BACKGROUND The imbalance of hormone levels in the body is closely related to the occurrence and progression of schizophrenia,especially thyroid hormones.AIM To study the relationship between triiodothyronine(T3),thyro...BACKGROUND The imbalance of hormone levels in the body is closely related to the occurrence and progression of schizophrenia,especially thyroid hormones.AIM To study the relationship between triiodothyronine(T3),thyroxine(T4),free T3(FT3),free T4(FT4),thyroid stimulating hormone(TSH)and schizophrenia.METHODS In this study,100 schizophrenia patients were selected from our hospital between April 2022 and April 2024.Their clinical data were analyzed retrospectively.Based on the Positive and Negative Syndrome Scale(PANSS)score,patients were divided into mild(1-3 points,n=39),moderate(4 points,n=45),and severe groups(5-7 points,n=16).Additionally,55 healthy individuals served as a control group.Venous blood samples were collected to measure T3,T4,FT3,FT4,TSH,and cortisol concentrations,analyzing their relationship with PANSS scores.RESULTS The serum levels of T3,FT3,FT4,TSH and cortisol in the schizophrenia group were lower than those in the control group(P<0.05).With the increase of the severity of the disease,the concentrations of T3 and T4 decreased,while the con-centrations of TSH and cortisol increased(P<0.05).The concentrations of TSH and cortisol were positively correlated with the PANSS score,while T3 and T4 were negatively correlated with the PANSS score(P<0.05).The receiver ope-rating characteristic curve results showed that T3,T4,TSH,and cortisol had good efficacy in the diagnosis of schizophrenia.Logistic results showed that decreased T3 level,decreased T4 level,decreased TSH level and increased cortisol level may be independent risk factors for schizophrenia.CONCLUSION Thyroid hormone levels are associated with the severity of schizophrenia symptoms,which can provide new solutions for the diagnosis and treatment of schizophrenia.展开更多
Food is a critical environmental factor that influences animal survival,especially for small passerines due to their high mass-specific metabolic rates.Basal metabolic rate(BMR)reflects the energy expended by endother...Food is a critical environmental factor that influences animal survival,especially for small passerines due to their high mass-specific metabolic rates.Basal metabolic rate(BMR)reflects the energy expended by endothermic animals for basic physiological processes and constitutes a major part of their daily energy budget.Some birds have been shown to employ compensatory mechanisms during food shortages,temporarily reducing these selfmaintenance expenditures without using hypothermia.However,the mechanisms of BMR adjustment remain unexplored.In the present study,we assessed the phenotypic variation in basal thermogenesis of Eurasian Tree Sparrows(Passer montanus)by comparing a control group to groups fasted for 6,12,18,and 24 h.We focused on the correlation between a reduction in energy metabolism and the alterations of cellular metabolic activities,mitochondrial substrate supply,and changes in serum thyroid hormones during fasting.Our data indicated that fasting groups had significantly lower body mass,BMR,body temperature,and body fat content.Furthermore,fasting groups had significantly lower glycogen levels,mitochondrial state 4 respiration and cytochrome c oxidase(CCO)activity in the liver,and CCO activity in pectoral muscle.The levels of avian uncoupling protein(avUCP)m RNA were significantly reduced,while the levels of myostatin protein in pectoral muscle were significantly increased in the fasting groups.Furthermore,the groups subjected to fasting exhibited significantly lower levels of serum glucose,triglyceride,thyroxine(T_(4)),and triiodothyronine(T_(3)).Positive correlations were observed between the following pairs of variables:log BMR and log body mass,log body mass and log body fat,log BMR and log state 4 respiration in the liver,log BMR and log CCO activity in the liver and muscle,log BMR and log av-UCP m RNA expression,whereas a negative correlation was observed between log BMR and log myostatin level.In addition,a positive correlation was also detected between log T_(3) and each of the following:log BMR,state 4 respiration,and log CCO activity in the liver.Our results suggested that decreased metabolic thermogenesis via down-regulation in cellular aerobic capacity of organs and serum thyroid hormones may be an important survival strategy for fasting Tree Sparrows to reduce energy expenditure.展开更多
Prostate cancer(PCa)is a prevalent malignancy in men,traditionally linked to androgen receptor signaling.Emerging evidence suggests thyroid hormones(THs,particularly T3/T4)play a complex role in PCa biology.THs regula...Prostate cancer(PCa)is a prevalent malignancy in men,traditionally linked to androgen receptor signaling.Emerging evidence suggests thyroid hormones(THs,particularly T3/T4)play a complex role in PCa biology.THs regulate gene transcription via nuclear receptors TRα/β,modulating proliferation,apoptosis,and AR signaling,while non-genomic pathways through integrin αvβ3 activate MAPK/PI3K-Akt signaling,driving metabolic reprogramming,migration,and angiogenesis.Local DIO enzymes fine-tune T3/T4 levels,with DIO2 enhancing proliferation and DIO3 creating a low-TH microenvironment to facilitate immune evasion.Epidemiological studies associate hyperthyroidism or low TSH with elevated PCa risk,whereas experimental models show inconsistent effects,reflecting regulation by hormone levels,receptor distribution,and tumor molecular features.Bibliometric analyses reveal a shift from epidemiological studies to molecular,immune,and metabolic mechanistic research,though clinical translation remains limited.This review synthesizes current knowledge on THs in PCa,highlighting mechanistic insights,evidence gaps,and future directions,aiming to inform early detection,stratification,and therapeutic strategies.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)surveillance is crucial for patients with compensated cirrhosis(CC)and decompensated cirrhosis(DC).Increasing evidence has revealed a connection between thyroid hormone(TH)and H...BACKGROUND Hepatocellular carcinoma(HCC)surveillance is crucial for patients with compensated cirrhosis(CC)and decompensated cirrhosis(DC).Increasing evidence has revealed a connection between thyroid hormone(TH)and HCC,although this relationship remains contentious.Complements and immunoglobulin(Ig),which serve as surrogates of cirrhosis-associated immune dysfunc-tion,are associated with the severity and outcomes of liver cirrhosis(LC).To date,there is a lack of evidence supporting the recommendation of TH,Ig,and com-plement tests in patients at high risk of HCC.AIM To assess the predictive value of TH,Ig,and complements for HCC development.METHODS Data from 142 patients,comprising 72 patients with CC and 70 patients with DC,were analysed as a training set.Among them,100 patients who underwent complement and Ig tests were considered for internal validation.Logistic regression was employed to identify independent risk factors for HCC development.RESULTS The median follow-up duration was 32(24-37 months)months.The incidence of HCC was significantly higher in the DC group(16/70,22.9%)compared to the CC group(3/72,4.2%)(χ^(2)=10.698,P<0.01).Patients with DC exhibited lower total tetraiodothyronine(TT4),total triiodothyronine(TT3),free triiodothyronine,complement C3,and C4(all P<0.01),and higher IgA and IgG(both P<0.01).In both CC and DC patients,TT3 and TT4 positively correlated with alanine transaminase(ALT),aspartate transaminase(AST),and gamma-glutamyl transpeptidase(GGT).IgG positively correlated with IgM,IgA,ALT,and AST,while it negatively correlated with C3 and C4.Multivariable analysis indicated that age,DC status,and GGT were independent risk factors for HCC development.CONCLUSION The predictive value of TH,Ig,and complements for HCC development is suboptimal.Age,DC,and GGT emerge as more significant factors during HCC surveillance in hepatitis B virus-related LC.展开更多
