Thyroid hormones and thyroid hormone receptors: Effects of thyromimetics on reverse cholesterol transport

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.

Involvement of chromatin and histone acetylation in the regulation of HIV-LTR by thyroid hormone receptor

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.

The roles of thyroid hormone receptor and T3 in metamorphosis of Haliotis diversicolor

Thyroid hormone is a kind of important hormone which regulates metamorphosis. Its role is well described in amphibian metamorphosis. Thyroid hormones (T3 and T4) have also been demonstrated to play a role in metamorphosis of marine invertebrates. However, the mechanism of thyroid hormone in metamorphosis of marine invertebrates remains unknown. A homolog of vertebrate thyroid hormone receptor (TR) was cloned and identified in abalone Haliotis diversicolor and was named HdTR . The mRNA expressions of HdTR , thyroid peroxidase ( TPO ), thyroid peroxidase 1 ( TPO1 ), idothyronine deiodinase Ⅲ( IDⅢ) and integrin alpha-V ( ITGAV ) had significant diff erence in metamorphosis of H . diversicolor . Metamorphosis rate and mortality rate were significantly diff erent in HdTR RNAi experiment and T3 inducing experiment. In RNAi experiment, ITGAV and CCND1 (cyclin D1) expression of dsRNA HdTR exposing group were significantly lower than those of blank control and negative control. But CTNNB (catenin beta) expression of dsRNA HdTR exposing group was higher than that those of blank control and negative control. ERK (extracellular signal regulated kinases) and PI3K (phosphoinositide-3-kinase) had no significant diff erence in RNAi experiment. Moreover, ITGAV of 1 μmol/L T3 group was significantly lower than that of 0 μmol/L T3 group, PI3K expression of 10 μmol/L T3 group was higher than that of 0 μmol/L T3 group, and the other genes expression had no significant diff erence in T3 inducing experiment. The data of genes expression suggested that CCND1 might be an eff ector gene of TR genomic action, while CTNNB might be regulated by unliganded TR. CCND1 and CTNNB may be involved in cell proliferation of metamorphosis. T3 might regulate the expression level of PI3K via nongenomic way. These results shed light on the mechanism of thyroid hormone in abalone metamorphosis.

Molecular Characterization of Thyroid Hormone Receptors (TRs) and their Responsiveness to T3 in Microhylafissipes

To explore and enrich the molecular mechanisms of thyroid hormone receptors （TRs） in the metamorphosis of amphibians, the cDNA sequences of TRa and TRβ in Microhyla fissipes were cloned and characterized. TRa was 1 706 bp in length with an open reading frame （ORF） of 1 257 bp encoding a predicted protein of 418 amino acids and TRβ was 1 422 bp with an ORF of 1 122 bp encoding a predicted protein of 373 amino acids. Their protein sequences contained 4 conserved domains of the nuclear receptor superfamily with two highly conserved cysteine-rich zinc fingers in the DNA-binding domain, whereas TRβ was 42 amino acids shorter in its A/B domain than TRot. Highly-conserved sequences and structures indicated their conserved functions during metamorphosis. TRa expression reached peak at 12 h and then decreased from 12 h to 48 h. While dramatically up-regulated TRβ was observed after exposure of T3 within 24 h, and it was down-regulated from 24 h to 48 h. The expression pattern of TRβ is similar to that in the natural metamorphosis. Furthermore, tadpoles treated 24 h also resembled the climax of metamorphosis tadpoles and TRβ expression had higher responsiveness than TRa to T3 in M. fissipes. These results suggest M. fissipes may serve as the model to assay environmental compounds on TH signaling disruption.

