Hypothalamic-pituitary-thyroid Axis Research Articles

Thyroid dysfunction in children and adolescents affected by undernourished and overnourished eating disorders.

Eating disorders (ED) are one of the most prevalent chronic disorders in adolescents and young adults, with a significantly increasing prevalence in younger children, particularly in girls. Even if obesity in essence is not framed as an eating disorder and has always been considered a separate pathology, ED and obesity could be considered part of a continuum. It has become evident that one condition can lead to another, such as binge eating disorder (BED) and bulimia nervosa, and that they share the same repercussions in terms of psychosocial, metabolic, and nutritional health. This narrative review aims to investigate the hypothalamic-pituitary-thyroid axis in undernourished and overnourished patients with ED, including obesity, in order to highlight the relationship between weight control and thyroid function and its effects and to consider therapeutic and preventive strategies in children and adolescents. Literature data report that thyroid alterations occur in patients with ED, both underweight and overweight, and represent a continuum of changes depending on the severity and time course of the disease involving the endocrine system. Considering the relevant role thyroid hormones (TH) play not only in energy expenditure (EE) but also in metabolic control and cardiovascular risks related to dysmetabolism and mood regulation, continuous monitoring of thyroid homeostasis in patients with ED is mandatory to prevent severe complications and to start early treatment when necessary.

Mechanism difference of ginseng medicines with different natures on hyperthyroidism

Ethnopharmacological relevanceMedicinal nature is a unique index in traditional Chinese medicine (TCM) to measure the efficacy of Chinese medicines. Hyperthyroidism, qi-Yin deficiency syndrome in TCM was regarded as the classic heat syndrome category in Chinese medicine. Moreover, it is extensively employed to evaluate the medicinal nature of herbs within the framework of the ‘hot/cold’ nature theory. Ginseng, red and black ginseng (GS, RG, and BG, respectively), and ginseng leaves (GL) are qi-tonifying herbs with different medicinal natures and were just right used to examine the underlying mechanisms between the nature of ginseng medicines and their tonifying effect. Aim of the studyTo examine the different mechanisms between different natures of ginseng medicines and their qi-tonifying action by comparison of their effects on hyperthyroidism and elucidate the nature of BG. Materials and methodsThe hyperthyroidism model was induced through the oral administration of Euthyrox. Steroids belonging to hypothalamus pituitary adrenal (HPA) and hypothalamic pituitary gonadal (HPG) axes were determined with an ultra-performance liquid chromatography-triple quadrupole tandem mass spectrometry (UPLC-QqQ-MS/MS) method. Furthermore, the biochemical indexes associated with energy metabolism, including the serum cyclic nucleotide system and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathways were examined. Additionally, the gut microbiota was subjected to 16 S rDNA sequencing, followed by gas chromatography-mass spectrometry (GC-MS) analysis of short-chain fatty acids (SCFAs). ResultsGS, RG, and BG could treat hyperthyroidism rats by regulating the hypothalamus pituitary thyroid (HPT) axis. The RG also had a strong regulatory effect on the HPA and HPG axis. The BG has a regulatory effect on the HPG axis. GL had a strong regulatory effect on HPA, HPG, and HPT axes. GS had the ability to regulate Firmicutes/Bacteroides of the intestinal flora, and GS, RG, and BG ameliorated the decrease of SCFAs induced by hyperthyroidism. According to PCA, BG is similar to GS, indicating a mild-warm nature. ConclusionThe nature of BG was attributable to mild-warm and the GL with cold nature is best for the treatment of hyperthyroidism based on PCA analysis with all the bio-indices. In addition, the mechanism study indicated that the qi-tonifying effects of ginseng medicines are involved in HPT, HPA, and HPG axes to alleviate hyperthyroidism. In addition, the primary indexes reflected different natures of ginseng medicines are cyclic adenosine monophosphate (cAMP)/cyclic guanosine monophosphate (cGMP), AchE, and substance metabolism associated with Na+-K+-ATPase and PI3K/AKT signaling pathways, which are potential biomarkers for evaluation on the natures of qi-tonifying medicines.