Objective To examine the mechanistic of organochlorine-associated changes in lung function.Methods This study investigated 76 healthy older adults in Jinan,Shandong Province,over a fivemonth period.Personal exposure t...Objective To examine the mechanistic of organochlorine-associated changes in lung function.Methods This study investigated 76 healthy older adults in Jinan,Shandong Province,over a fivemonth period.Personal exposure to organochlorines was quantified using wearable passive samplers,while inflammatory factors and thyroid hormones were analyzed from blood samples.Participants’lung function was evaluated.After stratifying participants according to their thyroid hormone levels,we analyzed the differential effects of organochlorine exposure on lung function and inflammatory factors across the low and high thyroid hormone groups.Mediation analysis was further conducted to elucidate the relationships among organochlorine exposures,inflammatory factors,and lung function.Results Bis(2-chloro-1-methylethyl)ether(BCIE),was negatively associated with forced vital capacity(FVC,–2.05%,95%CI:–3.11%to–0.97%),and associated with changes in inflammatory factors such as interleukin(IL)-2,IL-7,IL-8,and IL-13 in the low thyroid hormone group.The mediation analysis indicated a mediating effect of IL-2(15.63%,95%CI:0.91%to 44.64%)and IL-13(13.94%,95%CI:0.52%to 41.07%)in the association between BCIE exposure and FVC.Conclusion Lung function and inflammatory factors exhibited an increased sensitivity to organochlorine exposure at lower thyroid hormone levels,with inflammatory factors potentially mediating the adverse effects of organochlorines on lung function.展开更多
BACKGROUND Neuroendocrine dysfunction,especially involving the hypothalamic-pituitarythyroid axis,plays a critical role in the onset and progression of schizophrenia.Alterations in thyroid stimulating hormone(TSH),tri...BACKGROUND Neuroendocrine dysfunction,especially involving the hypothalamic-pituitarythyroid axis,plays a critical role in the onset and progression of schizophrenia.Alterations in thyroid stimulating hormone(TSH),triiodothyronine(T3),free T3(FT3),thyroxine(T4),and free T4 have been implicated in this process.Although previous studies have established an association between thyroid function and psychiatric symptoms,how thyroid hormone levels vary with disease duration remains underexplored.AIM To investigate duration stage-specific associations between thyroid hormones and psychotic symptoms among inpatients with stable schizophrenia.METHODS This cross-sectional study was conducted at Zigong Mental Health Center,China,and included 237 hospitalized patients with stable schizophrenia.Participants were stratified into three groups based on disease duration:0-10 years,10.1-20 years,and over 20 years.Peripheral blood samples were collected to measure serum thyroid hormone levels.Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale.Covariate-adjusted linear regression analyses were performed to assess the relationships between thyroid hormone levels and Positive and Negative Syndrome Scale sub-scale scores.RESULTS The relationship between thyroid hormones and psychotic symptoms varied by disease duration.In patients with a disease course of 0-10 years,T4[β=-0.848;95%confidence interval(CI):-1.564 to-0.133;P=0.021]and FT3(β=-2.483;95%CI:-4.693 to-0.273;P=0.028)levels were significantly inversely associated with general psychopathology scores.Among those with 10.1-20 years of disease,only TSH showed a significant negative correlation with general psychopathology(β=-1.429;95%CI:-2.348 to-0.509;P=0.003).No significant correlations were found in the>20 years group.CONCLUSION The associations between thyroid hormones and psychotic symptoms vary according to the duration of schizophrenia(T4/FT3 early;TSH mid),enabling the development of stage-adapted models and management.展开更多
BACKGROUND Diabetic peripheral neuropathy(DPN)is a common complication of type 2 diabetes mellitus(T2DM),significantly affecting patients’quality of life and imposing a substantial economic burden.Recent studies have...BACKGROUND Diabetic peripheral neuropathy(DPN)is a common complication of type 2 diabetes mellitus(T2DM),significantly affecting patients’quality of life and imposing a substantial economic burden.Recent studies have highlighted the role of thyroid hormones in diabetes complications,particularly in elderly patients with T2DM.However,the relationship between thyroid hormone sensitivity and DPN remains unclear.AIM To investigate the correlation between thyroid hormone sensitivity and DPN in elderly patients with T2DM.METHODS In a cohort of 256 elderly patients with T2DM,propensity score matching was used to balance age,sex,and diabetes duration.Clinical data were collected to calculate thyroid hormone sensitivity and analyze its correlation with DPN.A random forest model was used to evaluate the diagnostic value of free triiodothyronine/free thyroxine(FT_(3)/FT_(4))for DPN.RESULTS Patients with DPN had a lower FT_(3)/FT_(4) ratio[(0.302±0.053)vs(0.316±0.049),P=0.040].Quartile stratification showed decreasing DPN prevalence with higher FT_(3)/FT_(4) ratios.Spearman’s correlation analysis showed that a lower FT_(3)/FT_(4) ratio was associated with higher glycated hemoglobin,fasting blood glucose,reduced nerve conduction velocity,and electrical skin conductance.Logistic regression indicated a positive relationship between the median FT_(3)/FT_(4) ratio and bilateral foot electrochemical skin conductance[odds ratio(OR):1.019;95%CI:1.005-1.034;P=0.007]and sural nerve sensory amplitude(OR:1.310;95%CI:1.008-1.703;P=0.043).Receiver operating characteristic analysis using a random forest model showed that incorporating FT_(3)/FT_(4) improved predictive performance for DPN,with an area under the curve of 0.74,sensitivity of 0.79,specificity of 0.64,and accuracy of 0.77.CONCLUSION In elderly patients with T2DM with euthyroidism,a lower FT_(3)/FT_(4) ratio is correlated with increased DPN incidence,affecting both large and small nerve fibers.FT_(3)/FT_(4) is an effective predictor of DPN.展开更多
Reverse cholesterol transport (RCT) is a complex process which transfers cholesterol from peripheral cells to the liver for subsequent elimination from the body via feces. Thyroid hormones (THs) affect growth, develop...Reverse cholesterol transport (RCT) is a complex process which transfers cholesterol from peripheral cells to the liver for subsequent elimination from the body via feces. Thyroid hormones (THs) affect growth, develop- ment, and metabolism in almost all tissues. THs exert their actions by binding to thyroid hormone receptors (TRs). There are two major subtypes of TRs, TRα and TRβ, and several isoforms (e.g. TRα1, TRα2, TRβ1, and TRβ2). Activation of TRα1 affects heart rate, whereas activation of TRβ1 has positive effects on lipid and lipoprotein metabolism. Consequently, particular interest has been focused on the development of thyromimetic compounds targeting TRβ1, not only because of their ability to lower plasma cholesterol but also due their ability to stimulate RCT, at least in pre-clinical models. In this review we focus on THs, TRs, and on the effects of TRβ1-modulating thyromimetics on RCT in various animal models and in humans.展开更多
Injury to peripheral nerves is often observed in the clinic and severe injuries may cause loss of motor and sensory functions.Despite extensive investigation,testing various surgical repair techniques and neurotrophic...Injury to peripheral nerves is often observed in the clinic and severe injuries may cause loss of motor and sensory functions.Despite extensive investigation,testing various surgical repair techniques and neurotrophic molecules,at present,a satisfactory method to ensuring successful recovery does not exist.For successful molecular therapy in nerve regeneration,it is essential to improve the intrinsic ability of neurons to survive and to increase the speed of axonal outgrowth.Also to induce Schwann cell phenotypical changes to prepare the local environment favorable for axonal regeneration and myelination.Therefore,any molecule that regulates gene expression of both neurons and Schwann cells could play a crucial role in peripheral nerve regeneration.Clinical and experimental studies have reported that thyroid hormones are essential for the normal development and function of the nervous system,so they could be candidates for nervous system regeneration.This review provides an overview of studies devoted to testing the effect of thyroid hormones on peripheral nerve regeneration.Also it emphasizes the importance of combining biodegradable tubes with local administration of triiodothyronine for future clinical therapy of human severe injured nerves.We highlight that the local and single administration of triiodothyronine within biodegradable nerve guide improves significantly the regeneration of severed peripheral nerves,and accelerates functional recovering.This technique provides a serious step towards future clinical application of triiodothyronine in human severe injured nerves.The possible regulatory mechanism by which triiodothyronine stimulates peripheral nerve regeneration is a rapid action on both axotomized neurons and Schwann cells.展开更多
