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IntroductionThe current study investigated the value of urine selenium (Se) concentration as a biomarker of population Se status in rural sub-Saharan Africa.MethodUrine and plasma Se concentrations were measured among children aged 6–59 months (n = 608) and women of reproductive age (WRA, n = 781) living in rural Zimbabwe (Murehwa, Shamva, and Mutasa districts) and participating in a pilot national micronutrient survey. Selenium concentrations were measured by inductively coupled plasma-mass spectrometry (ICP-MS), and urine concentrations were corrected for hydration status.ResultsThe median (Q1, Q3) urine Se concentrations were 8.4 μg/L (5.3, 13.5) and 10.5 μg/L (6.5, 15.2) in children and WRA, respectively. There was moderate evidence for a relationship between urine Se concentration and plasma Se concentration in children (p = 0.0236) and WRA (p = < 0.0001), but the relationship had poor predictive value. Using previously defined thresholds for optimal activity of iodothyronine deiodinase (IDI), there was an association between deficiency when indicated by plasma Se concentrations and urine Se concentrations among WRA, but not among children.DiscussionUrine Se concentration poorly predicted plasma Se concentration at sub-district scales in Zimbabwe, limiting its value as a biomarker of population Se status in this context. Further research is warranted at wider spatial scales to determine the value of urine Se as a biomarker when there is greater heterogeneity in Se exposure.

Selenocysteine selenenic acids (Sec–SeOHs) and selenocysteine selenenyl iodides (Sec–SeIs) have long been recognized as crucial intermediates in the catalytic cycle of glutathione peroxidase (GPx) and iodothyronine deiodinase (Dio), respectively. However, the observation of these reactive species remained elusive until our recent study, where we successfully stabilized Sec–SeOHs and Sec–SeIs using a protective molecular cradle. Here, we report the first demonstration of the chemical transformation from a Sec–SeI to a Sec–SeOH through alkaline hydrolysis. A stable Sec–SeI derived from a selenocysteine methyl ester was synthesized using the protective cradle, and its structure was determined by crystallographic analysis. The alkaline hydrolysis of the Sec–SeI at −50 °C yielded the corresponding Sec–SeOH in an 89% NMR yield, the formation of which was further confirmed by its reaction with dimedone. The facile and nearly quantitative conversion of the Sec–SeI to the Sec–SeOH not only validates the potential involvement of this process in the catalytic mechanism of Dio, but also highlights its utility as a method for producing a Sec–SeOH. [ABSTRACT FROM AUTHOR]

Introduction: Depressive disorders are multifactorial diseases in that a variety of factors may play a role in their etiology, including inflammation and abnormalities in the thyroid hormone (TH) metabolism and levels. The purpose of this study was to evaluate iodothyronine deiodinases (DIOs) and DIO-interacting cytokines as possible biomarkers in the diagnosis of depressive disorders. Methods: This study enrolled 73 patients diagnosed with recurrent depressive disorder (rDD) and 54 controls. The expressions of DIO1, DIO2, DIO3, IL1B, IL6, TNFA, and IFNG genes, encoding three types of DIOs (1, 2, and 3), interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ, were assessed using the polymerase chain reaction in blood cells and an enzymatic immunoassay method in serum. The levels of examined molecules between patients and controls were compared, and correlations and diagnostic values were evaluated. Results: Lower levels of DIO2 and higher levels of IL1B, IL6, and TNFA were found in patients compared to controls. The protein concentrations of DIO1 and DIO2 were lower, while that of DIO3 was higher, in patients than in controls. Serum IL-1β, IL-6, and TNF-α were also higher in patients than in controls. The area under the curve (AUC) of the IL-1β, IL-6, DIO1, and DIO3 proteins was >0.7 for discriminating patients with rDD from controls. Conclusions: The expressions of genes for DIO2, IL-1β, IL-6, and TNF-α may have a role in the estimation of processes present in depressive disorders. We can cautiously claim that DIO1 and DIO3 and pivotal cytokines, mainly IL-1β and IL-6, may play a role in depression diagnosis, and further studies are suggested to explain the exact role of these molecules in larger samples with more precise methods. [ABSTRACT FROM AUTHOR]

