API

Event: 958

Key Event Title

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Displacement, Serum thyroxine (T4) from transthyretin

Short name

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Displacement, Serum thyroxine (T4) from transthyretin

Biological Context

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Level of Biological Organization
Molecular

Cell term

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Organ term

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Key Event Components

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Process Object Action
thyroxine increased

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
Transthyretin interference KeyEvent

Stressors

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Taxonomic Applicability

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Life Stages

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Sex Applicability

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Key Event Description

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Despite the two binding sites for T4 on the TTR serum binding protein, each molecule of TTR only carries a single T4 molecule due to the negative cooperativity displayed by these binding sites (Ferguson et al 1975). As such, xenobiotics and pharmacologic agents can displace T4 from TTR and early on, this was demonstrated for ethnacrynic acid, salicylates, penicillin and 2,4-dinitrophenol (Munro et al 1989). More recently, work with the flavonoid EMD 21388 (and other compounds structurally similar to thyroxine) showed competitive binding and displacement of T4 from the TTR carrier protein.

Rickenbacher et al (1986) provided initial direct evidence of competition for the T4 binding site using molecular modeling and binding assays using radiolabeled TH. Brouwer and van den Berg (1986) reported preferential binding of a metabolite of radiolabeled tetrachlorobiphenyl to TTR in rats (15 mg/kg, ip), using gel electrophoresis followed by HPLC analysis. Van den Berg (1990) used a competitive binding assay to assess the ability of hydroxylated chlorinated aromatic compounds to bind to radiolabeled T4. Van den Berg et al (1991) extended this work to 65 compounds from 12 different chemical groups in rats treated via a single ip dose and competitive binding assay. Chlorophenols were found to have higher affinity relative to other chlorinated aromatics, particular at higher levels of chlorination, and the combination of hydroxyl chlorine atoms in the ortho position. {insert Figure 2/Van den Berg 1990}

Kohrle et al (1989) showed complete displacement (via gel electrophoresis) of radiolabeled T3 and T4 by EMD 21388 in pooled rat serum followed by increase in the percent free TH as measured by equilibrium dialysis. Complete inhibition occurred at 10 umol and displaced T4 from TTR to serum albumin and thyroxine-binding globulin (TBG), which normally serve a lesser role in thyroid hormone transport in humans. {insert Figure 2}

Kohrle et al (1989) administered EMD 21388 via ip route to rats at 2 umol/100 g BW and observed displacement of radiolabeled T3 and T4 from TTR followed by a decrease of T3 and T4 in serum while the percent free TH remained unchanged. {insert Figures 3-5}

Lueprasitsakul et al (1990) repeated this protocol and found that inhibition of binding occurred within 3 minutes followed by a decrease in serum T4 concentration and an increase in both serum percent free T4 as well serum total T4. {insert Figures 1 and 4}

Mendel et al (1992) demonstrated in rats dosed via IP with EMD 21388 (2 μmol/100 g BW) both displacement of radiolabeled T4 from TTR (as assessed via electrophoresis of serum proteins) and susbsequent increase of free T4 in serum.

To initially evaluate the impact of EMD 21388 on maternal/fetal hormones, Pedraza et al (1996) administered 2.5 mg 21388/day subcutaneously in pregnant female rats which led to displacement of T4 from TTR, reduced total T4 and increased free T4 in maternal circulation.

 

Compounds that have been found to compete with TTR for binding to T4 (and thus lead to some degree of thyroid disruption) include pharmaceuticals and environmental contaminants, such as halogenated aromatic compounds.  This latter category include PCBs, PBBs, PBDEs and perfluoro compounds and specifically, hydroxylated metabolites of all these compounds often display greater binding affinity than the natural ligand; however, this is a function of degree of halogenation as well as orientation of the halogens and hydroxyl functional group.

Gutshall et al 1989 treated male Wistar rats with a single IP dose of perfluorodecanoic acid (PFDA) and 125I and then measured TH, uptake of 125I, liver enzymes and binding of [125I]-T4 to albumin.  The authors did not observe increased conversion of T4 to rT3 but did note that PFDA displaced [125I]-T4 from rat albumin with an affinity similar to T4.  While this study involved albumin, it showed that perfluoro compounds may also have potential to interact with thyroid serum transport proteins.

Meerts et al 2000 investigated the affinity of several polybrominated flame retardants (including 17 PBDE congeners) to TTR using human TTR in an in vitro competitive binding assay and [125I]-T4. Pentabromophenol and tetrabromobisphenol A were found to have affinities 7-10 fold that of T4; however, a microsomal enzyme mediated transformation was needed first (i.e. hydroxylation) for PBDEs.  It should be noted that no reference OH-PBDEs were available at the time of this experiment.  Like the PCB congeners, degree of bromination is a driver of binding potency as is the nature of the halogen substitution (as well as hydroxy substitution).  In addition, brominated analogs are more potent in general relative to chlorinated ones.  Hydroxylation of parent compound via CYP2B enzymes appears to be a prerequisite of binding to TTR.