The thyroid hormones L-thyroxine and triiodo-L-thyronine have profound effects on postembryonic development of most vertebrates. Analysis of their action in mammals is vitiated by the exposure of the developing foetus...The thyroid hormones L-thyroxine and triiodo-L-thyronine have profound effects on postembryonic development of most vertebrates. Analysis of their action in mammals is vitiated by the exposure of the developing foetus to a number of maternal factors which do not allow one to specifically define the role of thyroid hormone (TH)or that of other hormones and factors that modulate its action. Amphibian metamorphosis is obligatorily dependent on TH which can initiate all the diverse physiological manifestations of this postembryonic developmental process(morphogenesis, cell death, re-structuring, etc.) in free-living embryos and larvae of most anurans. This article will first describe the salient features of metamorphosis and its control by TH and other hormones. Emphasis will be laid on the key role played by TH receptor (TR), in particular the phenomenon of TR gene autoinduction, in initiating the developmental action of TH. Finally, it will be argued that the findings on the control of amphibian metamorphosis enhance our understanding of the regulation of postembryonic development by TH in other vertebrate species.展开更多
Anuran metamorphosis involves systematic transformations of individual organs in a thyroid hormone (TH)-dependent manner. Morphological and cellular studies have shown that the removal of larval or- gans/tissues such ...Anuran metamorphosis involves systematic transformations of individual organs in a thyroid hormone (TH)-dependent manner. Morphological and cellular studies have shown that the removal of larval or- gans/tissues such the tail and the tadpole intestinal epithelium is through programmed cell death or apop- tosis. Recent molecular investigations suggest that TH regulates metamorphosis by regulating target gene expression through thyroid hormone receptors (TRs), which are DNA-binding transcription factors. Cloning and characterization of TH response genes show that diverse groups of early response genes are induced by TH. The products of these TH response genes are believed to directly or indirectly affect the expression and/or functions of cell death genes, which are conserved at both sequence and function levels in different animal species. A major challenge for future research lies at determining the signaling pathways leading to the activation of apoptotic processes and whether different death genes are involved in the regulation of apoptosis in different tissues/organs to effect tissue-specific transformations.展开更多
Background Thyroid hormones(THs) including thyroxine(T4) and triiodothyronine(T3) with high biological activities have important effects on cardiovascular system by acting on renin-angiotensin-aldosterone system(RAAS)...Background Thyroid hormones(THs) including thyroxine(T4) and triiodothyronine(T3) with high biological activities have important effects on cardiovascular system by acting on renin-angiotensin-aldosterone system(RAAS), oxidative stress, mitochondria, endothelial cells, vascular smooth muscle cells(VSMC), cardiomyocytes, thyroid hormone receptor(TRs), cholesterol metabolism, insulin sensitivity, blood coagulation, etc. Excess or lack of THs is detrimental to cardiovascular function, so this article reviews the mechanism of THs on cardiovascular system.[S Chin J Cardiol 2019;20(4):269-279]展开更多
The importance of the thyroid hormone axis in the regulation of skeletal growth and maintenance has been well established from clinical studies involving patients with mutations in proteins that regulate synthesis and...The importance of the thyroid hormone axis in the regulation of skeletal growth and maintenance has been well established from clinical studies involving patients with mutations in proteins that regulate synthesis and/or actions of thyroid hormone. Data from genetic mouse models involving disruption and overexpression of components of the thyroid hormone axis also provide direct support for a key role for thyroid hormone in the regulation of bone metabolism. Thyroid hormone regulates proliferation and/or differentiated actions of multiple cell types in bone including chondrocytes, osteoblasts and osteoclasts. Thyroid hormone effects on the target cells are mediated via ligand-inducible nuclear receptors/transcription factors, thyroid hormone receptor （TR） a and ~, of which TRa seems to be critically important in regulating bone cell functions. In terms of mechanisms for thyroid hormone action, studies suggest that thyroid hormone regulates a number of key growth factor signaling pathways including insulin-like growth factor-I, parathyroid hormone related protein, fibroblast growth factor, Indian hedgehog and Wnt to influence skeletal growth. In this review we describe findings from various genetic mouse models and clinical mutations of thyroid hormone signaling related mutations in humans that pertain to the role and mechanism of action of thyroid hormone in the regulation of skeletal growth and maintenance.展开更多
Ioxynil, a phenolic herbicide, is known to exert thyroid hormone （TH） disrupting activity by interfering with TH-binding to plasma proteins and a step of the cellular TH-signaling pathway in restricted animal specie...Ioxynil, a phenolic herbicide, is known to exert thyroid hormone （TH） disrupting activity by interfering with TH-binding to plasma proteins and a step of the cellular TH-signaling pathway in restricted animal species. However, comparative studies are still lacking on the TH disruption. We investigated the interaction of [125I] ioxynil with serum proteins from rainbow trout, bullfrog, chicken, pig, rat, and mouse, using native polyacrylamide gel electrophoresis. Candidate ioxynil-binding proteins, which included lipoproteins, albumin and transthyretin （TTR）, differed among the vertebrates tested. Rainbow trout and bullfrog tadpole serum had the lowest binding activity for ioxynil, whereas the eutherian serum had the highest binding activity. The cellular uptake of, and response to, ioxynil were suppressed by rat serum greater than by tadpole serum. The cellular uptake of [125I]ioxynil competed strongly with phenols with a single ring, but not with THs. Our results suggested that ioxynil interferes with TH homeostasis in plasma and with a step of cellular TH-signaling pathway other than TH-uptake system, in a species-specific manner.展开更多