The adenoviral E1A protein relieves gene repression by receptors in v/vo displaces corepressors and unliganded thyroid hormone

The human adenovirus type 5 early region 1A （E1A） is one of two oncogenes present in the adenovirus genome and functions by interfering with the activities of cellular regulatory proteins. The E1A gene is alternatively spliced to yield five products. Earlier studies have revealed that E1A can regulate the function of thyroid hormone （T3） receptors （TRs）. However, analysis in yeast compared with transfection studies in mammalian cell cultures yields surprisingly different effects. Here, we have examined the effect of E1A on TR function by using the frog oocyte in vivo system, where the effects of E1A can be studied in the context of chromatin. We demonstrate that different isoforms of E1A have distinct effects on TR function. The two longest forms inhibit both the repression by unliganded TR and activation by T3-bound TR. We further show that E1A binds to unliganded TR to displace the endogenous corepressor nuclear receptor corepressor, thus relieving the repression by unliganded TR. On the other hand, in the presence of T3, E1A inhibits gene activation by T3-bound TR indirectly, through a mechanism that requires its binding domain for the general coactivator p300. Taken together, our results thus indicate that E1A affects TR function through distinct mechanisms that are dependent upon the presence or absence of T3.

Distinct expression profiles of transcriptional coactivators for thyroid hormone receptors during Xenopus laevis metamorphosis

The biological effects of thyroid hormone (T3) are mediated by the thyroid hormone receptor (TR). Amphibian metamorphosis is one of the most dramatic processes that are dependent on T3. T3 regulates a series of orchestrated developmental changes, which ultimately result in the conversion of an aquatic herbivorous tadpole to a terrestrial carnivorous frog. T3 is presumed to bind to TRs, which in turn recruit coactivators, leading to gene activation. The best-studied coactivators belong to the p160 or SRC family. Members of this family include SRC1/NCoA-1, SRC2/TIF2/GRIP1, and SRC3/pCIP/ACTR/AIB-1/RAC-3/TRAM-1. These SRCs interact directly with liganded TR and function as adapter molecules to recruit other coactivators such as p300/CBP. Here, we studied the expression patterns of these coactivators during various stages of development. Amongst the coactivators cloned in Xenopus laevis, SRC3 was found to be dramatically upregulated during natural and T3-induced metamorphosis, and SRC2 and p300 are expressed throughout postembryonic development with little change in their expression levels. These results support the view that these coactivators participate in gene regulation by TR during metamorphosis.

Stimulating effect of thyroid hormones in peripheral nerve regeneration:research history and future direction toward clinical therapy

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.

Amphibian metamorphosis as a model for studying the developmental actions of thyroid hormone

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.

Thyroid hormone regulation of apoptotic tissue remodeling during anuran metamorphosis

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.

Inhibition effects of parathyroid hormone on human medullary thyroid carcinoma cells

Objective： The purpose of the study was to investigate the effects of parathyroid hormone and parathyroid hormone receptor monoclonal antibody on in vitro growth and proliferation of human medullary thyroid carcinoma cell lines. Methods： The medullary thyroid carcinoma cell line was cultured in vitro, with parathyroid hormone and parathyroid hormone receptor monoclonal antibody treatment intervention, the growth of the cells was observed under an inverted contrast micro scope, the MTT assay was used to detect the cell growth inhibition rate. Results： Under the inverted contrast microscope, the cells changed significantly, the parathyroid hormone and parathyroid hormone receptor monoclonal antibodies can effectively inhibit the proliferation of medullary thyroid cancer cells in a time and dose dependent. When parathyroid hormone concentra tion reached a concentration of 2.0 IJmol/L, the parathyroid hormone receptor monoclonal antibody reached a concentration of 1.0 μmol/L, the cell growth was most significantly inhibited （P 〈 0.05）. Conclusion： Parathyroid hormone and parathyroid hormone receptor monoclonal antibody were able to inhibit the proliferation of medullary thyroid carcinoma cells and signifi cantly reduce the proliferation index.

Molecular characterization and developmental expression patterns of thyroid hormone receptors(TRs) and their responsiveness to TR agonist and antagonist in Rana nigromaculata

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.

