Mechanistic analysis of metabolomics patterns in rat plasma during administration of direct thyroid hormone synthesis inhibitors or compounds increasing thyroid hormone clearance

Montoya, G.; Strauss, Volker; Fabian, Eric; Kamp, Hennicke; Mellert, W.; Walk, T.; Looser, Ralf; Herold, Michael; Krennrich, G.; Peter, Erik; Ravenzwaay, B. van

doi:10.1016/j.toxlet.2013.12.010

Cited by 29 publications

(29 citation statements)

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“…As discussed below, our results regarding trigonelline, pyroglutamate or acetone support and extend previously observed associations between 3,5-T 2 and glucose or lipid metabolism as demonstrated by various animal models [4,5,8,25,26,27,28,29]. Furthermore, we observed thyromimetic, but TSH independent, associations regarding hippurate and pyroglutamate, as observed in recent animal studies [17,19]. …”

Section: Discussionsupporting

confidence: 92%

“…Urine, which is readily available, as a downstream product of human metabolism can especially mirror the impact of genetic determinants, environmental factors, personal behavior, nutrition and therapeutic intervention [16]. Despite these advantages, the use of metabolomics in the investigation of TH (metabolite) action is, to the best of our knowledge, limited to intervention studies in rodents [17,18,19,20,21] and, with the exception of a recent study on the relation between TH status and serum metabolites [22], completely lacking in humans. Therefore, the present study was designed to gain further insights into the metabolic profiles associated with circulating 3,5-T 2 by means of urine metabolomics in a large euthyroid study population.…”

Section: Introductionmentioning

confidence: 99%

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Urine Metabolomics by 1H-NMR Spectroscopy Indicates Associations between Serum 3,5-T2 Concentrations and Intermediary Metabolism in Euthyroid Humans

et al. 2015

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Context: 3,5-Diiodo-L-thyronine (3,5-T₂) is a thyroid hormone metabolite which exhibited versatile effects in rodent models, including the prevention of insulin resistance or hepatic steatosis typically forced by a high-fat diet. With respect to euthyroid humans, we recently observed a putative link between serum 3,5-T₂ and glucose but not lipid metabolism. Objective: The aim of the present study was to widely screen the urine metabolome for associations with serum 3,5-T₂ concentrations in healthy individuals. Study Design and Methods: Urine metabolites of 715 euthyroid participants of the population-based Study of Health in Pomerania (SHIP-TREND) were analyzed by ¹H-NMR spectroscopy. Multinomial logistic and multivariate linear regression models were used to detect associations between urine metabolites and serum 3,5-T₂ concentrations. Results: Serum 3,5-T₂ concentrations were positively associated with urinary levels of trigonelline, pyroglutamate, acetone and hippurate. In detail, the odds for intermediate or suppressed serum 3,5-T₂ concentrations doubled owing to a 1-standard deviation (SD) decrease in urine trigonelline levels, or increased by 29-50% in relation to a 1-SD decrease in urine pyroglutamate, acetone and hippurate levels. Conclusion: Our findings in humans confirmed the metabolic effects of circulating 3,5-T₂ on glucose and lipid metabolism, oxidative stress and enhanced drug metabolism as postulated before based on interventional pharmacological studies in rodents. Of note, 3,5-T₂ exhibited a unique urinary metabolic profile distinct from previously published results for the classical thyroid hormones.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Urine Metabolomics by 1H-NMR Spectroscopy Indicates Associations between Serum 3,5-T2 Concentrations and Intermediary Metabolism in Euthyroid Humans

et al. 2015

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“…3), partially replicating findings from other recent metabolome analyses [17, 32, 45]. Indeed, the LPs displayed opposite associations, depending on the presence of either choline (lysophosphatidylcholine (LPC); positively associated) or ethanolamine (lysophosphatidylethanolamine (LPE); negatively associated) as the head group (Fig.…”

Section: Resultssupporting

confidence: 85%

“…3). Threonate, which is either derived from glycated proteins or represents a degradation product of ascorbate [103], was previously linked to altered thyroid function in two murine models [45, 104], but not yet in humans.…”

Section: Resultsmentioning

confidence: 99%

Plasma proteome and metabolome characterization of an experimental human thyrotoxicosis model

