API

Event: 959

Key Event Title

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Increased, Free serum thyroxine (T4)

Short name

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Increased, Free serum thyroxine (T4)

Biological Context

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Level of Biological Organization
Tissue


Organ term

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Organ term
blood


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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Following displacement of T4 from its binding site on TTR by some competitive ligand (like EMD 21388, etc.), the T4 joins the small pool of free hormone found in serum. This increases the amount of free T4 and has been demonstrated in animal models following administration of a xenobiotic competitive ligand.

Kohrle et al (1989) administered 2 umol of EMD 21388 per 100g BW in a single ip injection to euthyroid adult male Sprague-Dawley rats. Rat serum was analyzed for T3 and T4 content via species-adapted RIA and percent free TH was determined via equilibrium dialysis. Serum T4 decreased significantly following 1 hr or administration and remained low for several hours, while % free T4 increased significantly at 1 hr and remained elevated. {insert Figure 5} Previously, both in vitro and in vivo electrophoretic data showed complete inhibition of radiolabeled T4 binding to TTR. Administration of EMD 21388 to rats did not impact T3 concentrations or deiodinase activity.

Lueprasitsakul et al (1990) also administered EMD 21388 to euthyroid adult male Sprague-Dawley rats as a single 2 umol ip injection with additional time points as well as a single injection of 0.3 umol. In addition, one treatment group were exposed to varying doses from 0.2 to 2 umol EDM21388 per 100 g BW. Significant decreases in radiolabeled T4 bound to TTR were found within 3 minutes, reaching a maximum at 10 minutes. A simultaneous increase in % free T4 was noted at 3 minutes and reached a maximum at 10 minutes. {insert Figure 3} These effects were observed for both the high dose of 2 umol and the low dose of 0.3 umol; however, it was noted that % T4 bound to TTR recovered to almost control levels after 3 hours at the low dose. The authors concluded that EMD 21388 administration increased both the free T4 concentration as well as the albumin-bound T4 (which is available in serum and can play a greater role in transport when needed).

Mendel et al (1992) performed additional kinetic studies with radiolabeled T4 and albumin using Sprague-Dawley rats receiving a single ip injection of 2 umol EMD 21388. To overcome the dilution effect found with equilibrium dialysis, ultrafiltration of undiluted serum was employed to measure the % free T4. The % free T4 increased significantly at 20 minutes and the compensatory response of albumin appears to have been saturated after 20 minutes, as shown by the plasma disappearance curve for radiolabeled albumin. {insert Figures 2 and 3} The authors concluded that these data did not confirm TTR is a major carrier of T4 from plasma to liver and other tissues; however, these data also did not distinguish between whether transfer in vivo could be via albumin or from the free pool of T4 in serum.

Chanoine et al (1992) administered low (0.3 umol) and high dose (2 umol) EMD 21388 to Sprague-Dawley rats via single ip injection and a second treatment group had radiolabeled T4 injected 15 minutes following the EMD 21388 adminisatration. Both doses produced a similar significant increase to free T4 in serum within 15 minuteas of administration. {insert Figure 1} Binding of T4 to albumin in serum increased an order of magnitude in both high and low dose treatments. The low dose had no effect on the %T4 bound to TTR in the choroid plexus or the cerebrospinal fluid; however, the high dose did significantly decrease this. {insert Figure 2}

Pedraza et al (1996)


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?

Total T4 is most often measured using a serum-based diagnostic kit; however, free T4 is considered a more reliable measure of thyroid dysfunction and the only direct measurements for unbound thyroid hormone are equilibrium dialysis and ultrafiltration (Zoeller et al 2007). Large volumes of serum must be used to capture the very low concentrations of free THs and this requires pooling in non-adult animals.

 

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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Data in humans focusing on the thyroid disruption potential of hydroxylated PCBs and PBDEs is scarce, the data are conflicting and suffer from differing analytical and reporting methods. 

Hagmar et al 2001a and 2001b examined 4-OH-CB107 and 4-OH-CB187 in adult females and male fishermen from the Baltic Sea and found no associations. Similarly, Bloom et al 2009 found no associations between PFOS and TH in a small study of New York anglers.

