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Background: Thyroid peroxidase (TPO) gene mutation leads to a change in enzyme built structure resulting in the anti-TPO autoantibodies production that may cause thyroid destruction., Aim: To evaluate the association of three single nucleotide polymorphisms (SNPs) of the TPO gene and anti-TPO levels in Egyptian patients with autoimmune hypothyroidism and correlate them with the disease severity., Methods: Two hundred patients with newly discovered autoimmune hypothyroidism were included in the study (100 with subclinical hypothyroidism and 100 of them with overt hypothyroidism) and 100 healthy individuals as a control group were genotyped by PCR-REFLP., Results: The TT genotype of rs2071400 C/T and the T allele were significantly more frequent in patients with subclinical hypothyroidism and overt hypothyroidism than in the control group. But there were no significant differences in the TT genotype and T allele between subclinical and overt hypothyroidism patients. As regards TPO rs732609 A/C polymorphism, the CC genotype of rs732609 A/C and the C allele were significantly increased in patients with subclinical hypothyroidism and overt hypothyroidism than in controls. There was a significant difference in the CC genotype and C allele between subclinical and overt hypothyroidism patients. Concerning TPO rs1126797 C/T polymorphism, there were no significant differences of genotype or allele frequencies between patients groups and control group., Conclusion: We found an association of rs2071400 C/T and rs732609A/C polymorphisms with autoimmune hypothyroidism and correlated anti-TPO levels with different genotypes in hypothyroid patients. Also, we found an association of rs732609A/C polymorphism with the disease severity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Autoimmune thyroid disease (AITD) may be detected prior to clinical symptoms through the presence of autoantibodies against thyroid peroxidase (TPOab), thyroglobulin (TGab), or both. The present study aimed to develop a novel radiobinding assay (RBA) for TPOab and to determine the prevalence of TPOab and TGab in the Swedish population. Patient samples from 27 newly diagnosed Graves' disease patients in longitudinal follow-up and 124 AITD autoantibody-positive children in prospective follow-up for increased risk of type 1 diabetes were included to validate the novel RBA for TPO. The results of RBA were compared with those obtained by commercial radioimmunoassay (RIA) and electrochemiluminescence (ECL). Furthermore, 476 serum samples from adult blood donors and 297 from 13-year-old school children were analyzed for the presence of TPOab and TGab. Receiver operating characteristics analysis for the novel TPOab resulted in an area under curve (AUC) value of 0.82 (p<0.0001), a sensitivity of 77.8%, and a specificity of 91.9% in adult blood donors, and an AUC value of 0.70 (p<0.0001), a sensitivity of 53.2% and a specificity of 95.3% in the 13-year-old school children, respectively. TPOab levels in RBA correlated with both ECL (r=0.8950, p<0.0001) and RIA (r=0.9295, p<0.0001). The prevalence of TPOab and TGab was 6.3% and 7.6% in adult blood donors and 2.9 and 3.7% in 13-year-old school children. In conclusion, a novel RBA for the determination of TPOab was developed and validated with current methodologies. This study also reports an increasing prevalence of thyroid autoantibodies from adolescence to adulthood. [ABSTRACT FROM AUTHOR]

Persistent organic pollutants (POPs) including polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB), and dichlorodiphenyltrichloroethane (p,p'-DDT) were reported to influence immunological activity. As endocrine-disrupting chemicals (EDC), these pollutants may disrupt normal thyroid function and act as catalysts for development of autoimmune thyroid disease by directly and indirectly affecting levels of thyroid peroxidase antibodies (TPOAbs). Native American communities are disproportionately exposed to harmful toxicants and are at an increased risk of developing an autoimmune disease. The aim of this study was to determine the association between POPs and TPOAbs in serum obtained from Native American women. This assessment was used to measure whether increased risk of autoimmune thyroid disease occurred as a result of exposure to POPs. Data were collected from 183 Akwesasne Mohawk women, 21–38 years of age, between 2009 and 2013. Multivariate analyses were conducted to determine the association between toxicant exposure and levels of TPOAbs. In multiple logistic regression analyses, exposure to PCB congener 33 was related to elevated risk of individuals possessing above normal levels of TPOAbs. Further, HCB was associated with more than 2-fold higher risk of possessing above normal levels of TPOAbs compared to women with normal levels of TPOAbs. p,p'-DDE was not associated with TPOAb levels within this study. Exposure to PCB congener 33 and HCB was correlated with above normal levels of TPOAbs, a marker of autoimmune thyroid disease. Additional investigations are needed to establish the causes and factors surrounding autoimmune thyroid disease which are multiple and complex. [ABSTRACT FROM AUTHOR]

Atrazine is a widely applied herbicide to improve crop yield and maintain general health. It has been reported to impair thyroid function and architecture in experimental animals. Alterations in thyroid hormones disrupt normal body function and metabolism. Silymarin, a hepatoprotective flavonolignan, was found to improve thyroid function and body metabolism. Additionally, garlic displays several protective effects on body organs. Therefore, this study explored the prophylactic impact of natural compounds comprising silymarin and garlic extract on disrupted thyroid function, hepatic iodothyronine deiodinase type 1, and metabolic parameters in atrazine-intoxicated male rats. We found that daily pre- and co-treatment of atrazine-intoxicated male rats with silymarin (100 mg/kg, p.o) and/or garlic extract (10 mg/kg, p.o) significantly improved thyroid activation and hepatic functionality as evidenced by the re-establishment of T3, T3/T4, and TSH values as well as ALT and AST activities. Interestingly, individual or concurrent supplementation of the atrazine group with silymarin and garlic extract prevented the down-regulation in hepatic iodothyronine deiodinase type 1. These effects were coupled with the repletion of serum and hepatic antioxidants and the amelioration of lipid peroxidation. In addition, current natural products markedly alleviated weight gain, dyslipidemia, hyperglycemia, glucose intolerance, and insulin resistance. Notably, a cocktail of silymarin and garlic extract exerted superior protection against atrazine-triggered deterioration of thyroid, hepatic, and metabolic functioning to individual treatments. Present findings pinpoint the prophylactic and synergistic influence of silymarin and garlic extract combinatorial regimen on thyroid activation and body metabolism via enhancing antioxidant potential, maintaining hepatic function, and iodothyronine deiodinase type 1., Competing Interests: Declaration of competing interest There is no competing interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Bis (2-ethylhexyl) tetrabromophthalate (TBPH) is a new type of brominated flame retardant. Some studies suggest that TBPH exposure may be associated with thyroid damage. However, there is a paucity of research on the authentic exposure-related effects and molecular mechanisms in animals or cells. In this study, we used male Sprague-Dawley (SD) rats and the Nthy ori3-1 cell line (the human thyroid follicular epithelial cell) to explore the potential effects of TBPH (5, 50, 500 mg/kg and 1, 10, 100 nM) on the thyroid. The genes and their proteins of cytokines and thyroid-specific proteins, thyroglobulin (TG), thyroid peroxidase (TPO), and sodium iodide cotransporter (NIS) were examined to investigate the possible mechanisms. At the end of the experiment, it was found that 50 and 500 mg/kg TBPH could increase the levels of total thyroxine (TT4) and free thyroxine (FT4) significantly. The messenger RNAs (mRNAs) of Tg, Tpo, Interleukin-6 (Il6), and Interleukin-10 (Il10) in the thyroid tissues from the rats treated with 500 mg/kg were enhanced clearly. Meanwhile, the mRNAs of TG, TPO, IL6, and IL10 were elevated in Nthy ori3-1 cells treated with 100 nM TBPH as well. The mRNAs of TG and TPO were elevated after the knockdown of IL6. To our surprise, after the knockdown of IL10 or the treatment of anti-IL-10-receptor (anti-IL-10-R) antibody, the mRNAs of TG and TPO were significantly reduced, and the effects of TBPH were diminished. In conclusion, our results suggested that the IL-10-IL-10R-TG/TPO-T4 axis is one important target of TBPH in the thyroid., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Developing neurons have high thyroid hormone and iron requirements to support their metabolically demanding growth. Early-life iron and thyroid-hormone deficiencies are prevalent and often coexist, and each independently increases risk of permanently impaired neurobehavioral function in children. Early-life dietary iron deficiency reduces thyroid-hormone concentrations and impairs thyroid hormone-responsive gene expression in the neonatal rat brain, but it is unclear whether the effect is cell-intrinsic., Objectives: This study determined whether neuronal-specific iron deficiency alters thyroid hormone-regulated gene expression in developing neurons., Methods: Iron deficiency was induced in primary mouse embryonic hippocampal neuron cultures with the iron chelator deferoxamine (DFO) beginning at 3 d in vitro (DIV). At 11DIV and 18DIV, thyroid hormone-regulated gene messenger ribonucleic acid (mRNA)concentrations indexing thyroid hormone homeostasis (Hairless, mu-crystallin, Type II deiodinase, solute carrier family member 1c1, and solute carrier family member 16a2) and neurodevelopment (neurogranin, Parvalbumin, and Krüppel-like factor 9) were quantified. To assess the effect of iron repletion, DFO was removed at 14DIV from a subset of DFO-treated cultures, and gene expression and adenosine 5'-triphosphate (ATP) concentrations were quantified at 21DIV., Results: At 11DIV and 18DIV, neuronal iron deficiency decreased neurogranin, Parvalbumin, and mu-crystallin, and by 18DIV, solute carrier family member 16a2, solute carrier family member 1c1, Type II deiodinase, and Hairless were increased, suggesting cellular sensing of a functionally abnormal thyroid hormone state. Dimensionality reduction with Principal component analysis reveals that thyroid hormone homeostatic genes strongly correlate with and predict iron status. Iron repletion from 14-21DIV did not restore ATP concentration, and Principal component analysis suggests that, after iron repletion, cultures maintain a gene expression signature indicative of previous iron deficiency., Conclusions: These novel findings suggest there is an intracellular mechanism coordinating cellular iron/thyroid hormone activities. We speculate this is a part of the homeostatic response to acutely match neuronal energy production and growth signaling. However, the adaptation to iron deficiency may cause permanent deficits in thyroid hormone-dependent neurodevelopmental processes even after recovery from iron deficiency., Competing Interests: Conflict of interest The authors report no conflicts of interest., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

