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Key Event Title
Increased, Clearance of thyroxine from serum
Key Event Components
Key Event Overview
AOPs Including This Key Event
Key Event Description
Thyroxin (T4) and T3 are metabolized and cleared from tissues in a number of ways: inner ring or outer ring deiodination via specific enzymes, conjugation (glucuronidation or sulfation), oxidative deamination and ether-linked cleavage (Zoeller et al 2007).
There are three types of deiodinase enzymes. D1 and D2 convert T4 to T3 by removing an iodine atom from the outer ring while D3 removes an iodine atom from the inner ring, converting T4 to reverse T3. Differential expression of these enzymes during brain development are critical to the functionality of thyroid hormone in different areas of the fetal brain.
Much of the T4 is carried to the liver, where it is transported across the cellular membrane, converted into T3 via deiodination as mediated by deiodinase enzymes, and it is this T3 that triggers the TH receptors found in the nucleus. Roughly 80% of the T3 needed is produced via outer-ring deiodination of T4, which "activates" T4 to T3 (as opposed to inner-ring deiodination, which "degrades" T4 to reverse T3 which is eliminated). About 30% of the T4 produced daily (~ 130 nmol) is converted to roughly 40 nmol of T3 (Visser 2012) via enzyme D1 (liver, kidney) while conversion to rT3 accounts for roughly 40% of T4 turnover and is mediated via enzyme D3 (brain, placenta, fetus).
Glucuronidation and sulfation of T4 accounts for the rest of the metabolized T4 and leads to rapid elimination through bile. It is thought that 20% of daily T4 production is eliminated through biliary excretion of glucuronide conjugates. Glucuronidation is carried out by UDP-glucuronoyltransferase (UGT) enzymes (Hood and Klaassen 2000a, 2000b) and appears to be more important in murine species than in man (Henneman and Visser 1997) and sulfation of T4 is done largely through an initial inner ring deiodination step (via D3). Circulating levels of THs in serum can be affected by compounds that induce the activity of UDP-UGT enzymes.
Uptake into the liver involves "high affinity, low capacity" and "low affinity, high capacity" processes with Km values in the nano- to micro-molar range (as opposed to the free T3 and T4 concentrations, which are in the picomolar range) (Henneman et al 2001 from Visser 2010). Both MCT8 and MCT 10 can transport THs; however, MCT8 is expressed in human liver where MCT10 is not and MCT8 display higher efficacy of cellular uptake and efflux relative to T3 (Ref 12 in Visser 2010).
Data in animals for PCBs
Previous reports have been made showing serum TH decreases in rats and mice in response to PCBs, PCB congeners and TCDD and these decreases have been thought to be driven by UDP-UGT (particularly 1A1 and 1A6)(Barter and Klaassen 1994, Schuur et al 1997, Van Birgelen et al 1995, Visser 1996)
Hallgren et al 2001, Hallgren and Darnerud 2002 showed that both T4 and T3 are significantly decreased following exposure to PCB mixtures or individual congeners.
Kato et al 2003 (and Kato et al 2002) showed for the first time that a commercial PCB mixture (Kanechlor-500, KC500) decreased serum TH without an increase in glucuronidation of T4. Male Wistar rats and ddy mice were given a single ip injection of 100 mg/kg and 4 days later, organ weights were measured and microsomal enzymes measured. Significant increases were noted for both endpoints in both species; however, treatment with PCBs led to significant increases in UDP-UGT activity in rats but not mice. Gene expression of UDP-UGTs was also examined and, again, rats (but not mice) displayed time-dependent increases in levels of UGT1A1 and UGT1A6 following treatment with PCBs. This agrees with past reports showing that clofibrate, phenobarbital, pregnenolone-16-alpha-carbonitrile and beta-naphthoflavone decrease serum TH and increase hepatic UDP-UGT activity in rats but not mice (Viollon-Abadie et al 1999).
This implies that mice may reduce serum TH through a mechanism that does not involve increased glucuronidation, but may involve a TTR-associated pathway (as hydroxylated metabolites of PCBs have been displayed high affinity for TTR in in vitro studies). Kanechlor-500 does not display any appreciable amount of outer ring deiodination activity (which would convert serum T4 to T3) and treatment with the mixture did not significantly change TSH levels (indicating there is no induction of the thyroid feedback loop from the measured decreases in serum TH).