IntroductionSelenium (Se) deficiency is increasingly recognized as a public health problem in sub-Saharan Africa.MethodsThe current cross-sectional study assessed the prevalence and geospatial patterns of Se deficiency among children aged 6–59 months (n = 741) and women of 15–49 years old (n = 831) selected by simple random sampling in rural Zimbabwe (Murewa, Shamva, and Mutasa districts). Venous blood samples were collected and stored according to World Health Organization guidelines. Plasma Se concentration was determined by inductively coupled plasma-mass spectrometry.ResultsMedian, Q1, and Q3 plasma Se concentrations were 61.2, 48.7, and 73.3 μg/L for women and 40.5, 31.3, and 49.5 μg/L for children, respectively. Low plasma Se concentrations (9.41 μg/L in children and 10.20 μg/L in women) indicative of severe Se deficiency risk was observed. Overall, 94.6% of children and 69.8% of women had sub-optimal Se status defined by plasma Se concentrations of

The regioselective deiodinations of L‐thyroxine (T4) play key roles in the thyroid hormone homeostasis. These reactions are catalyzed by three isoforms of the selenoenzymes, iodothyronine deiodinases (Dio1, Dio2 and Dio3), which are highly homologous in nature. Dio1 mediates 5′‐ or 5‐deiodinations of T4 to produce T3 and rT3, respectively. In contrast, Dio2 and Dio3 are selective to 5′‐ or 5‐deiodination to produce T3 and rT3, respectively. Understanding of the regioselectivity of deiodination at the molecular level is important as abnormal levels of thyroid hormone have been implicated in various clinical conditions, such as hypoxia, myocardial infarction, neuronal ischemia and cancer. In this paper, we report that the electronic properties of the iodine atoms in thyroxine (T4) can be modulated through a simple substitution in the 4′‐phenolic moiety. This leads to the change in the regioselectivity of deiodination by different small molecule mimics of Dio enzymes. By using this chemical approach, we also show that the substitution of a strong electron withdrawing group facilitates the removal of all four iodine atoms in the T4 derivative. Theoretical investigations on the hydrogen bonded adducts of T4 with imidazole indicate that the charge on the iodine atoms depend on the nature of hydrogen bond between the −OH group of T4 and the imidazole moiety. While the imidazole can act as either hydrogen bond acceptor (HBA) or hydrogen bond donor (HBD), the protonated imidazole acts exclusively as HBD in T4‐imidazole complex. These studies support the earlier observations that the histidine residue at the active sites of the deiodinases play an important role not only in the substrate binding, but also in altering the regioselectivity of the deiodination reactions. [ABSTRACT FROM AUTHOR]

lodothyronine deiodinases (DIOs) are important selenoproteins that play a key role in the bone and joint diseases. Osteoarthritis (OA) is the most prevalent joint disease especially in elders. This bioinformatic analysis was performed to explore the role of DIOs in OA pathogenesis. The biological functions of selenoprotein DIOs were analyzed by bioinformatic techniques, including GenCLip 3.0, Database for Annotation, Visualization and Integrated Discovery (DAVID), STRING, Cytoscape, and Network Analyst. The expression of DIOs in the healthy individuals and OA patients was determined by mining OA-related microarray data in the gene expression omnibus (GEO) database of National Center for Biotechnology Information and performing a Meta-analysis of the data with Review Manager 5.3. Cluster analysis revealed that the function of the DIOs was associated with thyroid hormone receptor and iodothyronine; GO analysis showed that DIOs were mainly involved in biological processes, such as ethanol metabolism and phenol-containing compound metabolism and primarily involved in the cytochrome P450 metabolism of exogenous organisms and thyroid hormone signaling; SULT1A1 was the core node of the PPI network; miRNAs and thyroid hormones had some iterations with DIO1 and DI02 ; Meta-analysis showed that DI03 expression was significantly up-regulated in OA patients (SMD = 0.31, 95% CI : 0.03, 0.59, P = 0.03). The main biological functions of DIOs were closely associated with the regulation of thyroid hormone. And the up-regulated expression of DI03 may have crucial impact on the occurrence of OA. [ABSTRACT FROM AUTHOR]