Causal relationships between gut microbiota and hypothyroidism: a Mendelian randomization study.

Previous studies have shown that the gut microbiota plays an important role in the maintenance of thyroid homeostasis. We aimed to evaluate the causal relationships between gut microbiota and hypothyroidism. Summary statistics for 211 gut microbiota taxa were obtained from the largest available genome-wide association study (GWAS) meta-analysis conducted by the MiBioGen consortium. Summary statistics for hypothyroidism were obtained from two distinct sources: the FinnGen consortium R9 release data (40,926 cases and 274,069 controls) and the UK Biobank data (22,687 cases and 440,246 controls), respectively. A two-sample Mendelian randomization (MR) design was employed, and thorough sensitivity analyses were carried out to ensure the reliability of the results. Based on the FinnGen consortium, we found increased levels of Intestinimonas (OR = 1.09; 95%CI = 1.02-1.16; P = 0.01) and Ruminiclostridium5 (OR = 1.11; 95%CI = 1.02-1.22; P = 0.02) may be associated with a higher risk of hypothyroidism, while increased levels of Butyrivibrio (OR = 0.95; 95%CI = 0.92-0.99; P = 0.02), Eggerthella (OR = 0.93; 95%CI = 0.88-0.98; P = 0.01), Lachnospiraceae UCG008 (OR = 0.92; 95%CI = 0.85-0.99; P = 0.02), Ruminococcaceae UCG011 (OR = 0.95; 95%CI = 0.90-0.99; P = 0.02), and Actinobacteria (OR = 0.88; 95%CI = 0.80-0.97; P = 0.01) may be associated with a lower risk. According to the UK Biobank data, Eggerthella and Ruminiclostridium5 remain causally associated with hypothyroidism. The sensitivity analysis demonstrates consistent results without evidence of heterogeneity or pleiotropy. This study highlights the impact of specific gut microbiota on hypothyroidism. Strategies to change composition of gut microbiota may hold promise as potential interventions.

Nickel as a potential disruptor of thyroid function: benchmark modelling of human data.

Nickel (Ni) is one of the well-known toxic metals found in the environment. However, its influence on thyroid function is not explored enough. Hence, the aim of this study was to analyse the potential of Ni to disrupt thyroid function by exploring the relationship between blood Ni concentration and serum hormone levels (TSH, T4, T3, fT4 and fT3), as well as the parameters of thyroid homeostasis (SPINA-GT and SPINA-GD) by using correlation analysis and Benchmark (BMD) concept. Ni concentration was measured by ICP-MS method, while CLIA was used for serum hormone determination. SPINA Thyr software was used to calculate SPINA-GT and SPINA-GD parameters. BMD analysis was performed by PROAST software (70.1). The limitations of this study are the small sample size and the uneven distribution of healthy and unhealthy subjects, limited confounding factors, as well as the age of the subjects that could have influenced the obtained results. The highest median value for blood Ni concentration was observed for the male population and amounted 8,278 µg/L. Accordingly, the statistically significant correlation was observed only in the male population, for Ni-fT4 and Ni-SPINA-GT pairs. The existence of a dose-response relationship was established between Ni and all the measured parameters of thyroid functions in entire population and in both sexes. However, the narrowest BMD intervals were obtained only in men, for Ni - SPINA-GT pair (1.36-60.9 µg/L) and Ni - fT3 pair (0.397-66.8 µg/L), indicating that even 78.68 and 83.25% of men in our study might be in 10% higher risk of Ni-induced SPINA-GT and fT3 alterations, respectively. Due to the relationship established between Ni and the SPINA-GT parameter, it can be concluded that Ni has an influence on the secretory function of the thyroid gland in men. Although the further research is required, these findings suggest possible role of Ni in thyroid function disturbances.

Associations of metal mixtures with thyroid function and potential interactions with iodine status: results from a cross-sectional study in MEWHC.