In vitro assay for human thyroid hormone receptor β agonist and antagonist effects of individual polychlorinated naphthalenes and Halowax mixtures

Polychlorinated naphthalenes (PCNs) are dioxin-like environmental contaminants. There is growing concern over the endocrine-disrupting effects of PCNs, but very few studies have investigated the effect of PCNs on the thyroid system. This study used a yeast two-hybrid assay, which included the recombinant human thyroid receptor(TR)-β and reporter genes, to characterize the TRβ-disrupting effects of five individual PCN congeners, five PCN Halowax mixtures, and naphthalene. Their agonist and antagonist effects were studied in the absence and presence of 5×10-7 mol/L 3,3′,5-triiodo-L-thyronine, which induced submaximal β-galactosidase activity. Naphthalene, 1,2,3,4,5,6,7,8-octachloronaphthalene and all of the Halowax mixtures (Halowax 1000, 1001, 1013, 1014 and 1099) showed no agonist or antagonist activity on TRβ at the concentrations tested (up to 10-2 g/L). The lighter PCN congeners, namely 1-chloronaphthalene, 2-chloronaphthalene, 1,4-dichloronaphthalene and 1,2,3,4-tetrachloronaphthalene showed no agonist activity but showed significant antagonist activity on TRβ. The 20% relative inhibitory concentrations of these PCNs were less than 9.13 × 10-3 g/L. Thus, bioaccumulation of these lighter PCN congeners may disrupt the thyroid hormone system and inhibit TR-mediated cellular responses. Studies in the future should investigate the possible associations between the presence PCNs and adverse health outcomes.

A new mutation in the thyroid hormone receptor gene of a Chinese family with resistance to thyroid hormone

Background Resistance to thyroid hormone （RTH） is a dominant inherited syndrome of reduced tissue responsiveness to thyroid hormone. It is usually due to mutations located at the ligand-binding domain and adjacent hinge region of the thyroid hormone receptor β（TRβ）. We report the clinical and laboratory characteristics and the genetic analysis of a patient with this rare disorder and his family members. Methods The clinical presentations and changes of thyroid function tests （TFTs） including magnetic resonance imaging （MRI） of pituitary and other laboratory tests were analysed. TFTs of his family＇s members were detected as well. Direct DNA sequencing of the TRβ gene was done for those with abnormal TFTs. Results The RTH child had goiter, irritability, aggressiveness, and sudoresis. His TFTs showed high levels of circulating free thyroid hormones （FT4 and FT3） and normal thyroid-stimulating hormone （TSH） concentrations. He felt worse when treated as hyperthyroidism （Grave disease） with thiamazole and his clinical presentations got improved obviously when treated as RTH with bromocriptine without obvious advert effect. We identified a novel missense mutation, A317D, located in exon 9 of the gene of this boy and his mother. His mother had not any clinical presentation, but having abnormal TFTs results. Conclusions This patient reported here was concordant with the criteria of RTH. The feature is dysfunction of hypothalamus-pituitary-thyroid axis. A novel mutation was found in the TRβ, A317D, of this family. This research verified the phenomena that there is a clinical heterogeneity within the same mutation of different RTH patients.

Cross-talk between the thyroid and liver:A new target for nonalcoholic fatty liver disease treatment

Nonalcoholic fatty liver disease(NAFLD)has been recognized as the most common liver metabolic disease,and it is also a burgeoning health problem that affects one-third of adults and is associated with obesity and insulin resistance now.Thyroid hormone(TH)and its receptors play a fundamental role in lipid metabolism and lipid accumulation in the liver.It is found that thyroid receptor and its isoforms exhibit tissue-specific expression with a variety of functions.TRβ1 is predominantly expressed in the brain and adipose tissue and TRβ2 is the major isoform in the liver,kidney and fat.They have different functions and play important roles in lipid metabolism.Recently,there are many studies on the treatment of NAFLD with TH and its analogues.We review here that thyroid hormone and TR are a potential target for pharmacologic treatments.Lipid metabolism and lipid accumulation can be regulated and reversed by TH and its analogues.