T3-induced Xenopus metamorphosis is an ideal model for detecting thyroid hormone（TH）signaling disruption of chemicals. To optimize the T3-induced Xenopus assay and improve its sensitivity and reproducibility, we int...T3-induced Xenopus metamorphosis is an ideal model for detecting thyroid hormone（TH）signaling disruption of chemicals. To optimize the T3-induced Xenopus assay and improve its sensitivity and reproducibility, we intend to develop quantitatively morphological endpoints and choose appropriate concentrations and exposure durations for T3 induction.Xenopus laevis at stage 52 were exposed to series of concentrations of T3（0.31–2.5 nmol/L）for 6 days. By comparing morphological changes induced by T3, we propose head area,mouth width, unilateral brain width/brain length, and hindlimb length/snout-vent length as quantitative parameters for characterizing T3-induced morphological changes, with body weight as a parameter for indicating integrated changes. By analyzing time-response curves, we found that following 4-day exposure, T3-induced grossly morphological changes displayed linear concentration–response curves, with moderate morphological changes resulting from 1.25 nmol/L T3 exposure. When using grossly morphological endpoints to detect TH signaling disruption, we propose 4 days as exposure duration of T3, with concentrations close to 1.25 nmol/L as induction concentrations. However, it is appropriate to examine morphological and molecular changes of the intestine on day 2 due to their early response to T3. The quantitative endpoints and T3 induction concentrations and durations we determined would improve the sensitivity and the reproducibility of the T3-induced Xenopus metamorphosis assay.展开更多
The HIV-1 LTR controls the expression of HIV-1 viral genes and thus is critical for viral propagation and pathology. Numerous host factors have been shown to participate in the regulation of the LTR promoter. Among th...The HIV-1 LTR controls the expression of HIV-1 viral genes and thus is critical for viral propagation and pathology. Numerous host factors have been shown to participate in the regulation of the LTR promoter. Among them is the thyroid hormone (T3) receptor (TR). TR has been shown to bind to the critical region of the promoter that contain the NFbB and Sp1 binding sites. Interestingly, earlier transient transfection studies in tissue culture cells have yielded contradicting conclusions on the role of TR in LTR regulation, likely due to the use of different cell types and/or lack of proper chromatin organization. Here, using the frog oocyte as a model system that allows replication-coupled chromatin assembly, mimicking that in somatic cells, we demonstrate that unliganded heterodimers of TR and RXR (9-cis retinoic acid receptor) repress LTR while the addition of T3 relieves the repression and further activates the promoter. More importantly, we show that chromatin and unliganded TR/RXR synergize to repress the promoter in a histone deacetylase-dependent manner.展开更多
We developed the T3-induced Xenopus metamorphosis assay, which is supposed to be able to sensitively detect thyroid hormone（TH） signaling disruption of chemicals. The present study aimed to validate the T3-induced X...We developed the T3-induced Xenopus metamorphosis assay, which is supposed to be able to sensitively detect thyroid hormone（TH） signaling disruption of chemicals. The present study aimed to validate the T3-induced Xenopus metamorphosis assay by re-evaluating the TH signaling antagonism of tetrabromobisphenol A（TBBPA）, a known TH signaling disruptor. According to the assay we developed, Xenopus tadpoles at stage 52 were exposed to 10–500 nmol/L TBBPA in the presence of 1 nmol/L T3. After 96 hr of exposure, TBBPA in the range of 10–500 nmol/L was found to significantly inhibit T3-induced morphological changes of Xenopus tadpoles in a concentration-dependent manner in term of body weight and four morphological endpoints including head area（HA）, mouth width（MW）, unilateral brain width/brain length（ULBW/BL）, and hind-limb length/snout-vent length（HLL/SVL）.The results show that these endpoints we developed are sensitive for characterizing the antagonistic effects of TBBPA on T3-induced metamorphosis. Following a 24-hr exposure,we found that TBBPA antagonized expression of T3-induced TH-response genes in the tail,which is consistent with previous findings in the intestine. We propose that the tail can be used as an alternative tissue to the intestine for examining molecular endpoints for evaluating TH signaling disruption. In conclusion, our results demonstrate that the T3-induced Xenopus metamorphosis assay we developed is an ideal in vivo assay for detecting TH signaling disruption.展开更多
The present study determined the thyroid hormone interference of tetrabromobisphenol A （TBBPA） in Sprague-Dawley （SD） rats, and the derived-reference dose （RfD） of different endpoint effects on mammals based on ...The present study determined the thyroid hormone interference of tetrabromobisphenol A （TBBPA） in Sprague-Dawley （SD） rats, and the derived-reference dose （RfD） of different endpoint effects on mammals based on experimental results and data collection. Based on repeated exposure toxicity tests on mammals and extensive research, the present study used BMDS240 Software to derive a benchmark dose, and analyzed the accuracy and uncertainty, and similarity with other studies. Test results on triiodothyronine （T3）, thyroxine （T4）, and thyroid stimulating hormone （TSH） demonstrated that all the indicators presented a non-monotonous dose-effect relationship clearly, except TSH in male rats exposed to 0-1000 mg/kg BW per day. Therefore, RfDs were derived from different critical effects. In summary, RfD for mammals in the present study was found to be 0.6 mg/kg per day.展开更多
Dechloranes are a group of halogenated flame retardants with a basic bicyclo[2.2.1]heptene,including Dechlorane Plus(DP),Dechlorane 602(Dec 602),Dechlorane 603(Dec 603)and Dechlorane 604(Dec 604).A few epidemiological...Dechloranes are a group of halogenated flame retardants with a basic bicyclo[2.2.1]heptene,including Dechlorane Plus(DP),Dechlorane 602(Dec 602),Dechlorane 603(Dec 603)and Dechlorane 604(Dec 604).A few epidemiological investigations and animal experiments have shown that DP exhibited thyroid-interfering effects.In the present study,we investigated whether DP and three other dechloranes could interfere the thyroid function through thyroid hormone receptors(TRs,TRαand TRβ)signaling pathways.The binding affinities of the four dechloranes to the two TRs were determined by fluorescence competitive binding assay.It was found that all the four dechloranes could bind with the two TRs.The relative potency(RP)values ranged from nd(not detectable)to 0.0667.Between the two TRs,dechloranes were more inclined to bind with TRβ,which implies that the thyroid interference effect of dechloranes may have selectivity in different tissues and organs.TRs-mediated luciferase reporter gene assay and T-screen assay showed that all the four dechloranes exhibited antagonistic activity to TRs in the cells.Taken together,our results demonstrated that dechloranes might interfere with thyroid function by binding with TRs and acting as TR antagonists.The health risk of highly exposed human populations should be of serious concern because of the high hazard quotient calculated from our cell assay results.展开更多
Considering some advantages of Rana nigromaculata as an experimental species, we propose that this species, like Xenopus laevis, could be used to assay thyroid hormone（TH） signaling disrupting actions. To validate t...Considering some advantages of Rana nigromaculata as an experimental species, we propose that this species, like Xenopus laevis, could be used to assay thyroid hormone（TH） signaling disrupting actions. To validate the utilizability of R. nigromaculata, we investigated the responsiveness of R. nigromaculata to a TH receptor（TR） agonist（T3） and antagonist（amiodarone） by analyzing expression, based on characterizing TR cDNA and developmental expression patterns. With high levels of identity with the corresponding genes in X. laevis, both TRα and TRβ in R. nigromaculata exhibited roughly similar developmental expression patterns to those of X. laevis, in spite of some species-specific differences. Both TRα and TRβ expression had greater changes in the liver and intestine than in the tail and brain during metamorphosis. T3 exposure for 2 days induced more dramatic increases of TRβ expression in stage 27 than in stage34 tadpoles but not in stage 42 tadpoles, showing that the responsiveness of R. nigromaculata to TH decreased with development and disappeared at the onset of metamorphic climax.Corresponding to greater changes of TRβ expression in the liver and intestine than in the tail and brain during metamorphosis, the liver and intestine had higher responsiveness to exogenous T3 than the tail and brain. Amiodarone inhibited T3-induced TRβ expression. Our results show that R. nigromaculata can be used as a model species for assaying TH signaling disrupting actions by analyzing TRβ expression, and intestine tissues at stage 27 are ideal test materials due to high responsiveness and easy accessibility.展开更多
