyroid hormone disruption is of high concern for neurodevelopmental and reproductive toxicities in particular. To date, only a small number of chemical classes have been identified as possible TR modulators, and the receptors appear highly selective with respect to the ligand structural diversity. Thus, the question of whether TRs are an important screening target for protection of human and wildlife health remains.ObjectiveOur goal was to evaluate the hypothesis that there is limited structural diversity among environmentally relevant chemicals capable of modulating TR activity via the collaborative interagency Tox21 project.MethodsWe screened the Tox21 chemical library (8,305 unique structures) in a quantitative high-throughput, cell-based reporter gene assay for TR agonist or antagonist activity. Active compounds were further characterized using additional orthogonal assays, including mammalian one-hybrid assays, coactivator recruitment assays, and a high-throughput, fluorescent imaging, nuclear receptor translocation assay.ResultsKnown agonist reference chemicals were readily identified in the TR transactivation assay, but only a single novel, direct agonist was found, the pharmaceutical betamipron. Indirect activation of TR through activation of its heterodimer partner, the retinoid-X-receptor (RXR), was also readily detected by confirmation in an RXR agonist assay. Identifying antagonists with high confidence was a challenge with the presence of significant confounding cytotoxicity and other, non-TR-specific mechanisms common to the transactivation assays. Only three pharmaceuticals-mefenamic acid, diclazuril, and risarestat-were confirmed as antagonists.DiscussionThe results support limited structural diversity for direct ligand effects on TR and imply that other potential target sites in the thyroid hormone axis should be a greater priority for bioactivity screening for thyroid axis disruptors. https://doi.org/10.1289/EHP5314.

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The Colorful Diversity of Thyroid Hormone Metabolites.

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The Colorful Diversity of Thyroid Hormone Metabolites.

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