Hallgren et al 2001 treated female Sprague Dawley rats and C57BL/6 mice daily with Aroclor 1254, PCB-105, Bromkal 70-5 DE (commercial PBDE mixture) or BDE-47 via gavage for 14 days and measured TH, induction of microsomal phase I enzymes (EROD, MROD, PROD) and UDP UGT activity.  Free and total T4 was decreased in both species with no significant change to TSH and minimal impact on UDP UGT activity.  Rats were found to be more sensitive than mice to the observed effects.  The findings suggested that PBDEs may be metabolized by CYP2B, but also CYP1A to an extent, and that these induced enzymes increased the availability of hydroxylated metabolites in vivo and increase binding to T4 transport proteins. 

Hallgren and Darnerud 2002 treated female Sprague Dawley rats with BDE-47, Aroclor 1254 and Witaclor 171P, alone or in combinations, daily via gastric intubation for 14 days. Microsomal enzyme (cytochrome P450 isozymes and UDP UGTs), ex vivo binding of [125I]-T4 to plasma proteins and light microscopy morphology of the thyroid was examined. Aroclor 1254 and BDE-47 was observed to decrease T4, decrease [125I]-T4 binding to TTR, induce several phase I enzymes as well as moderate elevation of UDP UGT activity.  These data suggested that decreased plasma T4 is mainly due to interference with serum transport binding of parent and metabolites to TTR; however, there was clearly some role for glucuronidation in reducing T4 in this study. (PCB mixtures have been demonstrated to impact a number of different endpoints affecting normal thyroid homeostasis.)

Metabolites of BDE 47 formed by CYP2B6 include hydroxylated BDE 47 in addition to other hydroxylated congeners (Erratico et al 2013, Feo et al 2013) and it should be noted that CYP2B6 is also expressed in brain which has implications for formation of hydroxylates in that tissue (Miksys and Tyndale 2004).

Cao et al 2004 performed molecular docking analysis on the TTR and OH-PBDE interactions and confirmed the effect of degree of bromination.

Darnerud et al 2006 treated female Sprague Dawley rats with BDE 47 or Bromkal 70-5 DE at 2 doses via gavage daily for 2 weeks.  Thyroid hormones were measured from plasma via radioimmunoassay and samples pooled for analysis for individual congeners (BDEs 28, 47, 66, 99, 100, 138, 153, 154) and internal plasma doses were calculated that corresponded with decreased free T4. This critical dose was estimated to be ~ 400 ug/g lipid BDE 47 based on significant reduction of free T4.

Hamers et al 2006, 2008 collectively found that OH-PBDEs act as agonists or antagonists at TH receptors, that OH-PBDEs with high affinity for T4 can be detected in human serum and all metabolites were found to be more potent than the natural ligand in vitro using rat liver microsomes (3-OH-BDE-47 was found to have the highest potency).

Lau et al 2007 and Chang et al 2008 reported that PFOS alters serum T4 via interference with binding proteins, leading to a transient increase in free T4 and decrease in TSH.

Weiss et al 2009 were the first to examine the potential of 24 perfluorinated compounds and 6 structurally-related fatty acids to compete with T4 for TTR via [125I]-T4 binding assay and HPLC-MS/MS analysis.  From this analysis, 56 chemical descriptors to evaluate the structure-activity relationship (SAR) of binding potency of perfluorinated compounds to TTR.  Binding potency was found to strengthen with degree of fluorination, with maximum potency found at a chain length of eight (8) carbons; however, in general, the perfluorinated compounds were found to have T4 binding potency at about 10% that of the natural ligand.

Cao et al 2010 looked at binding interactions for 14 OH-PBDEs with TTR and TBG using fluorescence probe & competitive binding assay, circular dichroism (spectroscopic measurement of a protein’s secondary structure) and molecular docking analyses.  Binding constant data was generated for the first time and affinity was observed to increase with degree of bromination, until a peak at the 5- and 6-brominated diphenyl ethers was reached.  CD analysis showed that the OH-PDBEs bind to TTR and TBG at the same sites as the natural ligand while the molecular docking studies revealed a ligand-binding channel in TTR that was mostly hydrophobic inside but characterized by a positive-charged Lys15 residue at the channel entrance. The novel binding constant allowed meaningful quantitative evaluation of competitive displacement, by assuming human serum levels reported in the literature (Athanasiadou et al 2008; Marchesini et al 2008) and choosing the congener with the highest potency (5-OH-BDE47).  This evaluation suggested that competitive displacement would be insignificant, as serum levels of protein-bound 5-OH-BDE47 are at least two orders of magnitude lower than protein-bound T4 (suggesting ~10% T4 displacement by 5-OH-BDE47).