Iodothyronine deiodinases (DIO) are key enzymes that influence tissue-specific thyroid hormone levels during thyroid-mediated amphibian metamorphosis. Within the larger context of evaluating chemicals for thyroid system disrupting potential, chemical activity toward DIOs is being evaluated using high-throughput in vitro screening assays as part of U.S. EPA's ToxCast program. However, existing data gaps preclude any inferences between in vitro chemical inhibition of DIOs and in vivo outcomes relevant to ecological risk assessment. This study aimed to generate targeted data in a laboratory model species (Xenopus laevis) using a model DIO inhibitor, iopanoic acid (IOP), to characterize linkages between in vitro potency, in vivo biochemical responses, and adverse organismal outcomes. In vitro potency of IOP toward DIOs was evaluated using previously developed in vitro screening assays, which showed concentration-dependent inhibition of human DIO1 (IC50: 97 µM) and DIO2 (IC50: 231 µM) but did not inhibit human or X. laevis DIO3 under the assay conditions. In vivo exposure of larval X. laevis to 0, 2.6, 5.3, and 10.5 µM IOP caused thyroid-related biochemical profiles in the thyroid gland and plasma consistent with hyperthyroxinemia but resulted in delayed metamorphosis and significantly reduced growth in the highest 2 exposure concentrations. Independent evaluations of dio gene expression ontogeny, together with existing literature, supported interpretation of IOP-mediated effects resulting in a proposed adverse outcome pathway for DIO2 inhibition leading to altered amphibian metamorphosis. This study highlights the types of mechanistic data needed to move toward predicting in vivo outcomes of regulatory concern from in vitro bioactivity data. [ABSTRACT FROM AUTHOR]

The metamorphosis process is a critical life-changing event for marine invertebrate planktonic larvae to transform into benthic adults, which is crucial for the shellfish bed’s ecosystem stability and seed production in aquaculture. The mechanism of neuroendocrine regulation in the larval metamorphosis of bivalves remains ambiguous. In the present study, the expression of two deiodinase genes, McDx and McDy, was analyzed by whole-mount in situ hybridization at four larval stages in the hard-shelled mussel Mytilus coruscus. The McDx and McDy localized in visceral tissues, nervous system, mantle, and velum, indicating that two deiodinase genes are essential for larval development in M. coruscus. Knockdown of the McDx and McDy in the pediveliger larvae of M. coruscus using electroporation of siRNA significantly (p < 0.001) reduced McDx and McDy expression. McDx and McDy knockdown reduced larval metamorphosis in 45% and 49% of the pediveliger larvae induced by epinephrine (EPI). It is hypothesised that the knockdown effects of McDx and McDy repress metamorphic induction rather than larval viability, which does not elicit a lethal effect. The present study corroborates a synergistic action of the adrenergic and thyroid hormones signalling pathway in M. coruscus, and suggests the role of McDx and McDy in larval development and metamorphic transition.

Nitrite in the aquatic environment potentially disturbs thyroid hormone (TH) homeostasis in peripheral tissues, but little is known about TH metabolism in the intestine. This study investigated the serum concentrations of THs and thyroid-stimulating hormone (TSH) as well as the activity of intestinal iodothyronine deiodinases (IDs) of grass carp (Ctenopharyngodon idellus) exposed to various concentrations of nitrite (0, 8, 25, or 50 mg/L) for 96 h. Acute nitrite exposure significantly altered the triiodothyronine (T3) levels and the morphology of thyroid follicles at 96 h. Thyroxine (T4), free T4 levels and intestinal IDs activities showed an increase trend under nitrite stress. After 96 h exposure, nitrite down-regulated the expressions levels of intestinal Akt1 protein, sugar transporter genes, and thyroid hormone receptor (TR) signaling pathway genes except for tr ɑ1 and tr ɑ2. Moreover, the expressions levels of pparγ, cpt1α, cd36, fabp2 and fatp4 were down-regulated, whereas fabp6 and lpl were up-regulated in the 50 mg/L exposure group at 96 h. The results indicate that acute nitrite exposure has the potential to disturb the homeostasis of intestinal TH metabolism, which in turn alters TRs genes transcription, down-regulates sugar transporter activities, and promotes the energy expenditure in gut of grass carp.