Athanasiadou et al 2008 assessed PBDEs in pooled serum samples from 11-15 year old children living near an urban municipal waste site as well as mothers who consume fish from a rural location in Nicaragua.  BDE-47 was the most abundant congener found in samples, followed by BDEs 99, 100 and 153. This study was the first to confirm that hydroxylated metabolites (OH-PBDEs) accumulate in human serum, identifying 19 OH-PBDEs – at least six (6) of which were also found and retained in rat serum following exposure to an artificial PBDE mixture (Malmberg et al 2005).  The dominant congeners were 4-OH-BDE17 and 4’-OH-BDE-49.  These data support the concept that residential exposure to PBDEs is strongly influenced by inhalation and ingestion of house dust rather than consumption of contaminated food.

Dalliare et al 2009 looked at the relationship between TH status and exposure to PCB-153, pentachlorophenol, hexachlorobenzene and hydroxylated PCBs in pregnant Inuit women and their infants. PCB-153 was the most predominant congener found to be elevated most in pregnant women, followed by infant and cord plasma levels.  OH-PCB results were a sum of 11 major congeners and found to be higher in pregnant women than cord blood, but highly intercorrelated.  Overall, the results suggest that the compounds measured in serum were not significant predictors of TH or TSH concentrations in this population.  The strongest results were found for PCP, which was negatively associated with free T4 in neonate cord blood, suggesting PCP reduces the transfer of T4 across the placenta.

Dallaire et al 2009b examined the relationship between TH status and TBG and exposure to 41 different contaminants, including PCBs and metabolites, PBDEs, PFOS, organochlorine pesticides and dioxin-like compounds, in over 500 Inuit adults. Negative associations were reported between rT3 and 14 PCBs, 7 hydroxylated metabolites, methylsulfonyl metabolites and 2 pesticides.  Negative associations were also reported between free T4 and hexachorobenzene as TBG concentrations were inversely related to 8 PCBs, 5 hydroxylated metabolites and three pesticides. This was the first large study to examine the effect of PFOS on TH homeostasis in exposed human adults, observing a significant negative associations with TSH, total T3 and TBG while observing a positive association with free T4.

Chevrier et al 2010 measured concentrations of 10 PBDE congeners and TH in 270 pregnant Californian (CHAMACOS cohort) women during the 27th week of gestation. This study reported significant inverse associations between TSH and serum concentrations of BDEs 28, 47, 99, 100 and 153 but did not observe an association between PBDEs and free T4.

Eskenazi et al 2013 measured PBDEs in maternal prenatal and child serum samples and examined the association between blood concentration and attention, motor functioning and cognition at ages 5 and 7 in an ongoing large California cohort (CHAMACOS).  They observed weak correlations between cognition, motor function and attention and PBDE concentration in maternal prenatal and child blood at age 7 and the authors claim it largely supporting previous findings in smaller cohorts exposed to both PDBEs and PCBs.

Eguchi et al 2015 measured PCBS, OH-PCBs, PBDEs, methoxylated PBDEs, OH-PBDEs and bromophenols and TH in the serum of Vietnamese cohort composed of human donors from an e-waste recycling site and a rural site.  In general, PCBs, OH-PCBs, PBDEs and bromophenols were higher in sera from the recycling site; however, the concentrations of methoxylated PBDEs were higher at the rural site.  Positive associations between PCBs and OH-PCBs concentrations and total and free T4 and T3, as well as a negative association with TSH, among females.

Dirinck et al 2016 examined the relationship between PCBs (n=29) and serum hydroxylated PCBs (n=18) and clinically available markers of thyroid function (TSH, free T4) in 180 subjects recruited upon visitation to the Antwerp University Hospital Department of Endocrinology from 2009 to 2012. The combined regression model for both PCBs and hydroxylates identified PCBs 95 and 99 and 3-OH-CB180 as significant predictors of free T4 , while the model run for just serum hydroxylate identified 3-OH-CB118 and 3-OH-CB180 as major predictors of free T4.  The former is a product of metabolizing PCBs 107, 118 and 126 while the latter comes from PCBs 172 and 180.


References

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