文摘BACKGROUND The imbalance of hormone levels in the body is closely related to the occurrence and progression of schizophrenia,especially thyroid hormones.AIM To study the relationship between triiodothyronine(T3),thyroxine(T4),free T3(FT3),free T4(FT4),thyroid stimulating hormone(TSH)and schizophrenia.METHODS In this study,100 schizophrenia patients were selected from our hospital between April 2022 and April 2024.Their clinical data were analyzed retrospectively.Based on the Positive and Negative Syndrome Scale(PANSS)score,patients were divided into mild(1-3 points,n=39),moderate(4 points,n=45),and severe groups(5-7 points,n=16).Additionally,55 healthy individuals served as a control group.Venous blood samples were collected to measure T3,T4,FT3,FT4,TSH,and cortisol concentrations,analyzing their relationship with PANSS scores.RESULTS The serum levels of T3,FT3,FT4,TSH and cortisol in the schizophrenia group were lower than those in the control group(P<0.05).With the increase of the severity of the disease,the concentrations of T3 and T4 decreased,while the con-centrations of TSH and cortisol increased(P<0.05).The concentrations of TSH and cortisol were positively correlated with the PANSS score,while T3 and T4 were negatively correlated with the PANSS score(P<0.05).The receiver ope-rating characteristic curve results showed that T3,T4,TSH,and cortisol had good efficacy in the diagnosis of schizophrenia.Logistic results showed that decreased T3 level,decreased T4 level,decreased TSH level and increased cortisol level may be independent risk factors for schizophrenia.CONCLUSION Thyroid hormone levels are associated with the severity of schizophrenia symptoms,which can provide new solutions for the diagnosis and treatment of schizophrenia.
基金financially supported by grants from the National Natural Science Foundation of China (Nos.32371573,32171497,and 31971420)。
文摘Food is a critical environmental factor that influences animal survival,especially for small passerines due to their high mass-specific metabolic rates.Basal metabolic rate(BMR)reflects the energy expended by endothermic animals for basic physiological processes and constitutes a major part of their daily energy budget.Some birds have been shown to employ compensatory mechanisms during food shortages,temporarily reducing these selfmaintenance expenditures without using hypothermia.However,the mechanisms of BMR adjustment remain unexplored.In the present study,we assessed the phenotypic variation in basal thermogenesis of Eurasian Tree Sparrows(Passer montanus)by comparing a control group to groups fasted for 6,12,18,and 24 h.We focused on the correlation between a reduction in energy metabolism and the alterations of cellular metabolic activities,mitochondrial substrate supply,and changes in serum thyroid hormones during fasting.Our data indicated that fasting groups had significantly lower body mass,BMR,body temperature,and body fat content.Furthermore,fasting groups had significantly lower glycogen levels,mitochondrial state 4 respiration and cytochrome c oxidase(CCO)activity in the liver,and CCO activity in pectoral muscle.The levels of avian uncoupling protein(avUCP)m RNA were significantly reduced,while the levels of myostatin protein in pectoral muscle were significantly increased in the fasting groups.Furthermore,the groups subjected to fasting exhibited significantly lower levels of serum glucose,triglyceride,thyroxine(T_(4)),and triiodothyronine(T_(3)).Positive correlations were observed between the following pairs of variables:log BMR and log body mass,log body mass and log body fat,log BMR and log state 4 respiration in the liver,log BMR and log CCO activity in the liver and muscle,log BMR and log av-UCP m RNA expression,whereas a negative correlation was observed between log BMR and log myostatin level.In addition,a positive correlation was also detected between log T_(3) and each of the following:log BMR,state 4 respiration,and log CCO activity in the liver.Our results suggested that decreased metabolic thermogenesis via down-regulation in cellular aerobic capacity of organs and serum thyroid hormones may be an important survival strategy for fasting Tree Sparrows to reduce energy expenditure.
基金Guangzhou Medical and Health Science and Technology Project(Project No.:20231A011103)General projects of Guangzhou municipal Science and Technology Bureau(Project No.:2023A04J0598)Guangdong Basic and Applied Basic Research Foundation(Project No.:2022A1515111122)。
文摘Prostate cancer(PCa)is a prevalent malignancy in men,traditionally linked to androgen receptor signaling.Emerging evidence suggests thyroid hormones(THs,particularly T3/T4)play a complex role in PCa biology.THs regulate gene transcription via nuclear receptors TRα/β,modulating proliferation,apoptosis,and AR signaling,while non-genomic pathways through integrin αvβ3 activate MAPK/PI3K-Akt signaling,driving metabolic reprogramming,migration,and angiogenesis.Local DIO enzymes fine-tune T3/T4 levels,with DIO2 enhancing proliferation and DIO3 creating a low-TH microenvironment to facilitate immune evasion.Epidemiological studies associate hyperthyroidism or low TSH with elevated PCa risk,whereas experimental models show inconsistent effects,reflecting regulation by hormone levels,receptor distribution,and tumor molecular features.Bibliometric analyses reveal a shift from epidemiological studies to molecular,immune,and metabolic mechanistic research,though clinical translation remains limited.This review synthesizes current knowledge on THs in PCa,highlighting mechanistic insights,evidence gaps,and future directions,aiming to inform early detection,stratification,and therapeutic strategies.
基金Supported by The Research Foundation of Jiangsu Province Administration of Traditional Chinese Medicine,No.MS2023088The Science and Technology Project of Changzhou,No.CE20225040+1 种基金The Research Foundation of Nanjing Medical University Changzhou Medical Center,No.CMCC202311Leading Talent of Changzhou“The 14th Five-Year Plan”High-Level Health Talents Training Project,No.2022CZLJ021.
文摘BACKGROUND Hepatocellular carcinoma(HCC)surveillance is crucial for patients with compensated cirrhosis(CC)and decompensated cirrhosis(DC).Increasing evidence has revealed a connection between thyroid hormone(TH)and HCC,although this relationship remains contentious.Complements and immunoglobulin(Ig),which serve as surrogates of cirrhosis-associated immune dysfunc-tion,are associated with the severity and outcomes of liver cirrhosis(LC).To date,there is a lack of evidence supporting the recommendation of TH,Ig,and com-plement tests in patients at high risk of HCC.AIM To assess the predictive value of TH,Ig,and complements for HCC development.METHODS Data from 142 patients,comprising 72 patients with CC and 70 patients with DC,were analysed as a training set.Among them,100 patients who underwent complement and Ig tests were considered for internal validation.Logistic regression was employed to identify independent risk factors for HCC development.RESULTS The median follow-up duration was 32(24-37 months)months.The incidence of HCC was significantly higher in the DC group(16/70,22.9%)compared to the CC group(3/72,4.2%)(χ^(2)=10.698,P<0.01).Patients with DC exhibited lower total tetraiodothyronine(TT4),total triiodothyronine(TT3),free triiodothyronine,complement C3,and C4(all P<0.01),and higher IgA and IgG(both P<0.01).In both CC and DC patients,TT3 and TT4 positively correlated with alanine transaminase(ALT),aspartate transaminase(AST),and gamma-glutamyl transpeptidase(GGT).IgG positively correlated with IgM,IgA,ALT,and AST,while it negatively correlated with C3 and C4.Multivariable analysis indicated that age,DC status,and GGT were independent risk factors for HCC development.CONCLUSION The predictive value of TH,Ig,and complements for HCC development is suboptimal.Age,DC,and GGT emerge as more significant factors during HCC surveillance in hepatitis B virus-related LC.