Few studies are available on associations between metal mixture exposures and disrupted thyroid hormone homeostasis; particularly, the role of iodine status was ignored. Here, we aimed to explore the cross-sectional relationship of blood cell metals with thyroid homeostasis and explore the potential modifying effect of iodine status. Among 328 workers from the manganese-exposed workers healthy cohort (MEWHC), we detected thyroid function parameters: thyroid stimulating hormone (TSH), total triiodothyronine (TT3), free triiodothyronine (FT3), total tetraiodothyronine (TT4), free tetraiodothyronine (FT4) as well as calculated sum activity of peripheral deiodinases (GD) and thyroid's secretory capacity (GT). Inductively coupled plasma mass spectrometry (ICP-MS) was used to measure 22 metal concentrations in blood cells. Based on the consistent results of least absolute shrinkage and selection operator (LASSO) and Bayesian kernel machine regression (BKMR) analyses, there were significant positive associations between copper and TSH (β = 2.016), iron and FT4 (β = 0.403), titanium and GD (β = 0.142), nickel and GD (β = 0.057), and negative associations between copper and FT4 (β = - 0.226), selenium and GD (β = - 0.332), among the participants. Interestingly, we observed an inverted-U shape relationship between magnesium and FT4. Furthermore, we found a synergistic effect between arsenic and copper on the TSH level, while antagonistic effects between nickel and copper as well as nickel and selenium on the TSH level. We observed a modified effect of iodine status on association between strontium and GD (Pinteraction = 0.026). It suggests metal mixture exposures can alter thyroid homeostasis among the occupational population, and deiodinase activity had a modified effect on association between strontium and GD. Validation of these associations and elucidation of underlying mechanisms require further researches in the future.

Modelling the Effect of the Exposure to Perfluorooctanoate (PFOA) and Perfluorooctane Sulfonate (PFOS) on Thyroid Homeostasis

Thyroid homeostasis is crucial for the human body. The imbalance of thyroid homeostasis might cause diseases such as hypothyroidism. Humans are exposed to PFOS/PFOA frequently since they have been used in various industrial products. As reported that PFOS/PFOA increase the metabolic clearance rate of thyroid hormones, we then develop a mathematical model in terms of a system of differential equations to investigate thyroid homeostasis based on the changes in the levels of thyrotropin-releasing hormone, thyroid-stimulating hormone and thyroid hormones when the effect of the exposure to PFOS and PFOA is also incorporated as well. The geometric singular perturbation technique is then employed to identify the possible dynamic behaviours obtained from the model. Numerical investigations are also presented to illustrate the results from theoretical analysis. Both theoretical and numerical results imply that a periodic behaviour that has been observed clinically in the pulsatile secretions of thyroid hormones, thyroid-stimulating hormone and thyrotropin-releasing hormone could be obtained from our model. In addition, the numerical experiment also shows that the levels of thyroid hormones and thyroid-stimulating hormone for the case when there is the effect of exposure to PFOS and PROA are lower than those of the case when there is no effect of the exposure to PFOS and PFOA which might lead to the imbalance of thyroid homeostasis.

Novel PFOS alternative OBS inhibits body growth of developing zebrafish by triggering thyroid function disorder and osteoclast differentiation

The extensive use of the perfluorooctane sulfonate (PFOS) alternative sodium p-perfluorous nonenoxybenzene sulfonate (OBS) has resulted in its widespread detection in the environment and enrichment in wildlife and humans. However, little is known about its potential toxicity, particularly in terms of body development. In this study, zebrafish embryos were acutely exposed to PFOS and OBS for a comparative developmental toxicity assessment. Both PFOS and OBS led to lower body weight and shorter body length, and the damaging effects of PFOS were more severe than those of OBS at the same exposure concentration. Biochemical assays of THs and transcription profiles correlated to the HPT axis demonstrated that OBS-induced body development inhibition resulted mainly from interference in THs synthesis, transfer, coupling with receptors, and conversion from T4 to T3, which was similar to the case of PFOS, except that the disruptive effects of OBS on thyroid function were more intense. Further transcriptome analysis showed that PFOS and OBS also promoted osteoclast differentiation, aggravating the inhibitory effects on body growth, and that PFOS had more obvious inhibitory effects than OBS. This study systematically explored the inhibitory effects of PFOS and OBS exposure on body development and tightly linked the toxic effects to thyroid function disorder and osteoclast differentiation. Our findings highlight that the health risks associated with OBS, an emerging substitute for PFOS, should not be ignored.