Kato et al 2004 performed the same experiment next with Wistar and Gunn rats, the latter species being a Wistar mutant strain that lacks UGT1A isoforms. Both species showed serum T4 (free and total) decrease after single injection of either KC500 or pentaCB and only Wistar rats showed an associated increase in UDP-UGT activity. Significant decrease in type I deiodinase was observed in both rats in addition to detection of hydroxylated PCB metabolites bound to TTR. Gunn rats treated with clofibrate also showed decreased serum T4 without an increase in UDP-UGT activity (Visser et al 1993). These results imply that decreases of serum TH by PCB or pentaCB were managed by formation of OH-PCB metabolites that were then transported by TTR. This is supported by the fact that the main metabolite found in KC500-treated rats was 4-OH-2,3,3’,4’,5-pentachlorobiphenyl, which displays a binding affinity towards TTR that exceeds that of T4 by more than 3-fold (Meerts et al 2002). In fact, the dihydrohxylated PCBs show several fold higher affinity than the monohydroxylated PCBs (Lans et al 1993). It should be noted that an increase in sulfation via SULT enzymes may also offer an esxplanation for the observed results.
Kato et al 2007 treated Wistar and Gunn rats with KC500 at a lower dose (10 mg/kg) once daily for 10 days, noting decrease in total and free serum T4 as well as the differential UDP-UGT response across the different strains. Clearance of [125I]T4 from serum was higher in both species treated with KC500 and accumulation in several tissues, particularly the liver, was observed. These data imply that reduction of serum TH from exposure to KC500 would be mediated through accumulation in the tissues and not through an increase in glucuronidation. In addition, competitive inhibition by PCB or its metabolites with serum transport proteins (like TTR) could also decrease serum T4 by inducing a change in tissue distribution, especially the liver where more than 40% of[125I]T4 accumulated following treatment.
Kato et al 2009 treated C57BL/6 and DBA/2 mice with the heptaCB metabolite 4-OH-CB187, decreasing free and total serum T4 with no observed UDP-UGT activity or effect on TSH. A number of OH-PCBs have been identified in human serum, including 4-OH-CB107, 3-OH-CB153, 4-OH-CB146, 3’-OH-CB138 and 4-OH-CB187 (which specifically has a 5-fold higher affinity for TTR relative to T4)(Hovander et al 2002). Levels of [125I]T4-TTR were decreased with accompanying increases in binding to TBG and albumin in both strains of mice. Finally, T4 levels increased in tissues, particularly the liver and kidney. Decreases in total and free serum T4 mediated by 4-OH-CB187 were observed in wild-type and TTR-heterozygous mice but not in TTR-deficient mice, with heterozygous mice displaying a smaller decrease in T4 relative to TTR-deficient mice. In both strains of mice, treatment with 4-OH-CB187 promoted clearance of [125I]T4 from serum relative to controls and serum pharmacokinetic data were estimated, along with tissue-to-serum (Kp value) concentration ratios and [125I]T4 tissue distribution levels. These data imply that 4-OH-CB187 inhibits formation of the [125I]T4-TTR complex, which may lead to a change in tissue distribution, with accumulation in the liver and kidney mainly.
Kato et al 2012 treated C57BL/6 (wild type) and TTR-null mice with single ip injections of pentaCB at 112 mg/kg, noting significant decreases in total serum T4 and T4-TTR complex and measuring [125I]T4 clearance from serum and accumulation in tissues. Treatment with pentaCB resulted in decrease of [125I]T4-TTR and increase in [125I]T4-albumin and [125I]T4-TBG complexes in wild type mice, but not in TTR-deficient mice, although liver accumulation was noted in both strains independent of UDP-UGT activity. These data imply that penta-CB mediated increases in T4 liver concentration occurs mainly through inhibition of efflux of T4 and/or promotion on influx of T4 into hepatic cells (which is a receptor mediated process independent of TTR transport at the liver).
Kato et al 2013 treated C57BL/6 and DBA/2 mice with 50 mg/kg CB118 (pentaCB) in a single ip injection for 5 days, noting decreased serum T4 in both strains and decrease in TSH for the DBA/2 mice but not C57BL/6. CB118-mediated changes in [125I]T4 complexes with TBG, albumin and TTR were only observed in C57BL/6 mice (and not DBA/2), despite [125I]T4 accumulation in the liver of both strains. It is thought that the strain differences are dependent on differences in induction of CYP1A enzymes responsible for the hydroxylation of PCBs (creating metabolites that display far greater affinity for TTR than the natural T4 ligand).