The widespread use of silver nanoparticles (AgNPs) in consumer products and animal husbandry raises the need to study their impact on living organisms. This study was conducted on Hy-Line Brown hens at the age of 25 weeks with an average weight of 1.58 kg. Hens for 2 weeks received a solution of 50 nm AgNPs at a concentration of 100 pm (experimental group; n = 6) or a solution in which the nanoparticles were suspended (control group; n = 6). Thyroid hormones (thyroxine - T4, triiodothyronine - T3) were evaluated in the blood plasma and expression profiles of genes involved in thyroid hormone (TH) synthesis (TSHR, NIS, TPO, TG), metabolism (DIO1, DIO2, DIO3) and transport (MCT8, MCT10, LAT1) were determined in the chicken thyroid gland. Furthermore, iodothyronine deiodinase, TH transporter and TH receptor (THRA, THRB) mRNA expressions were evaluated in the livers isolated from the same chickens. AgNPs did not affect serum T 4 levels but elevated serum T 3 concentration. The results showed that AgNPs increased DIO3 mRNA in the thyroid gland. In turn, in the liver AgNPs administration significantly upregulated DIO2 and downregulated MCT10 mRNA levels. These results indicate that exposure to AgNPs leads to a tissue-specific alternative expression of genes engaged in TH metabolism. Moreover, the mRNA expression of DIO2 in the liver showed a positive correlation with plasma T 3 levels. In conclusion, AgNPs may have an impact on TH metabolism by affecting deiodinases and TH transporter MCT10 mRNA expression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The deiodinases regulate the activation and inactivation of Thyroid hormones (TH), in both physiological and pathological conditions. The three deiodinases, DIO1, DIO2 and DIO3, have different catalytic role and cellular and tissue distribution. Aim of this study is to evaluate a rat model of regional ischemia/reperfusion (I/R), the modification of cardiac main function after the administration of 6 µg/kg/day of triiodothyronine (T3), and the associated to DIO1, DIO2 and DIO3 gene expression. We also aim to study DIO1 and DIO2 protein levels in different left ventricular regions after an ischemic event. Four groups of rats were studied: sham-operated, sham-operated + T3, I/R rats and I/R rats + T3. DIO1, DIO2 and DIO3 expression were evaluated in I/R region (AAR: area-at-risk) and in a more distant region from ischemic wound (RZ: remote zone). In I/R group, circulating free-T3 (FT3) levels were significantly decreased with respect to basal values, whereas in I/R + T3 rats, FT3 levels were comparable to basal values. In AAR of I/R + T3 rats, DIO1 and DIO2 gene expression significantly increased with respect to sham. In RZ, DIO1 and DIO3 gene expression was significantly lower in sham and I/R rats when compared to I/R + T3. In sham + T3 group, DIO1 and DIO2 gene expression was not detectable, whereas DIO3 was significantly higher than in the other three groups. The present study gives interesting new insights on DIO1, DIO2 and DIO3 in the ischemic heart and their role in relation to T3-mediated amelioration of cardiac function and structure.

Objective: Type 2 deiodinase (DIO2)-mediated thyroid hormone synthesis stimulates osteoblast activity and increases the expression of osteoblast differentiation markers, but there are no large cohort studies to identify the role of the DIO2 polymorphism in bone mineral density in humans., Methods: To investigate the hypothesis that individuals with the DIO2 gene polymorphism are susceptible to osteoporosis, we assessed the polymorphism of the DIO2 gene in 7,524 Koreans drawn from the large-scale Ansan-Anseong cohort of the Korean Genome and Epidemiology Study. All of the participants underwent genotyping of the DIO2 Thr92Ala polymorphism (rs225014)., Results: A total of 6,022 participants were recruited; 1991 (33.0%) were homozygous for the Thr allele, 2,967 (49.3%) were heterozygous (Thr/Ala), and 1064 (17.7%) were homozygous for the Ala allele. The effects of the DIO2 Thr92Ala polymorphism on axial speed of sound (SOS) and the T-score in the tibia and radius were assessed, with age, gender, oestrogen status, body mass index (BMI), serum calcium, 25-hydroxyvitamin D, and parathyroid hormone (PTH) included as covariables. Female subjects carrying the DIO2 Thr92Ala polymorphism had significantly lower SOS and T-scores than control participants. Cox regression analysis revealed a significant relationship between the DIO2 polymorphism and diagnosis of osteoporosis in female participants., Conclusion: DIO2 Thr92Ala polymorphism is associated with decreased SOS and T-scores in the tibia of female subjects independent of other clinical parameters, where this indicates a potential functional role of DIO2 in the maintenance of bone mineral density., (© 2020 John Wiley & Sons Ltd.)

Thyroid hormones (THs) are critical regulators of cellular processes, while changes in their levels impact all the hallmarks of cancer. Disturbed expression of type 3 deiodinase (DIO3), the main TH-inactivating enzyme, occurs in several human neoplasms and has been associated with adverse outcomes. Here, we investigated the patterns of DIO3 expression and its prognostic significance in breast cancer. DIO3 expression was evaluated by immunohistochemistry in a primary cohort of patients with breast cancer and validated in a second cohort using RNA sequencing data from the TCGA database. DNA methylation data were obtained from the same database. DIO3 expression was present in normal and tumoral breast tissue. Low levels of DIO3 expression were associated with increased mortality in the primary cohort. Accordingly, low DIO3 mRNA levels were associated with an increased risk of death in a multivariate model in the validation cohort. DNA methylation analysis revealed that the DIO3 gene promoter is hypermethylated in tumors when compared to normal tissue. In conclusion, DIO3 is expressed in normal and tumoral breast tissue, while decreased expression relates to poor overall survival in breast cancer patients. Finally, loss of DIO3 expression is associated with hypermethylation of the gene promoter and might have therapeutic implications.

To review the efficacy and safety of glucocorticoids combined with different regimens for treating severe immune thrombocytopenia (ITP). Eighty-five severe ITP patients from 2 tertiary hospitals treated with glucocorticoids were enrolled from January 2018 to May 2019 and divided into 4 treatment groups: group A (treated with glucocorticoids), group B (glucocorticoids plus intravenous immunoglobulin (IVIg)), group C (glucocorticoids plus recombinant human thrombopoietin (rhTPO)), and group D (glucocorticoids plus IVIg and rhTPO). Statistical analysis was performed with SPSS 19.0 software. Early responses and response maintenance were assessed at 14 days and 1 month after treatment. Groups B, C and D had higher complete response (CR) and overall response (OR) rates than group A (P < 0.05). Adverse reaction incidences were not significantly different among all groups (P > 0.05). Severe ITP patients who received glucocorticoids with IVIg and rhTPO had higher CRs and ORs at the platelet level, and no significant adverse reactions were observed. Glucocorticoids combined with different regimens had different clinical efficacies for treating severe ITP.