基金supported by the National Key Research and Development Program of China(No.2022YFC3702700)the National Natural Science Foundation of China(No.82025030)the National Research Program for Key Issues in Air Pollution Control of China(No.DQGG0401)。
文摘Objective To examine the mechanistic of organochlorine-associated changes in lung function.Methods This study investigated 76 healthy older adults in Jinan,Shandong Province,over a fivemonth period.Personal exposure to organochlorines was quantified using wearable passive samplers,while inflammatory factors and thyroid hormones were analyzed from blood samples.Participants’lung function was evaluated.After stratifying participants according to their thyroid hormone levels,we analyzed the differential effects of organochlorine exposure on lung function and inflammatory factors across the low and high thyroid hormone groups.Mediation analysis was further conducted to elucidate the relationships among organochlorine exposures,inflammatory factors,and lung function.Results Bis(2-chloro-1-methylethyl)ether(BCIE),was negatively associated with forced vital capacity(FVC,–2.05%,95%CI:–3.11%to–0.97%),and associated with changes in inflammatory factors such as interleukin(IL)-2,IL-7,IL-8,and IL-13 in the low thyroid hormone group.The mediation analysis indicated a mediating effect of IL-2(15.63%,95%CI:0.91%to 44.64%)and IL-13(13.94%,95%CI:0.52%to 41.07%)in the association between BCIE exposure and FVC.Conclusion Lung function and inflammatory factors exhibited an increased sensitivity to organochlorine exposure at lower thyroid hormone levels,with inflammatory factors potentially mediating the adverse effects of organochlorines on lung function.
基金Supported by the Zigong Key Science and Technology Plan(Collaborative Innovation Project of Zigong Institute of Brain Sciences),No.2023-NKY-02-04,No.2023-NKY-02-07,No.2023-NKY-03-03,and No.2024-NKY-02-07.
文摘BACKGROUND Neuroendocrine dysfunction,especially involving the hypothalamic-pituitarythyroid axis,plays a critical role in the onset and progression of schizophrenia.Alterations in thyroid stimulating hormone(TSH),triiodothyronine(T3),free T3(FT3),thyroxine(T4),and free T4 have been implicated in this process.Although previous studies have established an association between thyroid function and psychiatric symptoms,how thyroid hormone levels vary with disease duration remains underexplored.AIM To investigate duration stage-specific associations between thyroid hormones and psychotic symptoms among inpatients with stable schizophrenia.METHODS This cross-sectional study was conducted at Zigong Mental Health Center,China,and included 237 hospitalized patients with stable schizophrenia.Participants were stratified into three groups based on disease duration:0-10 years,10.1-20 years,and over 20 years.Peripheral blood samples were collected to measure serum thyroid hormone levels.Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale.Covariate-adjusted linear regression analyses were performed to assess the relationships between thyroid hormone levels and Positive and Negative Syndrome Scale sub-scale scores.RESULTS The relationship between thyroid hormones and psychotic symptoms varied by disease duration.In patients with a disease course of 0-10 years,T4[β=-0.848;95%confidence interval(CI):-1.564 to-0.133;P=0.021]and FT3(β=-2.483;95%CI:-4.693 to-0.273;P=0.028)levels were significantly inversely associated with general psychopathology scores.Among those with 10.1-20 years of disease,only TSH showed a significant negative correlation with general psychopathology(β=-1.429;95%CI:-2.348 to-0.509;P=0.003).No significant correlations were found in the>20 years group.CONCLUSION The associations between thyroid hormones and psychotic symptoms vary according to the duration of schizophrenia(T4/FT3 early;TSH mid),enabling the development of stage-adapted models and management.
基金National Natural Science Foundation of China,No.82270881 and No.82200928National High-Level Hospital Clinical Research Funding,No.BJ-2023-124 and No.BJ-2023-130.
文摘BACKGROUND Diabetic peripheral neuropathy(DPN)is a common complication of type 2 diabetes mellitus(T2DM),significantly affecting patients’quality of life and imposing a substantial economic burden.Recent studies have highlighted the role of thyroid hormones in diabetes complications,particularly in elderly patients with T2DM.However,the relationship between thyroid hormone sensitivity and DPN remains unclear.AIM To investigate the correlation between thyroid hormone sensitivity and DPN in elderly patients with T2DM.METHODS In a cohort of 256 elderly patients with T2DM,propensity score matching was used to balance age,sex,and diabetes duration.Clinical data were collected to calculate thyroid hormone sensitivity and analyze its correlation with DPN.A random forest model was used to evaluate the diagnostic value of free triiodothyronine/free thyroxine(FT_(3)/FT_(4))for DPN.RESULTS Patients with DPN had a lower FT_(3)/FT_(4) ratio[(0.302±0.053)vs(0.316±0.049),P=0.040].Quartile stratification showed decreasing DPN prevalence with higher FT_(3)/FT_(4) ratios.Spearman’s correlation analysis showed that a lower FT_(3)/FT_(4) ratio was associated with higher glycated hemoglobin,fasting blood glucose,reduced nerve conduction velocity,and electrical skin conductance.Logistic regression indicated a positive relationship between the median FT_(3)/FT_(4) ratio and bilateral foot electrochemical skin conductance[odds ratio(OR):1.019;95%CI:1.005-1.034;P=0.007]and sural nerve sensory amplitude(OR:1.310;95%CI:1.008-1.703;P=0.043).Receiver operating characteristic analysis using a random forest model showed that incorporating FT_(3)/FT_(4) improved predictive performance for DPN,with an area under the curve of 0.74,sensitivity of 0.79,specificity of 0.64,and accuracy of 0.77.CONCLUSION In elderly patients with T2DM with euthyroidism,a lower FT_(3)/FT_(4) ratio is correlated with increased DPN incidence,affecting both large and small nerve fibers.FT_(3)/FT_(4) is an effective predictor of DPN.
基金Supported by Research Award from KaroBio AB, Sweden (to Parini P)
文摘Reverse cholesterol transport (RCT) is a complex process which transfers cholesterol from peripheral cells to the liver for subsequent elimination from the body via feces. Thyroid hormones (THs) affect growth, develop- ment, and metabolism in almost all tissues. THs exert their actions by binding to thyroid hormone receptors (TRs). There are two major subtypes of TRs, TRα and TRβ, and several isoforms (e.g. TRα1, TRα2, TRβ1, and TRβ2). Activation of TRα1 affects heart rate, whereas activation of TRβ1 has positive effects on lipid and lipoprotein metabolism. Consequently, particular interest has been focused on the development of thyromimetic compounds targeting TRβ1, not only because of their ability to lower plasma cholesterol but also due their ability to stimulate RCT, at least in pre-clinical models. In this review we focus on THs, TRs, and on the effects of TRβ1-modulating thyromimetics on RCT in various animal models and in humans.