Cao et al 2011 generated binding constant data for the interactions of BPA and TH for TTR, TBG and human albumin via fluorescence probe, noting that concentrations of BPA commonly reported in human plasma are likely not high enough to interfere with T4 transport in serum.  A large excess of TTR and albumin in plasma are found relative to T4 and BPA and there is no competition for binding, which is further supported by the fact that affinity of BPA for T4 is much weaker than the natural ligand (by 2-3 orders of magnitude).

Ren and Guo 2012 designed a fluorescin T4 conjugate for use as a fluorescence probe in binding assays to examine interaction between eleven OH-PBDEs and transport proteins TTR and TBG. 3-OH-BDE47 and 3’-OH-BDE154 were found to be competitive with T4.

Ren et al 2013  higher brominated OH-PBDEs act as antagonists (i.e. BDEs 154 and 188) while lesser bromination (i.e. BDEs 47) found to be agonists

Grimm et al 2013 used fluorescence probe displacement and molecular docking simulations to characterize the binding of sulfated PCB metabolites to TTR, and stability and reversibility of these complexes were characterized by HPLC. The hydroxylated PCB metabolites (OH-PCBs) are excellent substrates for sulfation (phase II conjugation) via sulfotransferases (SULTs) and thus could represent another mechanism through which clearance can occur. Of the five lower-chlorinated sulfates for which Kd values were generated and compared against T4, only one would be considered a competitive inhibitor (4’PCB 11 sulfate) and the only case where the sulfate displays higher affinity than its corresponding OH metabolite (4’ OH-PCB 11).   Molecular docking simulation confirmed the affinity that PCB sulfates have for TTR, confirming previous reports showing higher affinity among those congeners with meta- and para-chlorination.  These data demonstrate the toxicological relevance of PCB sulfates to TTR-mediated transport of thyroid hormones in serum for the first time.  The generation of sulfates from OH-PCBs could be another mechanism through which PCBs may disrupt thyroid homeostasis.

Weiss et al 2015 compiled a database of 250 compounds and mixtures (including 33 never tested before), of which 144 were TTR binders and 36% (n=52) of these were found to be more potent than the natural ligand T4. The vast majority of these 52 (n=48) were aromatic, halogenated and hydroxylated. A subset of 220 compounds was further analyzed via PCA and a set of chemical descriptors to understand the chemical characteristics of TTR binders and four significant components were found to explain 85% of the variance.

Zhang et al 2015 developed a QSAR model and applied to a database of almost 500 dust contaminants taken from literature data and over 400 in silico derived metabolites, predicting 37 contaminants and 230 metabolites as potential TTR binders.  Twenty-three (23) contaminants were than analyzed via radioligand binding assay which identified four novel TTR ligands that were then analyzed via molecular docking studies. 


How It Is Measured or Detected

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Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

In humans, approximately 0.03% of total serum T4 is present in unbound/free condition (Refetoff et al 1970). Of the bound T4, approximately 75% is bound to TBG, approximately 20% to TTR and the remainder to ALB and some high density lipoprotein carriers. ALB is present at roughly 100-fold the molar concentration of TTR and roughly 2,000-fold higher than TBG; however, the affinity of T4 to TBG is 50-fold higher than TTR and 7,000-fold higher than ALB (Refetoff 2015). TTR binds roughly 80% of the T4 circulating in ventricular CSF although it constitutes only 25% of protein found there (Herbert et al 1986). In serum, only about 0.5% of circulating TTR is bound to T4, average serum concentration is 25 mg/dL (which can bind up to 300 ug T4/dL (Refetoff 2015).

TTR can be measured by densitometry after its separation from other serum proteins via electrophoresis, hormone saturation and/or immunoassays (Refetoff 2015).

Total T4 is most often measured using human serum based diagnostic kits, but free T4 (and T3) is only directly measured through equilibrium dialysis and ultrafiltration (Midgley 2001). Large volumes of serum must be used due to the very low concentrations of free T4 normally found (0.1% of total T4), which requires pooling of samples taken from fetus or pup. Some researchers have tried to “micronize” this process through combining RIA to measure total TH and dialysis to estimate the free fraction (Zoeller et al 2007).  Extracted materials can also be quantified by HPLC. The reference range for free T4 is 9.8 to 18.8 pM/L (Dirinck et al 2016).