Nutritional iodine status & thyroid homeostasis in pregnant women from iodine-deficient environments in india

Nutritional iodine status & thyroid homeostasis in pregnant women from iodine-deficient environments in india

Influence of two anti-tumor drugs, pazopanib, and axitinib, on the development and thyroid-axis of zebrafish (Danio rerio) embryos/larvae.

In recent years, the potential toxicities of different pharmaceuticals toward the thyroid system have received increasing attention. In this study, we aim to evaluate the toxic effects of pazopanib and axitinib, two anti-tumor drugs with widespread clinical use, on thyroid function in the zebrafish model. We measured levels of thyroid-related hormones using the commercial Enzyme-Linked Immunosorbent Assay (ELISA) kit. Whole-mount in situ hybridization (WISH) analysis was employed to detect target gene expression changes. Morphology of the thyroid were evaluated by using transgenic Tg (tg: EGFP) fish line under a confocal microscope. The relative mRNA expression of key genes was verified through quantitative real-time polymerase chain reaction (RT‒qPCR). The size and number of the follicles was quantified whereby Hematoxylin-Eosin (H & E) staining under a light microscope. The results revealed that fertilized zebrafish embryos were incubated in pazopanib or axitinib for 96 hours, development and survival were significantly affected, which was accompanied by significant disturbances in thyroid endocrine system (e.g., increased thyroid-stimulating hormone (TSH) content and decreased triiodothyronine (T3) and thyroxine (T4) content, as well as transcription changes of genes associated with the hypothalamus-pituitary-thyroid (HPT) axis. Moreover, based on whole-mount in situ hybridization staining of tg and histopathological examination of zebrafish embryos treated with pazopanib and axitinib, we observed a significantly abnormal development of thyroid follicles in the Tg (tg: EGFP) zebrafish transgenic line. Collectively, these findings indicate that pazopanib and axitinib may have toxic effects on thyroid development and function, at least partially, by influencing the regulation of the HPT axis. Thus, we believe that the potential thyroid toxicities of pazopanib and axitinib in their clinical applications should receive greater attention.

6:2 Chlorinated Polyfluoroalkyl Ether Sulfonates Exert Stronger Thyroid Homeostasis Disruptive Effects in Newborns than Perfluorooctanesulfonate: Evidence Based on Bayesian Benchmark Dose Values from a Population Study.

Growing toxicologic evidence suggests that emerging perfluoroalkyl substances (PFASs), like chlorinated polyfluoroalkyl ether sulfonate (Cl-PFESA), may be as toxic or more toxic than perfluorooctanesulfonate (PFOS) and perfluorooctanoic acid (PFOA). However, further investigations are needed in terms of the human health risk assessment. This study examined the effects of emerging and legacy PFAS exposure on newborn thyroid homeostasis and compared the thyroid disruption caused by 6:2 Cl-PFESA and PFOS using a benchmark dose approach. The health effects of mixture and individual exposure were estimated using the partial least-squares (PLS) model and linear regression, respectively. A Bayesian benchmark dose (BMD) analysis determined the BMD value for adverse effect comparison between 6:2 Cl-PFESA and PFOS. The median (interquartile range) concentrations of 6:2 Cl-PFESA (0.573 [0.351-0.872] ng/mL), PFOS (0.674 [0.462-1.007] ng/mL), and PFOA (1.457 [1.034, 2.405] ng/mL) were found to be similar. The PLS model ranked the PFAS variables' importance in projection (VIP) scores as follows: 6:2 Cl-PFESA > PFOS > PFOA. Linear regression showed that 6:2 Cl-PFESA had a positive association with free triiodothyronine (FT3, P = 0.006) and triiodothyronine (T3, P = 0.014), while PFOS had a marginally significant positive association with FT3 alone (P = 0.042). The BMD analysis indicated that the estimated BMD10 for 6:2 Cl-PFESA (1.01 ng/mL) was lower than that for PFOS (1.66 ng/mL) in relation to a 10% increase in FT3. These findings suggest that 6:2 Cl-PFESA, an alternative to PFOS, has a more pronounced impact on newborns' thyroid homeostasis compared to PFOS and other legacy PFASs.