Objective: A unique clinical course was observed in a patient with resistance to thyroid hormone β (RTHβ) caused by a variant of the THRB gene leading to the replacement of glycine with arginine in codon 347 (p.G347R). He presented with the syndrome of inappropriate secretion of thyrotropin (TSH) (free T4 [fT4]: 32.43 pmol/L, TSH: 4.67 mIU/L), but slowly developed progressive hypothyroidism (fT4: 8.37 pmol/L, TSH: 100.90 mIU/L) that resolved after suspending bezafibrate (BZ) treatment (fT4: 32.18 pmol/L, TSH: 7.14 mIU/L). This study clinically and experimentally evaluated this interesting phenomenon. Methods: A retrospective cohort analysis of non‐RTHβ patients was performed at Kyoto University Hospital. Data before BZ treatment were compared to the first data after treatment. Using reporter assays of iodothyronine deiodinases (DIO1, DIO2, DIO3) in HEK293T cells, we performed functional analyses of mutant thyroid hormone receptor β with p.G347R (G347R TRβ). Mice with G347R TRβ were generated by hydrodynamic gene delivery. Results: In non‐RTHβ patients (n = 7), BZ treatment did not change serum free T3 and TSH but significantly increased fT4 (p =.008). BZ administration increased DIO3 reporter activity in the context of G347R TRβ, whereas did not change DIO1 and DIO2 reporter activity. In the livers of mice with G347R TRβ, BZ administration increased reverse T3 content, which corresponded to an increase in Dio3 messenger RNA. Conclusions: While hypothyroidism associated with BZ treatment did not occur in non‐RTHβ patients, it was observed in a patient with RTHβ due to the p.G347R variant. Liver DIO3 upregulation might involve this hypothyroidism. [ABSTRACT FROM AUTHOR]

Background: Poorly differentiated thyroid carcinoma is rare and patients are typically euthyroid. We report a novel rare case of poorly differentiated thyroid carcinoma with triiodothyronine (T3) thyrotoxicosis. Patient's Findings: A 77-year-old man presented to Kuma Hospital due to a neck tumor. A thyroid ultrasonography revealed a 220-mL mass in the right lobe. Laboratory data showed low serum thyrotropin (TSH), low free thyroxine (fT4), and high free T3 (fT3) levels. Anti-TSH receptor antibodies and thyroid-stimulating antibodies were positive. 131I scintigraphy showed diffuse uptake only in the left thyroid lobe. The patient underwent a total thyroidectomy and histological examination identified as poorly differentiated thyroid carcinoma. He was diagnosed with poorly differentiated thyroid carcinoma coexisting with Graves' disease. The tumor showed elevated type 1 iodothyronine deiodinases (D1) and type 2 iodothyronine deiodinases (D2) activities compared with that of the left thyroid lobe. Summary and Conclusions: Increased D1 and D2 activities in poorly differentiated carcinoma resulted in T3 toxicosis with a high serum fT3/fT4 ratio. [ABSTRACT FROM AUTHOR]

Selenium, one of the essential trace minerals, is present in vivo in form of selenoproteins. Iodothyronine deiodinase, a selenoprotein, is involved in the activation and inactivation of thyroid hormone. Therefore, patients with selenium deficiency may present changes in thyroid hormone levels due to inhibition of T4 to T3 conversion; however, this assumption is still under debate. In the present study, we retrospectively investigated the thyroid function in 22 patients with selenium deficiency. Thyroid stimulating hormone (TSH) and free T4 (FT4) levels were increased in 3 (14%) and 5 (23%) patients, respectively, and free T3 (FT3) levels were decreased in 6 (27%) patients. The FT4/FT3 ratio was significantly higher in patients with selenium deficiency than that in the control group. There appeared to be a positive correlation between the decreased rate of selenium levels and FT4/FT3 ratio, thereby indicating that patients with severe selenium deficiency also exhibited abnormal thyroid hormone levels. Furthermore, when selenium was supplemented in seven patients with abnormal thyroid hormone levels, the TSH, FT4, and FT4/FT3 ratio were significantly decreased and FT3 levels were increased. Collectively, patients with selenium deficiency could present the characteristics of not only low FT3 but also high FT4 and FT4/FT3 ratio. [ABSTRACT FROM AUTHOR]