基金supported by the Swiss National Science FoundationSUVA foundationNovartis foundation
文摘Injury to peripheral nerves is often observed in the clinic and severe injuries may cause loss of motor and sensory functions.Despite extensive investigation,testing various surgical repair techniques and neurotrophic molecules,at present,a satisfactory method to ensuring successful recovery does not exist.For successful molecular therapy in nerve regeneration,it is essential to improve the intrinsic ability of neurons to survive and to increase the speed of axonal outgrowth.Also to induce Schwann cell phenotypical changes to prepare the local environment favorable for axonal regeneration and myelination.Therefore,any molecule that regulates gene expression of both neurons and Schwann cells could play a crucial role in peripheral nerve regeneration.Clinical and experimental studies have reported that thyroid hormones are essential for the normal development and function of the nervous system,so they could be candidates for nervous system regeneration.This review provides an overview of studies devoted to testing the effect of thyroid hormones on peripheral nerve regeneration.Also it emphasizes the importance of combining biodegradable tubes with local administration of triiodothyronine for future clinical therapy of human severe injured nerves.We highlight that the local and single administration of triiodothyronine within biodegradable nerve guide improves significantly the regeneration of severed peripheral nerves,and accelerates functional recovering.This technique provides a serious step towards future clinical application of triiodothyronine in human severe injured nerves.The possible regulatory mechanism by which triiodothyronine stimulates peripheral nerve regeneration is a rapid action on both axotomized neurons and Schwann cells.
文摘The thyroid hormones L-thyroxine and triiodo-L-thyronine have profound effects on postembryonic development of most vertebrates. Analysis of their action in mammals is vitiated by the exposure of the developing foetus to a number of maternal factors which do not allow one to specifically define the role of thyroid hormone (TH)or that of other hormones and factors that modulate its action. Amphibian metamorphosis is obligatorily dependent on TH which can initiate all the diverse physiological manifestations of this postembryonic developmental process(morphogenesis, cell death, re-structuring, etc.) in free-living embryos and larvae of most anurans. This article will first describe the salient features of metamorphosis and its control by TH and other hormones. Emphasis will be laid on the key role played by TH receptor (TR), in particular the phenomenon of TR gene autoinduction, in initiating the developmental action of TH. Finally, it will be argued that the findings on the control of amphibian metamorphosis enhance our understanding of the regulation of postembryonic development by TH in other vertebrate species.
文摘Anuran metamorphosis involves systematic transformations of individual organs in a thyroid hormone (TH)-dependent manner. Morphological and cellular studies have shown that the removal of larval or- gans/tissues such the tail and the tadpole intestinal epithelium is through programmed cell death or apop- tosis. Recent molecular investigations suggest that TH regulates metamorphosis by regulating target gene expression through thyroid hormone receptors (TRs), which are DNA-binding transcription factors. Cloning and characterization of TH response genes show that diverse groups of early response genes are induced by TH. The products of these TH response genes are believed to directly or indirectly affect the expression and/or functions of cell death genes, which are conserved at both sequence and function levels in different animal species. A major challenge for future research lies at determining the signaling pathways leading to the activation of apoptotic processes and whether different death genes are involved in the regulation of apoptosis in different tissues/organs to effect tissue-specific transformations.
基金supported Jining Medical University National Nature Fund Cultivation Fund(No.JYP201733)
文摘Background Thyroid hormones(THs) including thyroxine(T4) and triiodothyronine(T3) with high biological activities have important effects on cardiovascular system by acting on renin-angiotensin-aldosterone system(RAAS), oxidative stress, mitochondria, endothelial cells, vascular smooth muscle cells(VSMC), cardiomyocytes, thyroid hormone receptor(TRs), cholesterol metabolism, insulin sensitivity, blood coagulation, etc. Excess or lack of THs is detrimental to cardiovascular function, so this article reviews the mechanism of THs on cardiovascular system.[S Chin J Cardiol 2019;20(4):269-279]
基金Financial support was received from funding agencies in the United States (NIH grant AR048139 and VA merit review grant)
文摘The importance of the thyroid hormone axis in the regulation of skeletal growth and maintenance has been well established from clinical studies involving patients with mutations in proteins that regulate synthesis and/or actions of thyroid hormone. Data from genetic mouse models involving disruption and overexpression of components of the thyroid hormone axis also provide direct support for a key role for thyroid hormone in the regulation of bone metabolism. Thyroid hormone regulates proliferation and/or differentiated actions of multiple cell types in bone including chondrocytes, osteoblasts and osteoclasts. Thyroid hormone effects on the target cells are mediated via ligand-inducible nuclear receptors/transcription factors, thyroid hormone receptor （TR） a and ~, of which TRa seems to be critically important in regulating bone cell functions. In terms of mechanisms for thyroid hormone action, studies suggest that thyroid hormone regulates a number of key growth factor signaling pathways including insulin-like growth factor-I, parathyroid hormone related protein, fibroblast growth factor, Indian hedgehog and Wnt to influence skeletal growth. In this review we describe findings from various genetic mouse models and clinical mutations of thyroid hormone signaling related mutations in humans that pertain to the role and mechanism of action of thyroid hormone in the regulation of skeletal growth and maintenance.
基金supported by the Grant-in Aid of Science Research(C) (No. 20510062 to K. Yamauchi) from Japan Society for Promotion of Science
文摘Ioxynil, a phenolic herbicide, is known to exert thyroid hormone （TH） disrupting activity by interfering with TH-binding to plasma proteins and a step of the cellular TH-signaling pathway in restricted animal species. However, comparative studies are still lacking on the TH disruption. We investigated the interaction of [125I] ioxynil with serum proteins from rainbow trout, bullfrog, chicken, pig, rat, and mouse, using native polyacrylamide gel electrophoresis. Candidate ioxynil-binding proteins, which included lipoproteins, albumin and transthyretin （TTR）, differed among the vertebrates tested. Rainbow trout and bullfrog tadpole serum had the lowest binding activity for ioxynil, whereas the eutherian serum had the highest binding activity. The cellular uptake of, and response to, ioxynil were suppressed by rat serum greater than by tadpole serum. The cellular uptake of [125I]ioxynil competed strongly with phenols with a single ring, but not with THs. Our results suggested that ioxynil interferes with TH homeostasis in plasma and with a step of cellular TH-signaling pathway other than TH-uptake system, in a species-specific manner.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDB14040102)the National Natural Science Foundation of China(No.21377153)
文摘T3-induced Xenopus metamorphosis is an ideal model for detecting thyroid hormone（TH）signaling disruption of chemicals. To optimize the T3-induced Xenopus assay and improve its sensitivity and reproducibility, we intend to develop quantitatively morphological endpoints and choose appropriate concentrations and exposure durations for T3 induction.Xenopus laevis at stage 52 were exposed to series of concentrations of T3（0.31–2.5 nmol/L）for 6 days. By comparing morphological changes induced by T3, we propose head area,mouth width, unilateral brain width/brain length, and hindlimb length/snout-vent length as quantitative parameters for characterizing T3-induced morphological changes, with body weight as a parameter for indicating integrated changes. By analyzing time-response curves, we found that following 4-day exposure, T3-induced grossly morphological changes displayed linear concentration–response curves, with moderate morphological changes resulting from 1.25 nmol/L T3 exposure. When using grossly morphological endpoints to detect TH signaling disruption, we propose 4 days as exposure duration of T3, with concentrations close to 1.25 nmol/L as induction concentrations. However, it is appropriate to examine morphological and molecular changes of the intestine on day 2 due to their early response to T3. The quantitative endpoints and T3 induction concentrations and durations we determined would improve the sensitivity and the reproducibility of the T3-induced Xenopus metamorphosis assay.