The effects of glyphosate-based herbicide on the hypothalamic-pituitary thyroid axis are tissue-specific and dependent on age exposure

The significant increase in glyphosate-based herbicide (GBH) use raises concerns about residues in the environment and food, potentially jeopardizing human health. The involvement of GBHs in the increased incidence of thyroid disorders is speculated, since glyphosate has been linked to an increased risk of thyroid disease in farmers. In this sense, this study aims to investigate the potential effects of low levels of GBH exposure (0, 0.5 or 5 mg/kg) from weaning (postnatal day PND23) to adult life (PND60 and PND90) in male Wistar rats on hypothalamic-pituitary-thyroid (HPT) axis function. The serum levels of T4 were increased. The hypothalamus showed reduced expression of Dio2, Thra1, and Thra2. The pituitary showed reduced expression of Mct8 and Dio2 and increased expression of Thra1. The thyroid showed increased expression of Tshr and Thra1. The heart showed increased expression of Mct8 and Myh6. The liver showed reduced expression of Mct8 and Thra2 and increased expression of Thra1. In thyroid morphometry, a decrease in both follicular diameter and area and decreased follicular and colloid diameters and areas were observed. These results suggested that GBH may affect several steps of HPT axis regulation at the transcriptional level in an age-dependent manner and alter the morphometric parameters of the thyroid gland and TH synthesis, with potential repercussions in the TH-target organs.

The Microbiome-Thyroid Link: A Review of the Role of the Gut Microbiota in Thyroid Function and Disease

The gut microbiota has emerged as a potential regulator of thyroid homeostasis and disease. Recent studies suggest that the composition and diversity of intestinal bacteria can impact thyroid stimulating hormone levels, thyroid hormone synthesis & metabolism and the risk of thyroid conditions like hypothyroidism and autoimmune thyroiditis. However, the mechanisms through which the gut microbiota influences the thyroid remain poorly understood. This review aims to summarize the current evidence on the role of the gut-thyroid microbiome axis in thyroid physiology and pathophysiology. Studies investigating the association of gut dysbiosis with altered thyroid function and disorders like Hashimoto’s thyroiditis were discussed. Potential mechanisms through which gut bacteria may influence thyroid hormone levels and autoimmunity, such as interference with autoantigen presentation, induction of inflammation, and production of metabolites were evaluated. The impact of dietary and probiotic interventions targeting the gut microbiota for managing thyroid disease is assessed. Future research directions focusing on delineating key bacteria influencing thyroid health, characterizing longitudinal microbiota changes in thyroid conditions, and identifying novel microbiota-based therapies are proposed. A deeper understanding of the gut-thyroid axis may lead to microbiota-targeted strategies for managing thyroid disorders.

Exploring the repairing mechanisms of reduced graphene oxide (rGo) on the dysregulation of Xenopus Laevis larva hypothalamus-pituitary-thyroid (HPT) axis caused by chiral triazole fungicide metconazole