Background: Thyroid hormones (THs) are key regulators of development, tissue differentiation, and maintenance of metabolic balance in virtually every cell of the body. Accordingly, severe alteration of TH action during fetal life leads to permanent deficits in humans. The skin is among the few adult tissues expressing the oncofetal protein type 3 deiodinase (D3), the TH inactivating enzyme. Here, we demonstrate that D3 is dynamically regulated during epidermal ontogenesis. Methods: To investigate the function of D3 in a postdevelopmental context, we used a mouse model of conditional epidermal-specific D3 depletion. Loss of D3 resulted in tissue hypoplasia and enhanced epidermal differentiation in a cell-autonomous manner. Results: Accordingly, wound healing repair and hair follicle cycle were altered in the D3-depleted epidermis. Further, in vitro ablation of D3 in primary culture of keratinocytes indicated that various markers of stratified epithelial layers were upregulated, thereby confirming the pro-differentiative action of D3 depletion and the consequent increased intracellular triiodothyronine levels. Notably, loss of D3 reduced the clearance of systemic TH in vivo , thereby demonstrating the critical requirement for epidermal D3 in the maintenance of TH homeostasis. Conclusion: In conclusion, our results show that the D3 enzyme is a key TH-signaling component in the skin, thereby providing a striking example of a physiological context for deiodinase-mediated TH metabolism, as well as a rationale for therapeutic manipulation of deiodinases in pathophysiological contexts.

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., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The pathogenesis of autoimmune thyroid diseases (AITD) is poorly understood and the association between different immune features and the germline variants involved in AITD are yet unclear. We previously observed systemic depletion of IgG core fucosylation and antennary α1,2 fucosylation in peripheral blood mononuclear cells in AITD, correlated with anti-thyroid peroxidase antibody (TPOAb) levels. Fucose depletion is known to potentiate strong antibody-mediated NK cell activation and enhanced target antigen-expressing cell killing. In autoimmunity, this may translate to autoantibody-mediated immune cell recruitment and attack of self-antigen expressing normal tissues. Hence, we investigated the crosstalk between immune cell traits, secreted proteins, genetic variants and the glycosylation patterns of serum IgG, in a multi-omic and cross-sectional study of 622 individuals from the TwinsUK cohort, 172 of whom were diagnosed with AITD. We observed associations between two genetic variants (rs505922 and rs687621), AITD status, the secretion of Desmoglein-2 protein, and the profile of two IgG N-glycan traits in AITD, but further studies need to be performed to better understand their crosstalk in AITD. On the other side, enhanced afucosylated IgG was positively associated with activatory CD335 - CD314 + CD158b + NK cell subsets. Increased levels of the apoptosis and inflammation markers Caspase-2 and Interleukin-1α positively associated with AITD. Two genetic variants associated with AITD, rs1521 and rs3094228, were also associated with altered expression of the thyrocyte-expressed ligands known to recognize the NK cell immunoreceptors CD314 and CD158b. Our analyses reveal a combination of heightened Fc-active IgG antibodies, effector cells, cytokines and apoptotic signals in AITD, and AITD genetic variants associated with altered expression of thyrocyte-expressed ligands to NK cell immunoreceptors. Together, TPOAb responses, dysregulated immune features, germline variants associated with immunoactivity profiles, are consistent with a positive autoreactive antibody-dependent NK cell-mediated immune response likely drawn to the thyroid gland in AITD.

1. A number of chemicals have been shown to produce disruption of the thyroid gland, resulting in reduced thyroid hormone synthesis, by a mechanism involving inhibition of thyroid peroxidase (TPO) activity (EC 1.11.1.8).2. An assay was developed for rat thyroid gland microsomal TPO activity, employing L-tyrosine as the physiological substrate, with analysis of the formation of the 3-iodo-L-tyrosine (3MIT) metabolite by ultra-performance liquid chromatography-mass spectrometry-mass spectrometry.3. Formation of 3MIT was linear with respect to both rat thyroid gland microsomal protein concentration and incubation time, whereas only small quantities of 3,5-diodo-L-tyrosine were formed.4. Studies were performed with nine known TPO inhibitors. The most potent inhibitors were 3-amino-1,2,4-triazole, ethylene thiourea, methimazole and 6-propyl-2-thiouracil which had IC 50 values (i.e. concentration to produce a 50% inhibition of enzyme activity) of 0.059, 0.791, 1.07 and 1.96 μM, respectively, whereas the least potent inhibitor was sodium perchlorate which had an IC 50 value of 13,800 µM.5. For five inhibitors, where literature data were available, the observed IC 50 values obtained in this study employing rat thyroid gland microsomes and L-tyrosine as substrate were similar to those previously reported using the spectrophotometric guaiacol oxidation assay.

This study investigated the effects of microcystin (MC) on the regulation of thyroid hormone (TH) metabolism in juvenile zebrafish exposed to MC-LR. The results showed that acute MC-LR exposure at concentrations ranging from 50 μg/L to 400 μg/L led to significant reductions in thyroxine (T 4 ) and triiodothyronine (T 3 ) levels in juvenile zebrafish. The transcription levels of genes involved in TH synthesis, such as corticotropin-releasing hormone (crh), thyroid-stimulating hormone (tsh), thyroid peroxidase (tpo) and transthyretin (ttr), were significantly decreased followed by an increase after MC-LR exposure. Transcription of the TH nuclear receptors (tr-α and tr-β) was significantly reduced during the exposure period. Moreover, the activities of iodothyronine deiodinase type Ⅰ (ID1) and iodothyronine deiodinase type Ⅱ (ID2) showed initially decreased and then increased trend, while the activity of iodothyronine deiodinase type Ⅲ (ID3) significantly decreased during MC-LR exposure. In addition, the effect of MC-LR on deiodinase activities and T 4 contents were important causes of the decreased T 3 at the early exposure stage. These results indicated that acute MC-LR exposure significantly interfered with the transcription of genes related to TH synthesis, transport and metabolism, and affected normal function of the thyroid which leads to decrease of T 4 and T 3 in juvenile zebrafish. Therefore, the thyroid function is susceptible to interference by MC-LR, and it may cause adverse effects on the growth and development of juvenile zebrafish., (Copyright © 2019. Published by Elsevier Ltd.)

Impaired synthesis or action of thyroid hormones (THs) during critically sensitive periods of development can have long term adverse effects on health. Development of rapid assays to identify chemicals that impair THs physiology is an important goal for reducing risks from chemical use. Thyroid peroxidase (TPO) is a key enzyme regulating THs synthesis in thyroid gland and a vulnerable target for chemicals that disrupt THs synthesis. To develop a human-relevant, rapid assay for TPO inhibition, we have engineered two cell lines (CHO and LentiX- 293) to express active human TPO (hTPO) enzyme and applied them in a recently-described assay using a stable fluorescent product (Amplex UltraRed). Assay performance was assessed by comparing activity of 19 reference chemicals with known strong, weak or no TPO inhibitory activity. The assay using hTPO from either cell line consistently identified the relative potency of strong to moderate inhibitors and chemicals known to be inactive. Results were less consistent for chemicals reported to be weak inhibitors of rodent TPO, possibly suggesting some species specificity. Our studies support the use of hTPO from stably transfected cell lines to substitute for animal-derived thyroid microsomes for rapid high throughput screening assays to identify and characterize TPO inhibitors., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Loss of the tumor suppressor tuberous sclerosis complex 1 ( Tsc1 ) in the liver promotes gluconeogenesis and glucose intolerance. We asked whether this could be attributed to aberrant expression of small RNAs. We performed small-RNA sequencing on liver of Tsc1 -knockout mice, and found that miRNAs of the delta-like homolog 1 ( Dlk1 )-deiodinase iodothyronine type III ( Dio3 ) locus are up-regulated in an mTORC1-dependent manner. Sustained mTORC1 signaling during development prevented CpG methylation and silencing of the Dlk1-Dio3 locus, thereby increasing miRNA transcription. Deletion of miRNAs encoded by the Dlk1-Dio3 locus reduced gluconeogenesis, glucose intolerance, and fasting blood glucose levels. Thus, miRNAs contribute to the metabolic effects observed upon loss of TSC1 and hyperactivation of mTORC1 in the liver. Furthermore, we show that miRNA is a downstream effector of hyperactive mTORC1 signaling., Competing Interests: The authors declare no competing interest.