文摘The HIV-1 LTR controls the expression of HIV-1 viral genes and thus is critical for viral propagation and pathology. Numerous host factors have been shown to participate in the regulation of the LTR promoter. Among them is the thyroid hormone (T3) receptor (TR). TR has been shown to bind to the critical region of the promoter that contain the NFbB and Sp1 binding sites. Interestingly, earlier transient transfection studies in tissue culture cells have yielded contradicting conclusions on the role of TR in LTR regulation, likely due to the use of different cell types and/or lack of proper chromatin organization. Here, using the frog oocyte as a model system that allows replication-coupled chromatin assembly, mimicking that in somatic cells, we demonstrate that unliganded heterodimers of TR and RXR (9-cis retinoic acid receptor) repress LTR while the addition of T3 relieves the repression and further activates the promoter. More importantly, we show that chromatin and unliganded TR/RXR synergize to repress the promoter in a histone deacetylase-dependent manner.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDB14040102)the National Natural Science Foundation of China(No.21377153)
文摘We developed the T3-induced Xenopus metamorphosis assay, which is supposed to be able to sensitively detect thyroid hormone（TH） signaling disruption of chemicals. The present study aimed to validate the T3-induced Xenopus metamorphosis assay by re-evaluating the TH signaling antagonism of tetrabromobisphenol A（TBBPA）, a known TH signaling disruptor. According to the assay we developed, Xenopus tadpoles at stage 52 were exposed to 10–500 nmol/L TBBPA in the presence of 1 nmol/L T3. After 96 hr of exposure, TBBPA in the range of 10–500 nmol/L was found to significantly inhibit T3-induced morphological changes of Xenopus tadpoles in a concentration-dependent manner in term of body weight and four morphological endpoints including head area（HA）, mouth width（MW）, unilateral brain width/brain length（ULBW/BL）, and hind-limb length/snout-vent length（HLL/SVL）.The results show that these endpoints we developed are sensitive for characterizing the antagonistic effects of TBBPA on T3-induced metamorphosis. Following a 24-hr exposure,we found that TBBPA antagonized expression of T3-induced TH-response genes in the tail,which is consistent with previous findings in the intestine. We propose that the tail can be used as an alternative tissue to the intestine for examining molecular endpoints for evaluating TH signaling disruption. In conclusion, our results demonstrate that the T3-induced Xenopus metamorphosis assay we developed is an ideal in vivo assay for detecting TH signaling disruption.
基金supported by the National Natural Science Foundation of China(No.21377045)Joint Innovation Funding of Production and Research-a Prospective Joint Research Project(BY2015027-05)
文摘The present study determined the thyroid hormone interference of tetrabromobisphenol A （TBBPA） in Sprague-Dawley （SD） rats, and the derived-reference dose （RfD） of different endpoint effects on mammals based on experimental results and data collection. Based on repeated exposure toxicity tests on mammals and extensive research, the present study used BMDS240 Software to derive a benchmark dose, and analyzed the accuracy and uncertainty, and similarity with other studies. Test results on triiodothyronine （T3）, thyroxine （T4）, and thyroid stimulating hormone （TSH） demonstrated that all the indicators presented a non-monotonous dose-effect relationship clearly, except TSH in male rats exposed to 0-1000 mg/kg BW per day. Therefore, RfDs were derived from different critical effects. In summary, RfD for mammals in the present study was found to be 0.6 mg/kg per day.
基金supported by the National Natural Science Foundation of China(No.91543203)the Chinese Academy of Sciences(No.QYZDJ-SSW-DQC020)。
文摘Dechloranes are a group of halogenated flame retardants with a basic bicyclo[2.2.1]heptene,including Dechlorane Plus(DP),Dechlorane 602(Dec 602),Dechlorane 603(Dec 603)and Dechlorane 604(Dec 604).A few epidemiological investigations and animal experiments have shown that DP exhibited thyroid-interfering effects.In the present study,we investigated whether DP and three other dechloranes could interfere the thyroid function through thyroid hormone receptors(TRs,TRαand TRβ)signaling pathways.The binding affinities of the four dechloranes to the two TRs were determined by fluorescence competitive binding assay.It was found that all the four dechloranes could bind with the two TRs.The relative potency(RP)values ranged from nd(not detectable)to 0.0667.Between the two TRs,dechloranes were more inclined to bind with TRβ,which implies that the thyroid interference effect of dechloranes may have selectivity in different tissues and organs.TRs-mediated luciferase reporter gene assay and T-screen assay showed that all the four dechloranes exhibited antagonistic activity to TRs in the cells.Taken together,our results demonstrated that dechloranes might interfere with thyroid function by binding with TRs and acting as TR antagonists.The health risk of highly exposed human populations should be of serious concern because of the high hazard quotient calculated from our cell assay results.
基金supported by the Public Welfare Research Project for Environmental Protection (No. 201109048)the National High Technology Research and Development Program (863) of China (No. 2012AA06A302)the National Natural Science Foundation of China (No. 21077125)
文摘Considering some advantages of Rana nigromaculata as an experimental species, we propose that this species, like Xenopus laevis, could be used to assay thyroid hormone（TH） signaling disrupting actions. To validate the utilizability of R. nigromaculata, we investigated the responsiveness of R. nigromaculata to a TH receptor（TR） agonist（T3） and antagonist（amiodarone） by analyzing expression, based on characterizing TR cDNA and developmental expression patterns. With high levels of identity with the corresponding genes in X. laevis, both TRα and TRβ in R. nigromaculata exhibited roughly similar developmental expression patterns to those of X. laevis, in spite of some species-specific differences. Both TRα and TRβ expression had greater changes in the liver and intestine than in the tail and brain during metamorphosis. T3 exposure for 2 days induced more dramatic increases of TRβ expression in stage 27 than in stage34 tadpoles but not in stage 42 tadpoles, showing that the responsiveness of R. nigromaculata to TH decreased with development and disappeared at the onset of metamorphic climax.Corresponding to greater changes of TRβ expression in the liver and intestine than in the tail and brain during metamorphosis, the liver and intestine had higher responsiveness to exogenous T3 than the tail and brain. Amiodarone inhibited T3-induced TRβ expression. Our results show that R. nigromaculata can be used as a model species for assaying TH signaling disrupting actions by analyzing TRβ expression, and intestine tissues at stage 27 are ideal test materials due to high responsiveness and easy accessibility.
