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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:BACKGROUND:Phthalates, endocrine-disrupting chemicals that are commonly found in consumer products, may adversely affect thyroid hormones, but findings from prior epidemiologic studies are inconsistent. OBJECTIVES:In a prospective cohort study, we investigated whether maternal urinary phthalate metabolite concentrations and phthalate mixtures measured during pregnancy were associated with thyroid hormones among pregnant women and newborns. METHODS:We measured nine phthalate metabolites [monoethyl phthalate (MEP), mono-n-butyl phthalate, mono-isobutyl phthalate, monobenzyl phthalate (MBzP), and four monoesthers of di(2-ethylhexyl) phthalate] in urine collected at approximately 16 and 26 weeks' gestation among women in the Health Outcomes and Measures of the Environment Study (2003-2006, Cincinnati, Ohio). Thyroid stimulating hormone (TSH) and free and total thyroxine and triiodothyronine were measured in maternal serum at 16 weeks' gestation (n?=?202) and cord serum at delivery (n?=?276). We used multivariable linear regression to assess associations between individual urinary phthalate metabolites and concentrations of maternal or cord serum thyroid hormones. We used weighted quantile sum regression (WQS) to create a phthalate index describing combined concentrations of phthalate metabolites and to investigate associations of the phthalate index with individual thyroid hormones. RESULTS:With each 10-fold increase in 16-week maternal urinary MEP, maternal serum total thyroxine (TT4) decreased by 0.52??g/dL (95% CI: -1.01, -0.03). For each 10-fold increase in average (16- and 26-week) maternal urinary MBzP, cord serum TSH decreased by 19% (95% CI: -33.1, -1.9). Among mothers, the phthalate index was inversely associated with maternal serum TT4 (WQS beta?=?-0.60; 95% CI: -1.01, -0.18). Among newborns, the phthalate index was inversely associated with both cord serum TSH (WQS beta?=?-0.11; 95% CI: -0.20, -0.03) and TT4 (WQS beta?=?-0.53; 95% CI: -0.90, -0.16). CONCLUSION:Our results suggest that co-exposure to multiple phthalates was inversely associated with certain thyroid hormones (TT4 in pregnant women and newborns, and TSH in newborns) in this birth cohort. These findings highlight the need to study chemical mixtures in environmental epidemiology.

Project description:BackgroundIncreasing scientific evidence suggests that exposure to phthalates during pregnancy may be associated with an elevated risk of adverse reproductive outcomes such as preterm birth. Maternal endocrine disruption across pregnancy may be one pathway mediating some of these relationships. We investigated whether urinary phthalate metabolites were associated with maternal serum thyroid (free thyroxine [FT4], free triiodothyronine [FT3], and thyroid-stimulating hormone [TSH]), and sex (estradiol, progesterone, and sex hormone-binding globulin [SHBG]) hormone levels at multiple time points during pregnancy.MethodsPreliminary data (n = 106) were obtained from an ongoing prospective birth cohort in Northern Puerto Rico. We collected urine and serum sample at the first and third study visits that occurred at 18 +/- 2 and 26 +/- 2 weeks of gestation, respectively. To explore the longitudinal relationships between urinary phthalate metabolites and serum thyroid and sex hormone concentrations, we used linear mixed models (LMMs) adjusted for prepregnancy body mass index (BMI) and maternal age. An interaction term was added to each LMM to test whether the effect of urinary phthalate metabolites on serum thyroid and sex hormone levels varied by study visit. In cross-sectional analyses, we stratified BMI- and age-adjusted linear regression models by study visit.ResultsIn adjusted LMMs, we observed significant inverse associations between mono-3-carboxypropyl phthalate (MCPP) and FT3 and between mono-ethyl phthalate (MEP) and progesterone. In cross-sectional analyses by study visit, we detected stronger and statistically significant inverse associations at the third study visit between FT3 and MCPP as well as mono-carboxyisooctyl phthalate (MCOP); also at the third study visit, significant inverse associations were observed between FT4 and metabolites of di-(2-ethylhexyl) phthalate (DEHP). The inverse association between MEP and progesterone was consistent across study visits.ConclusionsIn this group of pregnant women, urinary phthalate metabolites may be associated with altered maternal serum thyroid and sex hormone levels, and the magnitude of these effects may depend on the timing of exposure during gestation.

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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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