Replacing chair fungicide racemate marketed product by its enantiomer with high activity and low environmental risk for application is a more environmentally friendly methods to control crop diseases. Moreover, carbon-based nanomaterials, with the desirable chemical and mechanical properties, exhibits latent reduce fungicide toxicity capability, while the mechanism is still poorly understood. Therefore, the present study characterized the toxicity of rac-metconazole (Mez; (1RS,5RS;1RS,5SR)-5-(4-chlorobenzyl)-2,2-dimethyl-1-(1H)) and its two cis-enantiomers as well as the repairing effect of reduced graphene oxide (rGo) on Xenopus Laevis larva by examining growth appearance indexes, Mez bioaccumulation, and hypothalamus-pituitary-thyroid (HPT) axis related hormone contents and gene expression after 14 and 28 days exposure. Compared with two cis-Mez, rac-Mez was preferentially bioaccumulated in tadpoles, and rac-Mez treatment showed a higher toxicity effect on tadpole including growth stage and body weight inhibition by dysregulating tadpole thyroid stimulating hormone (TSH) and thyroid hormone (TH) contents and related gene expression. Enantioselectivity was observed in two cis-Mez treatments. Compared with R,S-Mez, S,R-Mez treatment showed more severe damage on tadpole HPT axis related physiological and biochemical processes. rGo could effectively decrease the toxicity of Mez, especially shown the capacity of repairing the hormone dysregulation caused by R,S-Mez treatment. Moreover, the addition of rGo can decrease the bioaccumulation of Mez in tadpoles. Therefore, R,S-Mez is less toxic to Xenopus Laevis larva growth, and its toxicity could be effectively repaired by the addition of rGO.

Machine learning-aided metallomic profiling in serum and urine of thyroid cancer patients and its environmental implications

The incidence rate of thyroid cancer has been growing worldwide. Thyroid health is closely related with multiple trace metals, and the nutrients are essential in maintaining thyroid function while the contaminants can disturb thyroid morphology and homeostasis. In this study, we conducted metallomic analysis in thyroid cancer patients (n = 40) and control subjects (n = 40) recruited in Shenzhen, China with a high incidence of thyroid cancer. We found significant alterations in serumal and urinary metallomic profiling (including Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Sr, Cd, I, Ba, Tl, and Pb) and elemental correlative patterns between thyroid cancer patients and controls. Additionally, we also measured the serum Cu isotopic composition and found a multifaceted disturbance in Cu metabolism in thyroid disease patients. Based on the metallome variations, we built and assessed the thyroid cancer-predictive performance of seven machine learning algorithms. Among them, the Random Forest model performed the best with the accuracy of 1.000, 0.858, and 0.813 on the training, 5-fold cross-validation, and test set, respectively. The high performance of machine learning has demonstrated the great promise of metallomic analysis in the identification of thyroid cancer. Then, the Shapley Additive exPlanations approach was used to further interpret the variable contributions of the model and it showed that serum Pb contributed the most in the identification process. To the best of our knowledge, this is the first study that combines machine learning and metallome data for cancer identification, and it supports the indication of environmental heavy metal-related thyroid cancer etiology.

TRIAC disrupts cerebral thyroid hormone action via negative feedback and heterogenous distribution among organs

As 3,3',5-triiodothyroacetic acid (TRIAC), a metabolite of thyroid hormones (THs), was previously detected in sewage effluent, we aimed to investigate exogenous TRIAC's potential for endocrine disruption. We administered either TRIAC or 3,3',5-triiodo-L-thyronine (LT3) to euthyroid mice and 6-propyl-2-thiouracil-induced hypothyroid mice. In hypothyroid mice, TRIAC administration suppressed the hypothalamus-pituitary-thyroid (HPT) axis and upregulated TH-responsive genes in the pituitary gland, the liver, and the heart. We observed that, unlike LT3, TRIAC administration did not upregulate cerebral TH-responsive genes. Measurement of TRIAC contents suggested that TRIAC was not efficiently trafficked into the cerebrum. By analyzing euthyroid mice, we found that cerebral TRIAC content did not increase despite TRIAC administration at higher concentrations, whereas serum levels and cerebral contents of THs were substantially decreased. Disruption by TRIAC is due to the additive effects of circulating endogenous THs being depleted via a negative feedback loop involving the HPT axis and heterogeneous distribution of TRIAC among different organs.