This study evaluated the effects of food availability on the transcript levels of genes related to reproduction and growth in the sapphire devil (Chrysiptera cyanea), a tropical damselfish. Nonbreeding fish were reared at high‐food (HF) and low‐food (LF) levels for 4 weeks under long‐days. Vitellogenic oocytes could be observed in the ovaries of the HF group. The quantitative polymerase chain reaction analysis revealed that lhβ and cyp19b in the brains, vtg and igf1 in the livers and cyp19a in the ovaries of HF fish were significantly higher than that of LF fish, suggesting that estradiol‐17β (E2) synthesis in the ovary and brain is activated when suitable permissive factors are available to fish. Food limitation lowered hepatic igf1 and dio2, suggesting that the TH‐IGF1 signaling system functions in the liver, and that food availability altered hepatic deiodination activities related to intercellular levels of thyroid hormones. Hepatic dio2 significantly decreased when fish were immersed for 3 days in E2‐containing seawater; this suggests that E2 impedes the conversion of T4 to T3 in the liver. Our study shows that igf1 was upregulated in accordance with HF‐induced vitellogenesis but downregulated by E2 treatment, suggesting that igf1 is bidirectional and altered by maturational status. Once vitellogenesis begins under a suitable range of proximal factors, fish need to maintain their nutritional status because food availability is a permissive factor for their reproduction. Highlights: Nonbreeding sapphire devils were reared with high‐food (HF) and low‐food (LF) levels under suitable breeding condition.HF started vitellogenesis and upregulated igf1, dio2, lhβ, cyp19a, cyp19b, and vtg.Interplay between the reproduction and growth axis exists due to nutritional status. [ABSTRACT FROM AUTHOR]

The discovery of triiodothyronine (T3) and its binding to specific receptors have been instrumental in understanding the mode of thyroid hormone action. Equally so, the generation of T3 from its precursor T4 and secreted by the thyroid gland, have elucidated how the proper amount of active hormone is supplied to organs and cells in a specific manner and in tune with changing requirements. The latter is achieved through the action of specific iodothyronine deiodinases. This minireview addresses the properties and function of iodothyronine deiodinases, and their control of T3 supply to target tissues, using as model genetic errors of nature in human and mice as well as laboratory induced mutations in mice. [ABSTRACT FROM AUTHOR]

Polychlorinated biphenyl (PCB) flame retardants are persistent pollutants and inhibit neurodevelopment, particularly in the early stages of life. Halogen bonding (XB) to the iodothyronine deiodinases (Dio) that modulate thyroid hormones (THs) is a potential mechanism for endocrine disruption. Cl⋅⋅⋅Se XB interactions of PCBs with SeMe−, a small model of the Dio active site selenocysteine, are compared with previous results on polybrominated diphenylethers (PBDEs) and THs using density functional theory. PCBs generally display weaker XB interactions compared to PBDEs and THs, consistent with the dependence of XB strength on the size of the halogen (I>Br>Cl). PCBs also do not meet a proposed energy threshold for substrates to undergo dehalogenation, suggesting they may behave as competitive inhibitors of Dio in addition to other mechanisms of endocrine disruption. XB interactions in PCBs are position‐dependent, with ortho interactions slightly more favorable than meta and para interactions, suggesting that PCBs may have a greater effect on certain classes of Dio. Flexibility of PCBs around the biphenyl C−C bond is limited by ortho substitutions relative to the biphenyl linkage, which may contribute to the ability to inhibit Dio and other TH‐related proteins. [ABSTRACT FROM AUTHOR]

The present study investigated the alterations in nerve function and its potential mechanism of offspring result from the decabromodiphenyl ether (BDE209) orally gavage (0, 1.5, and 225 mg/kg.d body weight) in pregnant and lactating mice. Weight gain and litter size of maternal mice and body weight of offspring were examined. Learning and memory abilities of offspring were tested by the Morris water maze experiment. Thyroid hormones (THs) concentrations in peripheral blood of offspring were detected by the chemiluminescence enzyme immunoassay. Relative mRNA expression of type 1 iodothyronine deiodinase (dio1), type 2 iodothyronine deiodinase (dio2), and type 3 iodothyronine deiodinase (dio3) in the livers and brains of offspring were measured by QRT-PCR (quantitative real-time polymerase chain reaction). Protein expression of dio3 in the livers and brains of offspring was measured by Western blot. All indexes of offspring were tested at postnatal day (PND) 21 and PND 60, respectively. As a result, administration of BDE209 decreased weight gain and litter size of maternal mice, and reduced body weight of offspring mice, prolonged escape latency and declined guardant time of offspring in the Morris water maze experiment. Moreover, BDE209 elevated serum levels of total thyroxine (T4), total triiodothyronine (T3), free T4, and free T3 in offspring. In addition, maternal exposure to BDE209 inhibited dio1, dio2, dio3 mRNA expression in the livers of offspring, while elevated dio1 mRNA expression and reduced dio3 mRNA expression in the brains of offspring. BDE209 also inhibited the protein expression of dio3 in the livers and brains of offspring. These results indicate that BDE209 exposure to pregnant and lactating mice can cause disruption in serum THs of offspring by altering mRNA and protein expression of iodothyronine deiodinases, which might consequently result in neurologic impairment of offspring mice. [ABSTRACT FROM AUTHOR]