Thyroid hormone (TH) is involved in regulating the reproduction of vertebrates. Its physiological action in the target tissues is due to the conversion of TH by iodothyronine deiodinases. In this study, we aimed to clone and characterize type 2 (sdDio2) and type 3 (sdDio3) of the sapphire devil Chrysiptera cyanea, a tropical damselfish that undergoes active reproduction under long-day conditions, and to study the involvement of THs in the ovarian development of this species. When the cDNAs of sdDio2 and sdDio3 were partially cloned, they had deduced amino acid sequences of lengths 271 and 267, respectively, both of which were characterized by one selenocysteine residue. Real-time quantitative PCR (qPCR) revealed that both genes are highly expressed in the whole brain, and sdDio2 and sdDio3 are highly transcribed in the liver and ovary, respectively. In situ hybridization analyses showed positive signals of sdDio2 and sdDio3 transcripts in the hypothalamic area of the brain. Little change in mRNA abundance of sdDio2 and sdDio3 in the brain was observed during the vitellogenic phases. It is assumed that simultaneous activation and inactivation of THs occur in this area because oral administration of triiodothyronine (T3), but not of thyroxine (T4), upregulated mRNA abundance of both genes in the brain. The transcript levels of sdDio2 in the liver and sdDio3 in the ovary increased as vitellogenesis progressed, suggesting that, through the metabolism of THs, sdDio2 and sdDio3 play a role in vitellogenin synthesis in the liver and yolk accumulation/E2 synthesis in the ovary. Taken together, these results suggest that iodothyronine deiodinases act as a driver for vitellogenesis in tropical damselfish by conversion of THs in certain peripheral tissues., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: Investigation thyroid dysfunction and autoimmunity in pregnant women with gestational diabetes mellitus., Background: This article was written to evaluate the thyroid function and anti-thyroid peroxidase (anti- TPO) antibodies in pregnant women with gestational diabetes mellitus (GDM)., Methods: A total of 252 women with GDM and 252 healthy pregnant women were enrolled. Thyroid tests, including TSH, FreeT3, Free T4, and anti-TPO were performed for all women at 24-28 weeks of gestation. Data analysis was then carried out using SPSS ver. 22., Results: There was a significant difference between the experimental group (38.4%) and the control group (14.06%) in terms of the prevalence of subclinical hypothyroidism (p= 0.016). The frequency of anti-TPO was higher in the experimental group than the control group and positive anti-TPO was observed in 18.6% of women with GDM and 10.3% of healthy pregnant women (P= 0.008)., Conclusion: Thyroid disorders are observed in pregnant women with GDM more frequently than healthy individuals and it may be thus reasonable to perform thyroid tests routinely., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Thyroid gland is a probable goal tissue for radiation-related injury. Occupational exposure to ionizing radiation leads to thyroid dysfunction and exposure to high dose may lead to thyroid carcinoma., Objective: Evaluation of the role of Thyroid peroxidase antibody as a predictor for thyroid dysfunction among nurses and technicians in the radiology department in Mansoura Specialized Medical hospital (MSMH)., Subjects and Methods: Subjects were Nurses and technicians who are working in (MSMH) with persistent daily duty in the last 3 years and fulfilling the inclusion and exclusion criteria. All subjects included in the study were recruited in one month and divided into two groups; Group 1: 50 subjects who were working in radiology, coronary angiography and ERCP unit, Radiation -exposed group. Group 2: 33 subjects who were working in In-patient departments and in out- patient clinics and not exposed to any type of radiation. Non fasting blood sample was taken from all enrolled subjects for measurement of TSH and Anti-TPO., Results: TPO was positively and significantly correlated to age, TSH, duration of radiology/ y (r=0.388, 0.364, 0.342respectively) p value <0.05. Roc curve was done to detect the sensitivity and specificity of TSH in relation to TPO that revealed the cutoff value of TSH > 1.69 with Sensitivity and Specificity. PPV, NPV and accuracy at cutoff >1.69 were 70.6%, 51.5%, 42.8%, 77.3% and 58%., Conclusion: Working personnel with positive anti TPO and their TSH levels are more than 1.69 associated with symptoms of hypothyroidism, a trial of treatment is mandatory to relieve symptoms., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Iodothyronine deiodinases are selenoproteins that regulate thyroid hormone metabolism. Of the three types of deiodinases, type 2 is the major regulator of intracellular triiodothyronine concentration in both the hypothalamus and pituitary, and therefore the major regulator of thyrotropin secretion. A defect in iodothyronine deiodinase activity can lead to a reduced sensitivity to thyroid hormones action and the most recent literature includes these defects in the so-called "syndromes of reduced sensitivity to thyroid hormones". To date, the pathogenic variants of the selenocysteine insertion sequence-binding protein 2 ( SECISBP2 ) gene are the first and only inherited disorder of iodothyronine metabolism described. Moreover, there is a growing interest in understanding the possible role of polymorphisms of DIO1 and DIO2 genes in some pathological conditions and in determining the requirement of levothyroxine replacement and the role of combined levothyroxine-liothyronine therapy in carrying subjects affected by hypothyroidism and who need replacement therapy. Results on this topic are still conflicting and more studies are needed to assess the efficacy of combined levothyroxine-liothyronine replacement therapy in this subset of patients.

Background: Some clinicians used levothyroxine (LT4) treatment for mild subclinical hypothyroidism (SCH) pregnant women (2.5 < thyroid-stimulating hormone (TSH) ≤ the pregnancy-specific reference range with normal free thyroxine (FT4) level) with thyroid peroxidase antibody negative (TPOAb−), although the recent clinical guideline did not recommend it. It is unknown whether LT4 treatment for pregnant women with mild SCH and TPOAb− have impact on fetal growth. Therefore, the aim of the study was to investigate the effect of LT4 treatment on fetal growth and birth weight among mild SCH pregnant women with TPOAb−. Methods: This was a birth cohort study including 14,609 pregnant women between 2016 and 2019 in Tongzhou Maternal and Child Health Hospital of Beijing, China. Pregnant women were divided into 3 groups as follows: Euthyroid (n = 14,285, 0.03 ≤ TSH ≤ 2.5mIU/L, normal FT4), TPOAb−; Untreated mild SCH with TPOAb− (n = 248, 2.5 < TSH ≤ 2.9mIU/L, normal FT4, without LT4 treatment); Treated mild SCH with TPOAb− (n = 76, 2.5 < TSH ≤ 2.9mIU/L, normal FT4, with LT4 treatment). The main outcome measures were Z-scores of fetal growth indicators (abdominal circumference (AC), biparietal diameter (BPD), femur length (FL), head circumference (HC), estimated fetal weight (EFW)), fetal growth restriction (FGR) and birth weight. Results: There was no difference in fetal growth indicators and birth weight between the untreated mild SCH women with TPOAb− and the euthyroid pregnant women. But the HC Z-score was lower in the LT4 treated mild SCH women with TPOAb−, compared with the euthyroid pregnant women (β = -0.223, 95%CI: -0.422, -0.023). The LT4 treated mild SCH women with TPOAb− had lower fetal HC Z-score (β = -0.236, 95%CI: -0.457, -0.015), compared with the untreated mild SCH women with TPOAb−. Conclusions: We observed that LT4 treatment for mild SCH with TPOAb− was associated with decreased fetal HC, which was not observed for untreated mild SCH women with TPOAb−. The adverse effect of LT4 treatment for mild SCH with TPOAb− provided new evidence for the recent clinical guideline. [ABSTRACT FROM AUTHOR]

Thyroid dysfunction and TPOAb positivity during pregnancy are associated with adverse pregnancy outcomes such as preterm delivery. The aim of this study was to predict preterm delivery based on identified risk factors, especially TPOAb levels. A secondary analysis was run on data collected in the Tehran Thyroid and Pregnancy study (TTPs). We used the data of 1515 pregnant women with singletons. The association between risk factors and preterm birth (delivery before 37 completed weeks of gestation) was investigated in univariate analysis. Multivariate logistic regression analysis was performed to identify independent risk factors, and a stepwise backward elimination method was used to determine the helpful combination of risk factors. The nomogram was developed based on a multivariate logistic regression model. The performance of the nomogram was evaluated using a concordance index and calibration plots with bootstrap samples. Statistical analysis was performed using STATA software package; the significance level was set at P < 0.05. Based on multivariate logistic regression analysis, a combination of previous preterm delivery [OR: 5.25; 95 %CI: (2.13–12.90), p < 0.01], TPOAb [OR: 1.01; 95 %CI: (1.01–1.02), and T4 [OR: 0.90; 95 %CI: (0.83–0.97); p = 0.04] as independent risk factors that most precisely predicted preterm birth. The area under the curve (AUC) was 0.66 (95% CI: 0.61–0.72). The calibration plot suggests that the fit of the nomogram is reasonable. A combination of T4, TPOAb, and previous preterm delivery was identified as independent risk factors that accurately predicted preterm delivery. The total score obtained based on the nomogram designed based on risk factors can predict the risk of preterm delivery. [ABSTRACT FROM AUTHOR]