Pietzner

Engelmann

Kacprowski

et al. 2017

BMC Med

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BackgroundDeterminations of thyrotropin (TSH) and free thyroxine (FT4) represent the gold standard in evaluation of thyroid function. To screen for novel peripheral biomarkers of thyroid function and to characterize FT4-associated physiological signatures in human plasma we used an untargeted OMICS approach in a thyrotoxicosis model.MethodsA sample of 16 healthy young men were treated with levothyroxine for 8 weeks and plasma was sampled before the intake was started as well as at two points during treatment and after its completion, respectively. Mass spectrometry-derived metabolite and protein levels were related to FT4 serum concentrations using mixed-effect linear regression models in a robust setting. To compile a molecular signature discriminating between thyrotoxicosis and euthyroidism, a random forest was trained and validated in a two-stage cross-validation procedure.ResultsDespite the absence of obvious clinical symptoms, mass spectrometry analyses detected 65 metabolites and 63 proteins exhibiting significant associations with serum FT4. A subset of 15 molecules allowed a robust and good prediction of thyroid hormone function (AUC = 0.86) without prior information on TSH or FT4. Main FT4-associated signatures indicated increased resting energy expenditure, augmented defense against systemic oxidative stress, decreased lipoprotein particle levels, and increased levels of complement system proteins and coagulation factors. Further association findings question the reliability of kidney function assessment under hyperthyroid conditions and suggest a link between hyperthyroidism and cardiovascular diseases via increased dimethylarginine levels.ConclusionOur results emphasize the power of untargeted OMICs approaches to detect novel pathways of thyroid hormone action. Furthermore, beyond TSH and FT4, we demonstrated the potential of such analyses to identify new molecular signatures for diagnosis and treatment of thyroid disorders. This study was registered at the German Clinical Trials Register (DRKS) [DRKS00011275] on the 16th of November 2016.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0770-8) contains supplementary material, which is available to authorized users.

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“…BDE-209 exposure through oral administration disrupts thyroid hormone homeostasis in mice (Tseng et al, 2008), and in male rats exposed to hypothyroid treatments changes in tyrosine and arginine levels and possible effects on the citrate and urea cycles were reported (Montoya et al, 2014). The thyroid hormone system is an important endocrine target for many organohalogen contaminants, and thyroid hormones play a critical role in regulating biological processes such as growth, metabolism, and neurodevelopment (Gelfand et al, 1987, Zoeller, 2003.…”

Section: Discussionmentioning

confidence: 99%

The effects of early postnatal exposure to a low dose of decabromodiphenyl ether (BDE-209) on serum metabolites in male mice

2016

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-The toxicity of decabromodiphenyl ether (BDE-209) has been reported in several studies. However, there is not much known about the toxicological biomarkers that characterize BDE-209 exposure. In this study, we subcutaneously exposed mice to 0.025 mg/kg/day BDE-209 on postnatal days 1-5 and sacrificed the animals at 12 weeks of age (day 84). Flow injection analysis and hydrophilic interaction chromatography-triple quadrupole mass spectrometry were used to determine the serum metabolomes of these mice in order to characterize the effects of BDE-209 exposure. Data analysis showed a good separation between control and exposed mice (R 2 = 0.953, Q 2 = 0.728, and ANOVA of the crossvalidated residuals (CV-ANOVA): P-value = 0.0317) and 54 metabolites were identified as altered in the exposed animals. These were selected using variable importance (VIP) and loadings scaled by a correlation coefficient criteria and orthogonal partial least squares discriminant analysis (OPLS-DA). BDE-209-exposed mice showed lower levels of long-chain acylcarnitines and citrate cycle-related metabolites, and higher levels of some amino acids, long-chain phospholipids, and short-chain acylcarnitines. The disruption of fatty acid, carbohydrate, and amino acid metabolism observed in the serum metabolome might be related to the previously observed impaired spermatogenesis in mice with early postnatal exposure to a low dose of BDE-209.

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Mechanistic analysis of metabolomics patterns in rat plasma during administration of direct thyroid hormone synthesis inhibitors or compounds increasing thyroid hormone clearance

Cited by 29 publications

References 70 publications

Urine Metabolomics by 1H-NMR Spectroscopy Indicates Associations between Serum 3,5-T2 Concentrations and Intermediary Metabolism in Euthyroid Humans

Urine Metabolomics by 1H-NMR Spectroscopy Indicates Associations between Serum 3,5-T2 Concentrations and Intermediary Metabolism in Euthyroid Humans

Plasma proteome and metabolome characterization of an experimental human thyrotoxicosis model

The effects of early postnatal exposure to a low dose of decabromodiphenyl ether (BDE-209) on serum metabolites in male mice

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