Thyroid hormones (THs) are indispensable for each phyla in Chordata, while their functions in the non-chordate invertebrates are indistinct. Studies on the TH system in non-chordate invertebrates are important for understanding the evolution of TH system and may be applied in aquaculture or biofouling control at the same time. Iodothyronine deiodinases are keys to studying the TH system, as they are critical enzymes in maintaining TH homeostasis by catalyzing the initiation and termination of the effects of thyroid hormone in vertebrates. Here, we report the primary physiological effects of T4, the outer ring deiodinase activity, and a similar transcription regulation of two oyster deiodinases by TH receptor (CgTR) in an invertebrate, Pacific oyster Crassostrea gigas. L-thyroxine (T4) may have an important physiological function in the oyster, suggested by the growth retardation effect of excessive T4 in umbo larvae stage. The outer ring deiodinase activity transforming T4 to T3 (3, 3′, 5-triiodothyronine) was then detected in the Pacific oyster in vivo, which may be conducted by two oyster deiodinases (CgDx and CgDy). Transcription regulation of CgTR onto these two deiodinase genes was also verified by electrophoretic mobility shift assay and dual luciferase reporter assay in mammalian cells. These results contribute to a better understanding of the evolution of the TH system. [ABSTRACT FROM AUTHOR]

Purpose: The serum free triiodothyronine (FT3)/free thyroxine (FT4) ratio in patients with huge goitrous Hashimoto's thyroiditis (HG-HT) is relatively high. We investigated the cause of high FT3/FT4 ratios. Methods: We measured the serum FT3, FT4, and thyrotropin (TSH) levels of seven patients with HG-HT who had undergone a total thyroidectomy. Eleven patients with papillary thyroid carcinoma served as controls. The activities and mRNA levels of type 1 and type 2 iodothyronine deiodinases (D1 and D2, respectively) were measured in the thyroid tissues of HG-HT and perinodular thyroid tissues of papillary thyroid carcinoma. Results: The TSH levels in the HG-HT group were not significantly different from those of the controls. The FT4 levels in the HG-HT group were significantly lower than those of the controls, whereas the FT3 levels and FT3/FT4 ratios were significantly higher in the HG-HT group. The FT3/FT4 ratios in the HG-HT group who had undergone total thyroidectomy and received levothyroxine therapy decreased significantly to normal values. Both the D1 and D2 activities in the thyroid tissues of the HG-HT patients were significantly higher than those of the controls. However, the mRNA levels of both D1 and D2 in the HG-HT patients' thyroid tissues were comparable to those of the controls. Interestingly, there were significant correlations between the HG-HT patients' D1 and D2 activities, and their thyroid gland volume or their FT3/FT4 ratios. Conclusions: Our results indicate that increased thyroidal D1 and D2 activities may be responsible for the higher serum FT3/FT4 ratio in patients with HG-HT. [ABSTRACT FROM AUTHOR]