T3 is found in similar plasma concentrations to T4 (i.e. 5-10 pM) with < 0.4% being in the unbound state. Measuring free serum T3 is labor intensive and requires equipment not available in many clinical reference laboratories and thus ultrafiltration is often used (Abdalla and Bianco 2014). Immunoassays and MS/MS are also used.

Measuring displacement of T4 from serum transport proteins is done mainly via one of three in vitro methods: radioligand binding assay, plasmon resonance-based biosensor, or fluorescence displacement.

Radioligand binding assays, using [125I]-T4 as a label, were developed to demonstrate affinity for xenobiotics to human or rat TTR and TBG (Brouwer and van den Berg 1986, Lans et al 1994).  The most commonly used method was first published by Somack et al 1982 and adapted by Hamers et al 2006, Lans et al 1993 and Ucan-Marin et al 2010. Similar assays have been developed using [125I]-T3 as a label for affinity to chicken and bullfrog TTR (Yamauchi et al 2003).  Radioligand methods suffer from having to use heavily regulated isotopes and lower throughput to provide free T4 measurements (due to the extra wash/separation procedure needed). The most well-known protocol uses TTR purified from human serum (which may not be as stable as recombinant) and performed in a pure aqueous solution, which may not be as stable for lipophilic compounds (Chauhan et al 2000 is an example using PCBs).

Purkey et al 2001 published a binding assay using polyclonal TTR antibodies covalently bound to sepharose resin which is then mixed with plasma pre-treated with compound of interest, washed and analyzed via HPLC.

Marchesini et al 2006 reported on the development of two surface plasmon resonance(SPR)-based biosensor assays using recombinant TTR and TBG, validated with known thyroid disruptors and structurally related compounds including halogenated phenols, polychlorinated biphenyls, bisphenols and a hydroxylated PCB metabolite (4-OH-CB 14).  TH is covalently bound to a gold-layered chip and a mixture of the compound of interest and transport protein are injected in a flow cell passing over the bound TH.  The authors found that these biosensor methods were more sensitive (IC50 of 8.6 ± 0.7 nM for rTTR), easier to perform and more rapid that radioligand binding assays and immunoprecipitation-HPLC.

Marchesini et al 2008 applied their biosensor-based screen to 62 chemicals of public health concern and found that hydroxylated metabolites of PCBs (particularly para-hydroxylated ones) and PBDEs (BDEs 47, 49 and 99) displayed the most potent binding to TBG and TTR, confirming many other previous studies.  The authors conclude their optimized assays are suitable for high-throughput screening for potential thyroid disruption.

Cao et al 2010, Cao et al 2011 and Ren and Guo 2012 developed the FLU-TTR, based on a protein-binding fluorescent probe (ANSA, or 8-anilo-1-naphthalenesulfonic acid ammonium salt) that becomes highly fluorescent after binding to T4. When the compound of interest is introduced and displaces the ANSA-thyroxine probe, this fluorescence is reduced.  This allows generation of binding constant (K) data as opposed to past efforts that generated IC50 values.  Cao et al 2011 developed a fluorescent microtiter method for pTTR and TBG tested with bisphenol A.

Montano et al 2012 developed a competitive T4-TTR fluorescence displacement assay in a 96-well format, modified from the original method (Nilsson and Petersen 1975) and using a new selective method to extract hydroxylated metabolites while reducing fatty acid interference (modified from Hovander et al 2000).

Aqai et al 2012 described a rapid and isotope-free (13C6-T4) screening of thyroid transport protein ligands, using a competitive binding assay for rTTR using fast ultrahigh performance LC-electrospray ionization triple-quadrupole MS. The method involves the use of immunomagnetic beads followed by screening with flow cytometry and UPLC-MS. The high-throughput screening mode is capable of detecting T4 in water at the part-per-trillion level and in the part-per-billion level in urine.

Relevant Phase II enzymes that are responsible for TH metabolism include UGT1A1, UGT1A6 and SULT2A1 while relevant cellular import/export transport proteins include MCT8, OATP1A4 and MRP2. All contribute towards systemic clearance of TH and conjugates from serum whether increasing biliary excretion or moving TH into tissues and across the placenta and BBB.  Enzyme induction can only be measured via in vitro cell-based assays and since these enzymes are all controlled by specific nuclear receptors, assays targeting these receptors might act as surrogate measurement (Murk et al 2013). Several methods measuring expression of UGT or SULT mRNA have been published; however, there have been limited efforts to develop higher-throughput methods.  The EPA ToxCast Phase I efforts used quantitative nuclease protection assays (qNPA) to screen several hundred chemicals for UGT1A1 and SULT2A1 (Rotroff et al 2010, Sinz et al 2006).

 


Domain of Applicability

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Evidence for Perturbation by Stressor



References

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