This study aims to investigate the relationship between thyroid peroxidase antibody (TPO) and thyroid function tests (TSH, T3 and T4) in patients with type 2 diabetes mellitus (T2DM). Ninety women and men, with ages ranging between 35- 65 years and weighing 60-80 kgs, were selected for this study. They were classified into three groups: G1 included 15 healthy control group, G2 had15 patients with T2DM and G3 had 60 patients with T2DM and hypothyroidism. Blood samples were collected from each individual via vein puncture to assess thyroid hormone and TPO-Ab. The results showed highly significant (p < 0.01) increase in TSH level in the diabetic group with hypothyroidism when compared to the other groups. There was no significant difference between diabetic and control groups. T4 and T3 levels showed highly significant (p<0.01) decrease in the diabetic group with hypothyroidism when compared to the diabetic and healthy control groups. On the other hand, there was no significant difference between the diabetic and healthy control groups. The results showed highly significant (p < 0.01) increase in the TPO-AB level in diabetic group with hypothyroidism when compared with the diabetic and healthy control groups. [ABSTRACT FROM AUTHOR]

The aim of this study was to estimate the mode of thyroid peroxidase (TPO) inhibition by polyphenols: Chlorogenic acid, rosmarinic acid, quercetin, and rutin. All the tested polyphenols inhibited TPO; the IC 50 values ranged from 0.004 mM to 1.44 mM (for rosmarinic acid and rutin, respectively). All these pure phytochemical substances exhibited different modes of TPO inhibition. Rutin and rosmarinic acid showed competitive, quercetin-uncompetitive and chlorogenic acid-noncompetitive inhibition effect on TPO. Homology modeling was used to gain insight into the 3D structure of TPO and molecular docking was applied to study the interactions of the inhibitors with their target at the molecular level. Moreover, the type and strength of mutual interactions between the inhibitors (expressed as the combination index, CI) were analyzed. Slight synergism, antagonism, and moderate antagonism were found in the case of the combined addition of the pure polyphenols. Rutin and quercetin as well as rutin and rosmarinic acid acted additively (CI = 0.096 and 1.06, respectively), while rutin and chlorogenic acid demonstrated slight synergism (CI = 0.88) and rosmarinic acid with quercetin and rosmarinic acid with chlorogenic acid showed moderate antagonism (CI = 1.45 and 1.25, respectively). The mixture of chlorogenic acid and quercetin demonstrated antagonism (CI = 1.79). All the polyphenols showed in vitro antiradical ability against 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid), ABTS. The highest ability (expressed as IC 50 ) was exhibited by rosmarinic acid (0.12 mM) and the lowest value was ascribed to quercetin (0.45 mM).

Levothyroxine (LT4) is a form of thyroid hormone used to treat hypothyroidism. In the brain, T4 is converted to the active form T3 by type 2 deiodinase (D2). Thus, it is intriguing that carriers of the Thr92Ala polymorphism in the D2 gene (DIO2) exhibit clinical improvement when liothyronine (LT3) is added to LT4 therapy. Here, we report that D2 is a cargo protein in ER Golgi intermediary compartment (ERGIC) vesicles, recycling between ER and Golgi. The Thr92-to-Ala substitution (Ala92-D2) caused ER stress and activated the unfolded protein response (UPR). Ala92-D2 accumulated in the trans-Golgi and generated less T3, which was restored by eliminating ER stress with the chemical chaperone 4-phenyl butyric acid (4-PBA). An Ala92-Dio2 polymorphism-carrying mouse exhibited UPR and hypothyroidism in distinct brain areas. The mouse refrained from physical activity, slept more, and required additional time to memorize objects. Enhancing T3 signaling in the brain with LT3 improved cognition, whereas restoring proteostasis with 4-PBA eliminated the Ala92-Dio2 phenotype. In contrast, primary hypothyroidism intensified the Ala92-Dio2 phenotype, with only partial response to LT4 therapy. Disruption of cellular proteostasis and reduced Ala92-D2 activity may explain the failure of LT4 therapy in carriers of Thr92Ala-DIO2.

Objective: To investigate the association between positive anti-thyroid peroxidase antibody (TPOAb) and/or anti-thyroglobulin antibody (TgAb) and the occurrence of thyroid immune-related adverse events (irAEs) in patients with malignant tumors who treated with immune checkpoint inhibitors (ICIs). Methods: A case-control study. A total of 116 patients with malignant tumor who received ICIs treatment and underwent thyroid function evaluation at Peking Union Medical College Hospital from January 2017 to April 2023 were enrolled retrospectively, including 77 males and 39 females, with a median age of ( M ( Q 1 , Q 3 )) 63.0 (55.0, 70.0) years. The patients were divided into the euthyroid group ( n =58) and the thyroid irAEs group ( n =58) according to whether thyroid irAEs occurred after ICIs treatment. The clinical characteristics and baseline anti-thyroid antibodies associated with the occurrence of thyroid irAEs after ICIs treatment in patients with malignant tumors were evaluated. Variables with statistical significance in univariate analysis were included in multivariate logistic regression model to analyze the risk factors for thyroid irAEs in patients with malignant tumors who received ICIs treatment. Results: In irAEs group, therewore 4 (3.4%) cases of clinical thyrotoxicosis, 23(19.8%) cases of subclinical thyrotoxicosis, 23 (19.8%) cases of clinical hypothyroidism, and 8(6.9%) cases of subclinical hypothyroidism. The positive rate of anti-thyroid antibodies at baseline in the thyrioid irAEs group was higher than that in the euthyroid group［16/58（27.6%）vs 3/58（5.2%）， P =0.001］. After at least one course of ICIs treatment, the incidence of thyroid irAEs in patients with positive anti-thyroid antibodies at baseline was 84.2% (16/19), whereas it was 43.3% (42/97) in patients with negative anti-thyroid antibodies( P =0.001). Univariate logistic regression analysis showed that gender ( OR =2.812, 95% CI :1.257-6.293), baseline thyroid autoantibodies were positive ( OR =6.984, 95% CI : 1.909-25.547), baseline TgAb positivity ( OR =8.909, 95% CI : 1.923-41.280), and baseline TPOAb positivity ( OR =7.304, 95% CI : 1.555-34.308) were associated with thyroid irAEs (all P <0.05). Multivariate logistic regression analysis indicated that baseline TgAb positivity ( OR =7.637, 95% CI : 1.617-36.072) was a risk factor for thyroid irAEs ( P =0.01). Conclusions: The incidence of thyroid irAEs is higher in patients who are positive for baseline TPOAb and/or TgAb compared to those who are negative for TPOAb and TgAb. Patients with positive TgAb at baseline are at high risk of developing thyroid irAEs.

Objectives: To analyse and explore the association between thyroid autoantibodies and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM)., Design: A cross-sectional study., Setting: Patients were from the inpatient unit at The Second Endocrinology Department of Shengjing Hospital Affiliated to China Medical University (Shenyang, China) between January 2015 and September 2019., Participants: A total of 150 Chinese adults with T2DM were included in the study, including 83 men and 67 women. Their age ranged between 25 and 92 years., Methodology: They grouped by the presence of DKD, urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate, and levels of thyroid peroxidase antibodies (TPOAb) and thyroglobulin antibodies (TgAb). Data on the patients' general characteristics and laboratory measurements (levels of fasting plasma glucose, glycated haemoglobin, and albumin; renal function; and thyroid function) were collected. Binary logistic regression was performed to identify risk factors for DKD., Results: The level of TPOAb, the positivity rates of TPOAb (p<0.01) and TgAb (p<0.05) were higher in patients with DKD than in those without DKD. The TPOAb level in patients with a UACR<30 mg/g creatinine was lower than that in patients with a UACR between 30 and 300 mg/g creatinine (p<0.05). The prevalence of DKD was higher in patients with a TPOAb-positive or TgAb-positive status. The result of binary logistic regression analysis showed that a TPOAb-positive status was significantly associated with DKD in patients with T2DM (OR=7.683, 95% CI 1.583 to 37.286, p<0.05)., Conclusions: TPOAb-positive status is in association with DKD in patients with T2DM. Large scale, prospective cohort studies are warranted to confirm our findings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

(1) Autoimmune thyroiditis (AIT) is the most common cause of primary hypothyroidism and one of the most frequent organ-specific autoimmune diseases. Its pathogenesis is polygenic and still requires further research. The aim of the study was to assess, for the first time in the Caucasian population, the role of selected TPO gene promoter polymorphisms (rs2071399 G/A, rs2071400C/T, rs2071402 A/G, and rs2071403 A/G) in the development of AIT. A total of 237 patients diagnosed with AIT and 130 healthy controls were genotyped for four TPO gene polymorphisms, and the results were statistically analyzed to check for the role of these polymorphisms. There were no significant differences in the genotype and allele frequencies of the studied TPO gene promoter polymorphisms between patients and controls ( p > 0.05). The haplotype distribution (rs2071400-rs2071402-rs2071403) between the two studied groups was similar for the most common variants (CGA, CAG, TGG). Only a rare haplotype (CGG) occurred more frequently among patients compared to controls ( p = 0.04). The studied TPO gene promoter polymorphisms did not show an association with susceptibility to AIT in the Caucasian Polish population, contrary to the results in Japanese patients.