Iodothyronine deiodinases (Dios) are involved in the regioselective removal of iodine from thyroid hormones (THs). Deiodination is essential to maintain TH homeostasis, and disruption can have detrimental effects. Halogen bonding (XB) to the selenium of the selenocysteine (Sec) residue in the Dio active site has been proposed to contribute to the mechanism for iodine removal. Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) are known disruptors of various pathways of the endocrine system. Experimental evidence shows PBDEs and their hydroxylated metabolites (OH-BDEs) can inhibit Dio, while data regarding PCB inhibition are limited. These xenobiotics could inhibit Dio activity by competitively binding to the active site Sec through XB to prevent deiodination. XB interactions calculated using density functional theory (DFT) of THs, PBDEs, and PCBs to a methyl selenolate (MeSe−) arrange XB strengths in the order THs > PBDEs > PCBs in agreement with known XB trends. THs have the lowest energy C−X*-type unoccupied orbitals and overlap with the Se lp donor leads to high donor-acceptor energies and the greatest activation of the C−X bond. The higher energy C−Br* and C−Cl* orbitals similarly result in weaker donor-acceptor complexes and less activation of the C−X bond. Comparison of the I···Se interactions for the TH group suggest that a threshold XB strength may be required for dehalogenation. Only highly brominated PBDEs have binding energies in the same range as THs, suggesting that these compounds may inhibit Dio and undergo debromination. While these small models provide insight on the I···Se XB interaction itself, interactions with other active site residues are governed by regioselective preferences observed in Dios.

A primary-alkyl-substituted selenenyl iodide was successfully synthesized through oxidative iodination of a selenol with N-iodosuccinimide by taking advantage of a cavity-shaped steric protection group. The selenenyl iodide exhibited high thermal stability and remained unchanged upon heating at 100 °C for 3 h in [D8]toluene. The selenenyl iodide was reduced to the corresponding selenol by treatment with dithiothreitol. Hydrolysis of the selenenyl iodide under alkaline conditions afforded the corresponding selenenic acid almost quantitatively, corroborating the chemical validity of the recent proposal that hydrolysis of a selenenyl iodide to a selenenic acid is potentially involved in the catalytic mechanism of an iodothyronine deiodinase.

As a feed additive, betaine is widely used in livestock production for its ability to promote growth. Our previous studies had reported that maternal betaine supplementation altered hepatic metabolism in offspring. But it remains unknown whether and how maternal betaine modulates metabolism of thyroid hormones in the offspring chickens by epigenetic modification. In this study, one hundred and twenty Rugao yellow-feathered laying hens were randomly divided into two groups, and were fed basal diet with or without 0.5% betaine supplementation for 28 days. After that, all the hens were artificially inseminated and then four hundreds fertilized eggs were selected. After hatching, the newborn chicks were raised until 56 days old. Betaine fed female chicks showed significantly lower body weight and lower level of biologically active thyroid hormone in plasma compared to control group, which was associated with significantly decrease in expression of type 1 iodothyronine deiodinase (Dio1). Moreover, betaine also changed hepatic expression of betaine-homocysteine - S -methyltransferase (BHMT) and DNA methyltransferase 1 (DNMT1), which may contribute to hypermethylation of the Dio1 promoter. Interestingly, betaine treatments of hens caused none of these effects in male chicks except Dio1 expression. These results indicate that maternal betaine administration effects growth of offspring through differential modification of Dio1 gene methylation and expression in liver and this model of transgenerational effects may help elucidate the mechanisms of maternal effects arise in natural systems. [ABSTRACT FROM AUTHOR]

Background: Subclinical hypothyroidism is associated with dyslipidemia and atherosclerosis. Whether these effects are in part mediated via direct effects of thyrotropin (TSH) on peripheral thyroid hormone (TH) metabolism and/or concentrations of serum lipids is not clear. Objective: This study examined whether TSH has direct effects on peripheral TH metabolism and serum lipids. Methods: Eighty-two patients with differentiated thyroid cancer were retrospectively analyzed. All patients had undergone total thyroidectomy and 131I remnant ablation. During follow-up, two successive injections of recombinant human TSH (rhTSH) were administered to patients on a stable dose of levothyroxine. In all patients, TSH, thyroxine (T4), free T4 (fT4), triiodothyronine (T3), reverse T3 (rT3), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, lipoprotein(a), and triglyceride levels were measured immediately before the first and approximately 72 hours after the second injection of rhTSH. Results: After rhTSH stimulation, T3 values decreased (from 1.91 to 1.81 nmol/L; p < 0.001). T4, fT4, and rT3 did not change. After rhTSH, median apolipoprotein B increased from 0.90 to 0.92 g/L ( p = 0.03), lipoprotein(a) from 0.21 to 0.24 g/L ( p < 0.001), and triglycerides from 1.98 to 2.50 mmol/L ( p < 0.001). Serum high-density lipoprotein cholesterol decreased from 0.98 to 0.81 mmol/L (p < 0.001). Multiple regression analysis showed that the changes in lipids were most closely associated with the decrease in T3 levels. Conclusions: TSH has direct effects on peripheral TH metabolism by decreasing T3 levels in levothyroxine-treated thyroidectomized patients. This decrease in T3 levels is accompanied by unfavorable changes in serum lipids. [ABSTRACT FROM AUTHOR]