Thyroid disruption by technical decabromodiphenyl ether (DE-83R) at low concentrations in Xenopus laevis

Decabromodiphenyl ether （decaBDE）,as a flame retardant,is widely produced and used.To study the thyroid disruption by technical decaBDE at low concentrations,Xenopus laevis tadpoles were exposed to technical decaBDE mixture DE-83R （1-1000 ng/L） in water from stage 46/47 （free swimming larvae,system of Nieuwkoop and Faber） to stage 62.DE-83R at concentration of 1000 ng/L significantly delayed the time to metamorphosis （presented by forelimb emergence,FLE）.Histological examination showed that DE83R at all tested concentrations caused histological alterations-multilayer follicular epithelial cell and markedly increased follicle size accompanied by partial colloid depletion and increase in the peripheral colloid vacuolation,in thyroid glands.All tested concentrations of DE-83R also induced a down-regulation of thyroid receptor mRNA expression.These results demonstrated that technical decaBDE disrupted the thyroid system in X.laevis tadpoles.Analysis of polybrominated diphenyl ethers （PBDEs） （sum of 39 congeners） in X.laevis indicated that mean concentrations of total PBDEs in X.laevis exposed to 1,10,100,1000 ng/L were 11.0,128.1,412.1,1400.2 ng/g wet weight,respectively.Considering that PBDEs burden of X.laevis tadpoles was close to PBDEs levels in amphibians as reported in previous studies,our study has raised new concerns for thyroid disruption in amphibians of technical decaBDE at environmentally relevant concentrations.

Fibroblast growth factor receptor 3 effects on proliferation and telomerase activity in sheep growth plate chondrocytes

Background： Fibroblast growth factor receptor 3 （FGFR3） inhibits growth-plate chondrocyte proliferation and limits bone elongation. Gain-of-function FGFR3 mutations cause dwarfism, reduced telomerase activity and shorter telomeres in growth plate chondroyctes suggesting that FGFR3 reduces proliferative capacity, inhibits telomerase, and enhances senescence. Thyroid hormone （1-3） plays a role in cellular maturation of growth plate chondrocytes and a known target of T3 is FGFR3. The present study addressed whether reduced FGFR3 expression enhanced telomerase activity, mRNA expression of telomerase reverse transcriptase （TERT） and RNA component of telomerase （TR）, and chondrocyte proliferation, and whether the stimulation of FGFR3 by T3 evoked the opposite response. Results： Sheep growth-plate proliferative zone chondrocytes were cultured and transfected with siRNA to reduce FGFR3 expression; FGFR3 siRNA reduced chondrocyte FGFR3 mRNA and protein resulting in greater proliferation and increased TERT mRNA expression and telomerase activity （p 〈 0.0.5）. Chondrocytes treated with T3 significantly enhanced FGFR3 mRNA and protein expression and reduced telomerase activity （p 〈 0.05）; TERT and TR were not significantly reduced. The action of T3 at the growth plate may be partially mediated through the FGFR3 pathway. Conclusions： The results suggest that FGFR3 inhibits chondrocyte proliferation and reducing telomerase activity indicating an important role for telomerase in capacity during bone elongation. by down-regulating TERT expression sustaining chondrocyte proliferative

Lost expression of thyroid hormone receptor-β1 mRNA in esophageal cancer

Thyroid hormone receptors （TR）, ligand-mediated transcription factors, regulate cell growth, differentiation, and apoptosis. In humans, two different genes encode TR-α and TR-β and they are often co-expressed in various tissues at different levels. To explore the role of TR in esophageal cancer, we analyzed expression of TR-β1 mRNA （most abundantly expressed in the majority of normal cells） in normal and malignant esophageal tissue specimens using in situ hybridization. The TR-β1 mRNA was detected in 92.3% （96 of 104） of normal esophageal mucosa, whereas TR-β1 mRNA was only detected in 55.8% （58 of 104 cases） of esophageal squamous cell carcinoma specimens （P〈 0.00001）. Expression of TR-β1 mRNA was associated with well-differentiated cancers （P〈 0.001）. Furthermore, we determined whether the loss of heterozygosity （LOH） in TR-β1 gene locus would be responsible for the lost TR-β1 expression. Analysis of 73 esophageal tissue specimens generated 39 informative cases, 17 of which showed LOH （43.6%） but only 9 of these 17 cases were correlated with lost TR-β1 expression. This study demonstrated that expression of TR-β1 mRNA was lost in esophageal cancer tissues, which may be due to multiple mechanisms.