Autoimmune thyroiditis (AITD) is a T-cell-mediated, organ- specific autoimmune disease caused by interactions between genetic and environmental factors. Patients with AITD show thyroid lymphocyte infiltration and an increase in the titer of thyroid autoimmune antibodies, thereby altering the integrity of thyroid follicle epithelial cells and dysregulating their metabolism and immune function, leading to a decrease in multi-tissue metabolic activity. Research has shown that patients with AITD have a significantly higher risk of adverse pregnancy outcomes, such as infertility and miscarriage. Levothyroxine(LT 4 ) treatment can improve the pregnancy outcomes of normal pregnant women with thyroid peroxidase antibodies(TPOAb) positivity, but it is not effective for invitro fertilization embryo transfer (IVF-ET) in women with normal thyroid function and positive TPOAb. Other factors may also influence pregnancy outcomes of patients with AITD. Recent studies have revealed that the gut microbiota participates in the occurrence and development of AITD by influencing the gut-thyroid axis. The bacterial abundance and diversity of patients with Hashimoto thyroiditis (HT) were significantly reduced, and the relative abundances of Bacteroides , fecal Bacillus , Prevotella , and Lactobacillus also decreased. The confirmation of whether adjusting the composition of the gut microbiota can improve pregnancy outcomes in patients with AITD is still pending. This article reviews the characteristics of the gut microbiota in patients with AITD and the current research on its impact in pregnancy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Song, Bai, Liu, Zhai and Zhang.)

The US Environmental Protection Agency is evaluating the ecological and toxicological effects of per- and polyfluorinated chemicals. A number of perfluorinated chemicals have been shown to impact the thyroid axis in vivo suggesting that the thyroid hormone system is a target of these chemicals. The objective of this study was to evaluate the activity of 136 perfluorinated chemicals at seven key molecular initiating events (MIE) within the thyroid axis using nine in vitro assays. The potential MIE targets investigated are Human Iodothyronine Deiodinase 1 (hDIO1), Human Iodothyronine Deiodinase 2 (hDIO2), Human Iodothyronine Deiodinase 3 (hDIO3), Xenopus Iodothyronine Deiodinase (xDIO3); Human Iodotyrosine Deiodinase (hIYD), Xenopus Iodotyrosine Deiodinase (xIYD), Human Thyroid Peroxidase (hTPO); and the serum binding proteins Human Transthyretin (hTTR) and Human Thyroxine Binding Globulin (hTBG). Of the 136 PFAS chemicals tested, 85 had sufficient activity to produce a half-maximal effect concentration (EC50) in at least one of the nine assays. In general, most of these PFAS chemicals did not have strong potency towards the seven MIEs examined, apart from transthyretin binding, for which several PFAS had potency similar to the respective model inhibitor. These data sets identify potentially active PFAS chemicals to prioritize for further testing in orthogonal in vitro assays and at higher levels of biological organization to evaluate their capacity for altering the thyroid hormone system and causing potential adverse health and ecological effects., Competing Interests: Declaration of Competing Interest The authors claim no conflicts of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Congenital hypothyroidism (CH) is the most common neonatal metabolic disorder. In patients with CH in China, thyroid dyshormonogenesis is more common than thyroid dysgenesis; however, the genetic causes of CH due to thyroid dyshormonogenesis remain largely unknown. Therefore, we aimed at identifying novel candidate causative genes for CH. Methods: To identify novel CH candidate genes, a total of 599 patients with CH were enrolled and next-generation sequencing was performed. The functions of the identified variants were confirmed using HEK293T and FTC-133 cell lines in vitro and in a mouse model organism in vivo . Results: Three pathogenic contactin 6 ( CNTN6 ) variants were identified in two patients with CH. Pedigree analysis showed that CH caused by CNTN6 variants was inherited in an autosomal recessive pattern. The CNTN6 gene was highly expressed in the thyroid in humans and mice. Cntn6 knockout mice presented with thyroid dyshormonogenesis and CH due to the decreased expression of crucial genes for thyroid hormone biosynthesis ( Slc5a5 , Tpo , and Duox2 ). All three CNTN6 variants resulted in the blocking of the release of the Notch intracellular domain, which could not translocate into the nucleus, impaired NOTCH1 transcriptional activity, and decreased expression of SLC5A5 , TPO , and DUOX2 . Further, we found that DTX1 was required for CNTN6 to promote thyroid hormone biosynthesis through Notch signaling. Conclusions: This study demonstrated that CNTN6 is a novel causative gene for CH through the mediation of thyroid hormone biosynthesis via Notch signaling, which provides new insights into the genetic background and mechanisms involved in CH and thyroid dyshormonogenesis.

Aim: To evaluate and compare the efficacy of platelet-rich plasma (PRP) therapy in alopecia areata (AA) patients with normal and with elevated levels of anti-thyroglobulin antibodies and/or anti-thyroid peroxidase antibodies., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Genome-wide association studies (GWAS) have identified genetic variants linked to fat metabolism and related traits, but rarely pinpoint causative variants. This limitation arises from GWAS not considering functional implications of noncoding variants that can affect transcription factor binding and potentially regulate gene expression. The aim of this study is to investigate a candidate noncoding functional variant within a genetic locus flagged by a GWAS SNP associated with non-alcoholic fatty liver disease (NAFLD), a condition characterized by liver fat accumulation in non-alcohol consumers., Methods: CRISPR-Cas9 gene editing in HepG2 cells was used to modify the regulatory element containing the candidate functional variant linked to NAFLD. Global gene expression in mutant cells was assessed through RT-qPCR and targeted transcriptomics. A phenotypic assay measured lipid droplet accumulation in the CRISPR-Cas9 mutants., Results: The candidate functional variant, rs2294510, closely linked to the NAFLD-associated GWAS SNP rs11206226, resided in a regulatory element within the DIO1 gene's promoter region. Altering this element resulted in changes in transcription factor binding sites and differential expression of candidate target genes like DIO1, TMEM59, DHCR24, and LDLRAD1, potentially influencing the NAFLD phenotype. Mutant HepG2 cells exhibited increased lipid accumulation, a hallmark of NAFLD, along with reduced LDL-C, HDL-C and elevated triglycerides., Conclusions: This comprehensive approach, that combines genome editing, transcriptomics, and phenotypic assays identified the DIO1 promoter region as a potential enhancer. Its activity could regulate multiple genes involved in the NAFLD phenotype or contribute to defining a polygenic risk score for enhanced risk assessment in NAFLD patients., (© 2024. The Author(s).)

Spirotetramat (SPT), a tetronic acid-derived insecticide, is implicated in reproductive and lipid metabolism disorders, as well as developmental toxicity in fish. While these effects are documented, the precise mechanisms underlying its developmental toxicity are not fully elucidated. In this study, zebrafish embryos (2 h post-fertilization, hpf) were exposed to four concentrations of SPT (0, 60, 120, and 240 μg/L) until 21 dpf (days post-fertilization). We delved into the mechanisms by examining its potential disruption of the thyroid endocrine system, employing in vivo, in vitro, and in silico assays. The findings showed notable developmental disturbances, including reduced hatching rates, shortened body lengths, and decelerated heart rates. Additionally, there was an increase in malformations and a decline in locomotor activity. Detailed analyses revealed that SPT exposure led to elevated thyroid hormone levels, perturbed the hypothalamic-pituitary-thyroid (HPT) axis transcript levels, amplified deiodinase type I (Dio1) and deiodinase type II (Dio2) activities, and both transcriptionally and proteomically upregulated thyroid receptor beta (TRβ) in larvae. Techniques like molecular docking and surface plasmon resonance (SPR) confirmed SPT's affinity for TRβ, consistent with in vitro findings suggesting its antagonistic effect on the T3-TR complex. These insights emphasize the need for caution in using tetronic acid-derived insecticides., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Thyroid autoimmunity is one of the most prevalent autoimmune diseases. However, its association with extra-thyroid diseases and mortality risk in the general population remains uncertain. Our study aims to evaluate the association of thyroid autoimmunity with extra-thyroid disease and the risk of mortality., Methods: A prospective cohort study was conducted using data from the National Health and Nutrition Examination Survey (NHANES) with participants from 2007-2008, 2009-2010, and 2011-2012, tracking their mortality until 2019. Associations between thyroid autoimmunity, which was defined as having positive thyroid peroxidase antibody (TPOAb) and/or thyroglobulin antibody (TgAb), and extra-thyroid disease including diabetes, hypertension, cardiovascular disease, chronic lung disease, arthritis, cancer and chronic renal disease and the risk of mortality were investigated., Results: A total of 7431 participants were included in this study. Positive The prevalence of positive TgAb was 7.54%, and positive TPOAb prevalence was 11.48%. TgAb was significantly associated with diabetes (Model 1: OR=1.64, 95% CI:1.08-2.50; Model 2: OR=1.93, 95% CI: 1.21-3.08) and hypertension (Model 1: OR=0.67, 95% CI: 0.49-0.91; Model 2: OR=0.62, 95% CI: 0.44-0.88). TPOAb was associated with a lower prevalence of chronic lung disease (model 1: OR=0.71, 95% CI: 0.54-0.95; model 2: OR=0.71, 95% CI: 0.53-0.95). No associations were observed between TgAb, TPOAb and other extra-thyroid diseases. Neither TgAb nor TPOAb were associated with all-cause mortality or heart disease mortality., Conclusion: TgAb was linked to a higher prevalence of diabetes and a lower prevalence of hypertension, while TPOAb was associated with a decreased prevalence of chronic lung disease. However, neither TgAb nor TPOAb posed a risk for all-cause mortality or heart disease mortality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Song, Hu, Li, Xu, Li, Sun and Chen.)