Association analysis of gut microbiota-metabolites-neuroendocrine changes in male rats acute exposure to simulated altitude of 5500 m

Hyperactivation of hypothalamic–pituitary–adrenal (HPA) axis and hypothalamic–pituitary–thyroid (HPT) axis were found in acute high altitude challenge, but the role of gut microbiota and metabolites is unknown. We utilized adult male Sprague–Dawley rats at a simulated altitude of 5500 m for 3 days in a hypobaric-hypoxic chamber. ELISA and metabolomic analyses of serum and 16S rRNA and metabolomic analyses of fecal samples were then performed. Compared with the normoxic group, serum corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), corticosterone (CORT), and thyroxine (tT4) were increased in the hypoxia group, whereas thyrotropin-releasing hormone (TRH) was decreased. Bacteroides, Lactobacillus,Parabacteroides,Butyricimonas,SMB53,Akkermansia,Phascolarctobacterium, and Aerococcus were enriched in hypoxia group, whereas [Prevotella], Prevotella,Kaistobacter,Salinibacterium, and Vogesella were enriched in normoxic group. Metabolomic analysis indicated that acute hypoxia significantly affected fecal and serum lipid metabolism. In addition, we found five fecal metabolites may mediate the cross-talk between TRH, tT4, and CORT with [Prevotella], Kaistobacter,Parabacteroides, and Aerococcus, and 6 serum metabolites may mediate the effect of TRH and tT4 on [Prevotella] and Kaistobacter by causal mediation analysis. In conclusion, this study provides new evidence that key metabolites mediate the cross-talk between gut microbiota with HPA and HPT axis under acute hypobaric hypoxia challenge.

Tris(2-chloroethyl) Phosphate Exerts Hepatotoxic Impacts on Zebrafish by Disrupting Hypothalamic-Pituitary-Thyroid and Gut-Liver Axes.

The ubiquitous environmental presence of tris(2-chloroethyl) phosphate (TCEP) poses a potential threat to animals; however, little is known about its hepatotoxicity. In this study, the effects of TCEP exposure (0.5 and 5.0 μg/L for 28 days) on liver health and the potential underlying toxification mechanisms were investigated in zebrafish. Our results demonstrated that TCEP exposure led to hepatic tissue lesions and resulted in significant alterations in liver-injury-specific markers. Moreover, TCEP-exposed fish had significantly lower levels of thyrotropin-releasing hormone and thyroid-stimulating hormone in the brain, evidently less triiodothyronine whereas more thyroxine in plasma, and markedly altered expressions of genes from the hypothalamic-pituitary-thyroid (HPT) axis in the brain or liver. In addition, a significantly higher proportion of Bacteroidetes in the gut microbiota, an elevated bacterial source endotoxin lipopolysaccharide (LPS) in the plasma, upregulated expression of LPS-binding protein and Toll-like receptor 4 in the liver, and higher levels of proinflammatory cytokines in the liver were detected in TCEP-exposed zebrafish. Furthermore, TCEP-exposed fish also suffered severe oxidative damage, possibly due to disruption of the antioxidant system. These findings suggest that TCEP may exert hepatotoxic effects on zebrafish by disrupting the HPT and gut-liver axes and thereafter inducing hepatic inflammation and oxidative stress.

Altered thyroid feedback loop in Klinefelter syndrome: a cohort study from infancy through the transition into adulthood.

Thyroid dysfunction has been claimed contributing to the spectrum of Klinefelter syndrome (KS); however, studies are scarce. In a retrospective longitudinal study, we aimed at describing the hypothalamus-pituitary-thyroid (HPT) axis and thyroid ultrasonographic (US) appearance in patients with KS throughout the life span. 254 patients with KS (25.9±16.1 years) were classified according to their pubertal and gonadal status and compared with different groups of non-KS age-matched subjects with normal thyroid function, treated and untreated hypogonadism, or chronic lymphocytic thyroiditis. We assessed serum thyroid hormone levels, anti-thyroid antibodies, US thyroid parameters, in vitro pituitary type 2 deiodinase (D2) expression and activity. Thyroid autoimmunity was more prevalent among subjects with KS at all ages, although the Ab negative vs. positive cohorts were not different. Signs of thyroid dysfunction (reduced volume, lower echogenicity, and increased inhomogeneity) were more prominent in KS than in euthyroid controls. Free thyroid hormones were lower in pre-pubertal, pubertal, and adult subjects with KS, while TSH values were only lower in adults. Peripheral sensitivity to thyroid hormones was unaltered in KS, suggesting a dysfunctional HPT axis. Testosterone (T) was the only factor associated with thyroid function and appearance. In vitro testing demonstrated an inhibitory effect of T on pituitary D2 expression and activity, supporting enhanced central sensing of circulating thyroid hormones in hypogonadism. From infancy through adulthood, KS is characterized by increased morpho-functional abnormalities of the thyroid gland, combined with a central feedback dysregulation sustained by the effect of hypogonadism on D2 deiodinase.