Selenium is an essential trace element with multi significant role in the body. In contrast to other trace elements that appear as cofactors of certain enzymes, its physiological role is directly related to functions of proteins in composition of which it is cotranslationally installed by atypical amino acid selenocysteine. The group of proteins, in which composition selenocysteine is an integral functional part of polypeptides, are referred to as selenoproteins. The first enzyme that has been proven to have selenocysteine incorporated in its composition, is glutathione peroxidase (GPx). So far there have been identified 5 isoenzyme forms of GPx which reduce hydrogen peroxide and organic hydroperoxides, protecting cells from oxidative damage. Iodothyronine deiodinases (ID) are among the most important selenopoteins, being responsible for both activation and deactivation of thyroid hormones. So far there have been found over twenty selenoproteins, but only for some of them a physiological role is known.

Nitrite has the potential to disturb thyroid hormone homeostasis, but little is known about the underlying mechanisms. In the present study, juvenile grass carp ( Ctenopharyngodon idellus ) were exposed to various concentrations of nitrite (0, 0.5, 1, 4, and 16 mg/L, respectively). Serum concentrations of triiodothyronine (T 3 ), thyroxine (T 4 ), free triiodothyronine (FT 3 ), free thyroxine (FT 4 ), 3,3,5ʹ-triiodothyronine (rT 3 ), thyroid-stimulating hormone (TSH), and the activity of iodothyronine deiodinases were assayed at 0, 12, 24, 48, and 96 h after exposure. It was found that acute nitrite exposure significantly altered the TH levels and iodothyronine deiodinase activities. The rT 3 levels were significantly increased in the treatment groups, whereas the concentrations of T 3 , FT 3 , FT 4 , and TSH decreased significantly. The concentration of T 4 was elevated in the lower-dose exposure group, but was reduced in the higher-dose exposure group. Increases in type I iodothyronine deiodinase (ID1) and type III iodothyronine deiodinase (ID3) activities were observed in the exposure groups. The activity of type II iodothyronine deiodinase (ID2) decreased at 12 and 24 h after exposure. A decrease of colloid in the thyroid follicles was observed in the exposure group. The results indicate that acute nitrite exposure has the potential to disturb the homeostasis of thyroid hormone metabolism, leading to a hypothyroidism state in the juvenile grass carp. [ABSTRACT FROM AUTHOR]

Purpose: Levothyroxine supplementation is insufficient for the management of one tenth of patients with hypothyroidism. Iodothyronine deiodinases have been suggested to play a role in residual hypothyroid symptoms of these patients by controlling local thyroid hormone homeostasis. Previous research has suggested a relationship between commonly inherited variations in type 2 iodothyronine deiodinase and impaired well-being. We evaluated the prevalence of iodothyronine deiodinase genotypes and their association with psychological well-being in the Korean hypothyroid population. Methods: A prospective observational study. We enrolled 196 hypothyroid subjects (136 chronic autoimmune thyroiditis and 60 thyroid cancer) and assessed baseline well-being using six validated questionnaires. Genotyping was conducted for 19 single nucleotide polymorphisms in type 1, 2, and 3 iodothyronine deiodinase using Sequenom MassARRAY matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in all patients. Results: Frequencies of iodothyronine deiodinase genotypes and well-being scores were not different in hypothyroid subjects according to their disease types. Minor genotypes of a few iodothyronine deiodinase 1 variants (rs11206244, rs2294512, and rs4926616) were associated with reduced psychological well-being. However, iodothyronine deiodinase 2 and 3 variants had no effect on baseline well-being. Conclusion: Minor variations in iodothyronine deiodinase 1 were associated with decreased well-being in the Korean hypothyroid population, whereas iodothyronine deiodinase 2 and 3 were not. Due to controversial results among different ethnicities, further studies to clarify the effects of iodothyronine deiodinase polymorphisms on psychological well-being are warranted in hypothyroid individuals. [ABSTRACT FROM AUTHOR]