Low levels of triiodothyronine (T3) in the brain lead to increased dopamine receptor sensitivity, potentially resulting in schizophrenia. Iodothyronine deiodinase 2 (DIO2) is the only enzyme which converts tetraiodothyronine (T4) to T3 in the brain. DIO2 polymorphism of rs225014 results in the expression of non-functioning DIO2. Therefore, this study aimed to investigate the association of rs255014 with schizophrenia and its impact on thyroid hormone levels. This study included 150 schizophrenia cases and 150 controls. DNA was extracted from blood and subjected to PCR and amplicon sequencing. Serum thyroid profiles were determined using chemiluminescent magnetic microparticle immunoassay. Statistical analyses involved independent sample t-tests, Chi-square, and Pearson's correlation tests. The results revealed a higher frequency of the reference genotype (TT) in controls compared to cases ( p < 0.05). However, rs225014 did not influence serum thyroid levels or the severity of schizophrenia ( p > 0.05). Interestingly, control subjects exhibited significantly higher T3 levels ( p < 0.001) than cases. Regardless of the genotype (TT or CC), the control group had higher mean T3 levels than the corresponding case group ( p < 0.05). In conclusion, rs225014 is associated with schizophrenia and has no effect on serum thyroid hormone levels.

Context: Some evidence suggests gene-treatment interactions might cause persistent symptoms in individuals receiving levothyroxine (LT4) treatment., Objective: We investigated, as previously hypothesized, if single-nucleotide variations (SNVs; formerly single-nucleotide polymorphisms) in rs225014 (Thr92Ala), rs225015, or rs12885300 (ORFa-Gly3Asp) in the deiodinase 2 gene (DIO2), or rs17606253 in the monocarboxylate transporter 10 gene (MCT10) were associated with outcomes indicative of local tissue hypothyroidism in LT4-treated patients and controls., Methods: We included 18 761 LT4-treated patients and 360 534 controls in a population-based cross-sectional study in the UK Biobank. LT4 treatment was defined as a diagnosis of hypothyroidism and self-reported use of LT4 without use of 3,5,3'-triiodothyronine. Outcomes were psychological well-being, cognitive function, and cardiovascular risk factors. Associations were evaluated by linear, logistic, or ordinal logistic multiple regression. Adjustments included sex, age, sex-age interaction, and genetic principal components 1 to 10., Results: Compared to controls, LT4 treatment was adversely associated with almost all outcomes, most noteworthy: Increased frequency of tiredness (P < .001), decreased well-being factor score (P < .001), increased reaction-time (P < .001), and increased body mass index (P < .001). Except for a significant association between the minor rs225015 A allele and financial dissatisfaction, there was no association of rs225014, rs225015, rs12885300, or rs17606253 with any outcomes in LT4-treated patients. For all outcomes, carrying the risk allele at these 4 SNVs did not amplify symptoms associated with LT4 treatment compared to controls., Conclusion: rs225014, rs225015, rs12885300, and rs17606253 could not explain changed psychological well-being, cognitive function, or cardiovascular risk factors in LT4-treated patients. Our findings do not support a gene-treatment interaction between these SNVs and LT4 treatment., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The etiology of recurrent spontaneous abortion (RSA) remains elusive despite specific investigations affirming the association between RSA and thyroid autoimmunity (TAI). This study explores the immunological and metabolic profiles of RSA patients exhibiting positive thyroid antibodies and their connection with the rates of first-trimester miscarriage and live births. The aim is to provide further guidance for clinical interventions., Methods: A retrospective analysis included 478 women with RSA. Thyroid profile, thyroid peroxidase antibodies, and anti-thyroglobulin antibodies were measured in all participants. The clinical characteristics and pregnancy outcomes of RSA women were compared between thyroid autoimmunity (TAI)-positive and TAI-negative patients. Significant factors associated with adverse pregnancy outcomes and risk prediction models were explored in TAI-positive patients. Correlation analysis was used to identify specific metabolic or immune biomarkers associated with thyroid autoantibodies., Results: The prevalence of TAI was 18.6%. Compared with women without TAI, the thyroid-stimulating hormone (TSH) concentration of TAI-positive RSA was significantly higher (2.80 ± 2.98 vs 1.89 ± 1.17, p=0.006). After 28 weeks, the live birth rate of the TAI-positive group was lower than that of the TAI-negative group, with statistical significance (p<0.05). The immune biomarkers that differed between RSA women with live births and those with first-trimester miscarriages were complement C4 and interleukin-6, respectively, in TAI-negative and TAI-positive women. Then, a risk prediction model for first-trimester miscarriage was constructed for TAI-positive women with an AUC of 0.81. Finally, some factors related to thyroid peroxidase antibody (TPO-Ab) levels were explored, and it was found that TPO-Ab levels were positively correlated with free thyroxine and negatively correlated with 25 hydroxyvitamin D, interleukin-4, and fasting blood glucose in RSA patients., Conclusion: TAI-positive RSA patients have higher first-trimester miscarriage rates and a lower live birth rate, which may be related to metabolic immune shifts in TAI-positive RSA patients., Competing Interests: Author HY is employed by the company Dian Diagnostics Group Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Box 1Final optimal prediction model to facilitate individual predictions.The equation representing the prediction model for assessing the risk of first-trimester miscarriage in women with TAI was derived from a logistic regression model incorporating factors determined through random forest ranking: percent risk=exp(Y)/(1+exp(Y))*100Where Y = (-6.65) + (0.16 * age in years) - (0.48 * interleukin 6 in pg/ml) - (0.03 * total bilirubin in umol/L) + (1.27* total triiodothyronine in mIU/L) + (0.43 * interferon-γ in pg/ml) + (0.31 * number of previous miscarriages) -(0.01* complement C1q in g/l)., (Copyright © 2024 Zhang, Song, Yuan and Cai.)

Background: Chinese topography appears a three-rung ladder-like distribution of decreasing elevation from northwest to southeast, which is divided by two sloping edges. Previous studies have reported that prevalence of thyroid diseases differed by altitude, and geographical factors were associated with thyroid disorders. To explore the association between three-rung ladder-like regions and thyroid disorders according to unique Chinese topographic features, we conducted an epidemiological cross-sectional study from 2015-2017 that covered all 31 mainland Chinese provinces., Methods: A total of 78,470 participants aged ≥ 18 years from a nationally representative cross-sectional study were included. Serum thyroid peroxidase antibody, thyroglobulin antibody, and thyroid-stimulating hormone levels; urine iodine concentration; and thyroid volume were measured. The three-rung ladder-like distribution of decreasing elevation from northwest to southeast in China was categorized into three topographic groups according to elevation: first ladder, > 3000 m above sea level; second ladder, descending from 3000-500 m; and third ladder, descending from 500 m to sea level. The third ladder was further divided into groups A (500-100 m) and B (< 100 m). Associations between geographic factors and thyroid disorders were assessed using linear and binary logistic regression analyses., Results: Participants in the first ladder group were associated with lower thyroid peroxidase (β = -4.69; P = 0.00), thyroglobulin antibody levels (β = -11.08; P = 0.01), and the largest thyroid volume (β = 1.74; P = 0.00), compared with the other groups. The second ladder group was associated with autoimmune thyroiditis (odds ratio = 1.30, 95% confidence interval [1.18-1.43]) and subclinical hypothyroidism (odds ratio = 0.61, 95%confidence interval [0.57-0.66]) (P < 0.05) compared with the first ladder group. Group A (third ladder) (500-100 m) was associated with thyroid nodules and subclinical hypothyroidism (P < 0.05). Furthermore, group B (< 100 m) was positively associated with autoimmune thyroiditis, thyroid peroxidase and thyroglobulin antibody positivity, and negatively associated with overt hypothyroidism, subclinical hypothyroidism, and goiter compared with the first ladder group(P < 0.05)., Conclusion: We are the first to investigate the association between different ladder regions and thyroid disorders according to unique Chinese topographic features. The prevalence of thyroid disorders varied among the three-rung ladder-like topography groups in China, with the exception of overt hyperthyroidism., (© 2023. The Author(s).)