A biologically based computational model for the hypothalamic-pituitary-thyroid (HPT) axis in Xenopus laevis larvae

A biologically based computational model was developed to describe the hypothalamic-pituitary-thyroid (HPT) axis in developing Xenopus laevis larvae. The goal of this effort was to develop a tool that can be used to better understand mechanisms of thyroid hormone-mediated metamorphosis in X. laevis and predict organismal outcomes when those mechanisms are perturbed by chemical toxicants. In this report, we describe efforts to simulate the normal biology of control organisms. The structure of the model borrows from established models of HPT axis function in mammals. Additional features specific to X. laevis account for the effects of organism growth, growth of the thyroid gland, and developmental changes in regulation of thyroid stimulating hormone (TSH) by circulating thyroid hormones (THs). Calibration was achieved by simulating observed changes in stored and circulating levels of THs during a critical developmental window (Nieuwkoop and Faber stages 54–57) that encompasses widely used in vivo chemical testing protocols. The resulting model predicts that multiple homeostatic processes, operating in concert, can act to preserve circulating levels of THs despite profound impairments in TH synthesis. Represented in the model are several biochemical processes for which there are high-throughput in vitro chemical screening assays. By linking the HPT axis model to a toxicokinetic model of chemical uptake and distribution, it may be possible to use this in vitro effects information to predict chemical effects in X. laevis larvae resulting from defined chemical exposures.

Regulation of Thyroid Hormone Levels by Hypothalamic Thyrotropin-Releasing Hormone Neurons.

Background: Thyrotropin-releasing hormone (TRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) have been identified as direct regulators of thyrotropin (TSH) and thyroid hormone (TH) levels. They play a significant role in context of negative feedback by TH at the level of TRH gene expression and during fasting when TH levels fall due, in part, to suppression of TRH gene expression. Methods: To test these functions directly for the first time, we used a chemogenetic approach and activated PVN TRH neurons in both fed and fasted mice. Next, to demonstrate the signals that regulate the fasting response in TRH neurons, we activated or inhibited agouti-related protein (AgRP)/neuropeptide Y (NPY) neurons in the arcuate nucleus of the hypothalamus of fed or fasted mice, respectively. To determine if the same TRH neurons responsive to melanocortin signaling mediate negative feedback by TH, we disrupted the thyroid hormone receptor beta (TRβ) in all melanocortin 4 receptor (MC4R) neurons in the PVN. Results: Activation of TRH neurons led to increased TSH and TH levels within 2 hours demonstrating the specific role of PVN TRH neurons in the regulation of the hypothalamic-pituitary-thyroid (HPT) axis. Moreover, activation of PVN TRH neurons prevented the fall in TH levels in fasting mice. Stimulation of AgRP/NPY neurons led to a fall in TH levels despite increasing feeding. Inhibition of these same neurons prevented the fall in TH levels during a fast presumably via their ability to directly regulate PVN TRH neurons via, in part, the MC4R. Surprisingly, TH-mediated feedback was not impaired in mice lacking TRβ in MC4R neurons. Conclusions: TRH neurons are major regulators of the HPT axis and the fasting-induced suppression of TH levels. The latter relies, at least in part, on the activation of AgRP/NPY neurons in the arcuate nucleus. Interestingly, present data do not support an important role for TRβ signaling in regulating MC4R neurons in the PVN. Thus, it remains possible that different subsets of TRH neurons in the PVN mediate responses to energy balance and to TH feedback.