BRAF V600E/TERT promoter mutations and NIS/TSHR expression in differentiated thyroid carcinomaand their clinical significance

Objective Telomerase reverse transcriptase(TERT) promoter mutations have recently been described in thyroid carcinoma.The purpose of this study was to investigate the clinical significance of(v-raf murine sarcoma viral oncogene homolog B1) BRAF V600 E and TERT promoter mutations in differentiated thyroid carcinoma(DTC).The relationship between the two mutations and NIS/TSHR expression was also analyzed.Methods We have detected BRAF V600 E and TERT promoter mutations by direct sequencing and NIS/TSHR expression by immunohistochemistry in 229 cases of DTC,52 cases of benign nodular goiter,and 31 cases of normal thyroid tissue.Results The BRAF V600 E mutation was detected in 142(62.0%) of 229 cases of DTC [141 cases of papillary thyroid carcinoma(PTC) and 1 case of follicular thyroid carcinoma(FTC)].TERT promoter mutations were detected in 18(7.9%) of 229 cases of DTC(14 cases of PTC and 4 cases of FTC),including the mutations C228T(0.9%) and C250T(7.0%),which were mutually exclusive.Moreover,11(61.1%) cases also harbored the BRAF V600 E mutation,which was not associated with gender,age,tumor size,lymph node metastasis,and recurrence risk stratification(P >0.05).The rate of TERT promoter mutation was higher in males,age ≥45,and in the middle/high-risk group(P <0.05),and the rate of simultaneous BRAF V600 E and TERT promoter mutations were higher in the middle/high-risk group(P <0.05).In addition,NIS positive rate in the concurrent BRAF V600 E and TERT promoter mutation group(45.5 %) was lower than in other groups(that is,the DTC group with BRAF V600 E or TERT promoter mutations(55.1%),the DTC group with no BRAF V600 E or TERT promoter mutation(57.5%),the nodules and normal group(75.9%);| r | = 0.171,P = 0.002).Conclusion TERT promoter mutations were lower in patients with DTC,with the C250 T mutation being the most common.The detection of BRAF V600 E mutation combined with TERT promoter mutations was instructive for the prognosis assessment and treatment of DTC.

Analyses of levels of thyroid hormones and its receptor expression in puerperants and newborns from an e-waste dismantling site

In this study,the serum levels,including thyr-oid hormones free triiodothyronine(FT3),free thyroxine(FT4),thyroid stimulating hormone(TSH)among the sub-jects from the exposed group(n 548)and the control group(n 545)were detected by immuno radiometric assay(IRMA).The expression levels of TRa1,TRb1,TSHR mRNA in placentas and umbilical cords were detected by fluorescent quantitative real-time PCR(FQ-PCR).The correlations between the thyroid hormone levels in maternal serum and umbilical serum,and between the expression levels of its receptors mRNA in placentas and umbilical cords were determined.We found that the FT4 levels of both maternal serum and umbilical cord serum in the exposed group were lower than those in the control(P<0.05).However,the increased TSH levels in the exposed group had statistically significance com-pared to those in the control group(P<0.05).The TRa1 and TRb1 mRNA levels both in placentas and umbilical cords in the exposed group were lower than those in the control group(P<0.05 and 0.01).How-ever,the TSHR mRNA levels in the exposed group were significantly different compared to those in the control group(P<0.01).The serum FT4 and TSH levels of par-turient women were positively correlated with those of the newborns in both groups(P<0.05 and 0.01).The mRNA levels of TRa1,TRb1 and TSHR in the placentas were positively correlated with those in umbilical cords in both groups(P<0.01).The findings suggest that some envir-onmental pollutants existing in the electronic waste(e-waste)dismantling region may affect the health of local parturient women and newborns,representing changes both in serum levels of thyroid hormones and in mRNA expression of its receptors.

Dechloranes exhibit binding potency and activity to thyroid hormone receptors

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.