In this chapter, we present an experimental protocol to conduct DNA methylation editing experiments, that is, to induce loss or gain of DNA methylation, targeting Dlk1-Dio3 imprinted domain, a well-studied imprinted locus, in ES cells. In this protocol, plasmid vectors expressing the DNA methylation editing tools, combining the CRISPR/dCas9 system and the SunTag system coupled to a DNA methyltransferase or a TET enzyme, are introduced into cells for transient expression. By employing this strategy, researchers can effectively investigate a distinct DNA methylation signature that has an impact on the imprinting status, including gene expression and histone modifications, across the entire domain. We also describe strategies for allele-specific quantitative analyses of DNA methylation, gene expression, and histone modifications and binding protein levels for assessing the imprinting state of the locus., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Miscarriages constitute a significant aspect of failed pregnancies and a source of worry for the patient and caregiver. Some of the causes of miscarriages remain unknown. Immunological conditions such as thyroid autoimmunity could play significant roles. Our objective was to determine the relationship between raised thyroid peroxidase antibodies and first trimester miscarriages in a low resource setting. This was a case control study at the Gynaecological Clinic of the University of Calabar Teaching Hospital, Nigeria; from 14th February 2020 to 13th January 2021, involving 145 cases who had first trimester miscarriages, and their matched controls who had apparently normal pregnancies, at same gestational ages. Sera of venous blood from both participants and controls were analysed for thyroid peroxidase antibodies using enzyme-linked immunosorbent assay, and analysed using SPSS version 20, and GraphPad Prism 8.4.3 statistical software. Being a civil servant and low social status had significant odds for first trimester miscarriage. Raised thyroid peroxidase antibodies in the first trimester had 10-fold odds for miscarriage. Odds ratio 10.34, 95% CI: 3.22 to 32.98, P-value = 0.0001. The test had a sensitivity of 89.66% and specificity of 54.41%. The positive predictive value was 17.93%, while the negative predictive value was 97.93% and a likelihood ratio of 1.966. Rising thyroid peroxidase antibodies in early pregnancy could be a predictor for miscarriage. This is so because patients with raised thyroid peroxidase antibodies in the first trimester had a 10-fold risk of having a first trimester miscarriage.

Objectives: To assess the effect of daily zinc supplementation for 12 weeks on thyroid auto-antibodies - thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb), and oxidative stress in children with autoimmune thyroid disease (AITD) compared to standard therapy., Methods: This open-labeled, parallel, randomized controlled trial was done in a tertiary care teaching institute in south India. Children aged 3-18 years with AITD were randomized to receive 25 mg elemental zinc daily for 12 weeks or standard therapy alone. The change in thyroid function tests (thyroid stimulating hormone, free T3, free T4), thyroid auto-antibody (TPOAb, TgAb) titers, oxidative stress markers (glutathione peroxidase, malondialdehyde, superoxide dismutase, and total antioxidant capacity) were compared., Results: Forty children, 20 in each arm, were recruited in the study. We observed a female-to-male ratio of 7:1. Median duration of disease was 2 (0.25, 4.25) years. A total of 37 (92.5 %) children were hypothyroid, two hyperthyroid, and one euthyroid at enrolment. A total of 13 children (32.5 %) had associated co-morbidities, most commonly type 1 diabetes mellitus and systemic lupus erythematosus, three (7.5 %) each. We did not find any significant change in thyroid function tests, thyroid auto-antibody titers, and oxidative stress markers. However, the requirement of levothyroxine dose was significantly increased in the control arm, compared to the zinc group (p=0.03). Only four (20 %) children had minor adverse effects like nausea, metallic taste, and body ache., Conclusions: Zinc supplementation did not have any effect on thyroid auto-antibodies and oxidative stress. Zinc-supplemented children did not require escalation in levothyroxine dose., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

A 7-month-old male French bulldog was referred for abnormal mentation and gait. Physical examination revealed a dome shaped calvarium and persistent bregmatic fontanelle. Neurological examination revealed proprioceptive ataxia, pelvic limb paraparesis and strabismus with moderate ventriculomegaly, thinning of the cerebral parenchyma, and widened cerebral sulci on magnetic resonance imaging. Masses were identified in the region of the thyroid, which appeared heterogeneous and hyperintense in T1-weighted and T2-weighted compared with the adjacent muscle signal masses were identified. Radiological diagnosis was hydrocephalus "ex vacuo" and goiter. Blood test revealed abnormally low total thyroxine (TT4), free thyroxine (FT4), and normal thyrotropin concentration. A diagnosis of congenital hypothyroidism was confirmed by positive genetic test for thyroid peroxidase mutation. Thyroxine supplementation treatment rapidly improved clinical signs., (© 2024 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Thyroid hormone (TH) levels are low during development, and the deiodinases control TH signaling through tissue-specific activation or inactivation of TH. Here, we studied human induced pluripotent stem cell-derived (iPSC-derived) hepatic organoids and identified a robust induction of DIO2 expression (the deiodinase that activates T4 to T3) that occurs in hepatoblasts. The surge in DIO2-T3 (the deiodinase that activates thyroxine [T4] to triiodothyronine [T3]) persists until the hepatoblasts differentiate into hepatocyte- or cholangiocyte-like cells, neither of which expresses DIO2. Preventing the induction of the DIO2-T3 signaling modified the expression of key transcription factors, decreased the number of hepatocyte-like cells by ~60%, and increased the number of cholangiocyte-like cells by ~55% without affecting the growth or the size of the mature liver organoid. Physiological levels of T3 could not fully restore the transition from hepatoblasts to mature cells. This indicates that the timed surge in DIO2-T3 signaling critically determines the fate of developing human hepatoblasts and the transcriptome of the maturing hepatocytes, with physiological and clinical implications for how the liver handles energy substrates.

Background: Numerous organs, including the thyroid gland, depend on vitamin D to function normally. Insufficient levels of serum 25-hydroxyvitamin D [25(OH)D] are seen as a potential factor contributing to the emergence of several thyroid disorders, however, the causal relationship remains unclear. Here we use a Mendelian randomization (MR) approach to investigate the causal effect of serum 25(OH)D concentration on the indicators of thyroid function. Methods: We conducted a two-sample MR analysis utilizing summary data from the most extensive genome-wide association studies (GWAS) of serum 25(OH)D concentration (n = 443,734 and 417,580), thyroid-stimulating hormone (TSH, n = 271,040), free thyroxine (fT4, n = 119,120), free triiodothyronine (fT3, n = 59,061), total triiodothyronine (TT3, n = 15,829), as well as thyroid peroxidase antibody levels and positivity (TPOAb, n = 12,353 and n = 18,297), low TSH (n = 153,241), high TSH (n = 141,549), autoimmune hypothyroidism (n = 287,247) and autoimmune hyperthyroidism (n = 257,552). The primary analysis was conducted using the multiplicative random-effects inverse variance weighted (IVW) method. The weighted mode, weighted median, MR-Egger, MR-PRESSO, and Causal Analysis Using Summary Effect estimates (CAUSE) were used in the sensitivity analysis. Results: The IVW, as well as MR Egger and CAUSE analysis, showed a suggestive causal effect of 25(OH)D concentration on high TSH. Each 1 SD increase in serum 25(OH)D concentration was associated with a 12% decrease in the risk of high TSH (p = 0.02). Additionally, in the MR Egger and CAUSE analysis, we found a suggestive causal effect of 25(OH)D concentration on autoimmune hypothyroidism. Specifically, each 1 SD increase in serum 25(OH)D concentration was associated with a 16.34% decrease in the risk of autoimmune hypothyroidism (p = 0.02). Conclusions: Our results support a suggestive causal effect which was negative in direction across all methods used, meaning that higher genetically predicted vitamin D concentration possibly lowers the odds of having high TSH or autoimmune hypothyroidism. Other thyroid parameters were not causally influenced by vitamin D serum concentration. [ABSTRACT FROM AUTHOR]