Martin and Klaassen 2010 treated male Sprague Dawley rats with Aroclors 1242 and 1254; PCBs 95, 99, 118, 126 or TCDD at 4 doses via gavage daily for 7 days, then measured serum TH via radioimmunoassay and induction of hepatic Cyp1a and Cyp2b. This study was the first to examine all three classes of PCB congeners: TCDD-type (no chlorine substitutions in ortho position, high affinity for arylhydrocarbon receptor, induce Cyp1a, PCBs 77 and 126), PB-type (at least 2 ortho substitutions, low affinity for AhR, induce Cyp2b, PCBs 28, 95, 99, 101 and 153) or mixed type (1 ortho substitution, low affinity for AhR, induce both Cyp1a and Cyp2b, Aroclors and PCB 118). This study showed that PB-type and mixed type PCB congeners are more effective than TCDD type in reducing serum T4, with Aroclor 1254 (mixed) and PCBs 99 (PB) and 118 (mixed) producing the greatest reduction in serum T4 (as well as T3). Serum TSH was not affected by any compound. Total and free serum T4 was decreased by all treatments in a dose-dependent manner; however marked reduction were noted following treatment with Aroclor 1254, PCB 99 and PCB 118. PCB 118 and 126 caused significant increase in Cyp1a activity while Aroclor 1254 and PCBs 99 and 118 significantly induced Cyp2b. Thus, it appears TCDD type congeners induce CYP1A2 (EROD) activity and UGT-UDP activity in the liver (associated wth binding at AhR) while PB type congeners induce CYP1B2 (PROD) activity and do not induce UGT-UDPs in the liver (associated with increased tissue uptake).
The PB type congeners may induce Oatp1a4 activity to increase clearance from plasma and enhance tissue uptake. Guo et al 2002 reported increase of Oatp1a4 following treatment with PCB 99 (and a decrease following treatment with PCB 126, a TCDD type congener). There are also reports of PB type congeners that accumulate in the liver with little to no increase in glucuronidation or biliary excretion and no changes in serum binding proteins, such as PCB 153, which implies a possible induction of OATP hepatic cellular transport proteins (Kato et al 2011).
Martin et al 2012 treated male Wistar rats with Aroclors 1242 and 1254, PCBs 95, 99, 118 and 126 and TCDD via gavage one per day for 7 days, followed 24 hours later with injection of [125I]T4 and collection of urine, blood, bile and urine. No treatments increased urinary excretion of [125I]T4, but serum T4 was reduced in all treatments and biliary excretion increased following treatment of Aroclor 1254, PCBs 118 and 126, and TCDD as measured by induction of UDP-UGT activity in the liver. PCBs 95 and 99 (PB type congeners) did not induce UGT-UDP activity despite very large and rapid decrease of serum [125I]T4 by PCB 99. These data imply that increased tissue uptake (perhaps through increased TH transport across cell membranes) is another mechanism by which serum T4 can be reduced.
Kato et al 2013 showed that PCB 118 (mixed type) mediated changes in tissue distribution and transport proteins in C57BL/6 mice, but not DBA/2 mice. Kato et al 2012 showed the same with synthesized 2,2’,4,5,5’-pentaCB (PCB 101, PB type). Kato et al 2014 showed that PCB 77 (TCDD type) mediated changes in tissue distribution and transport proteins in DBA/2 mice, but not C57BL/6 mice.
Erratico et al 2012 used pooled and single-donor human liver microsomes, human recombinant cytochrome P450 (CYP) enzymes and CYP-specific antibodies to evaluate the oxidative metabolism of BDE-99. Ten (10) hydroxylated metabolites were produced by human microsomes and identified via HPLC-MS/MS and rates of formation were determined, including several that are much more potent than the natural ligand. All ten were found to be catalyzed solely by CYP2B6. Previous studies had also shown formation of hydroxylated metabolites of BDE-99 by human hepatic preparations (Lupton et al 2009, 2010; Stapleton et al 2009); however, fewer OH-PBDEs and additional CYP enzymes were found in similar work done with rat microsomes (Erratico et al 2011).
Feo et al 2013 incubated BDE-47 and recombinant CYPs, measuring the metabolites via GC-MS/MS, as well as specific kinetic studies with BDE-47, CYP2B6 and pooled human liver microsomes. Six (6) OH-PBDEs were found to be catalyzed by CYP2B6 and additional metabolites were identified upon GC-MS/MS (including the novel finding of dihydroxylated metabolites) and these metabolites have been previously found in human serum (Athanasiadou et al 2008; Qui et al 2009). The kinetic studies showed that hydroxylation can occur at low concentrations and that CYPT2B6 has high affinity for BDE-47. CYP2C19 and CYP3A4 were also suggested to play minor roles in the formation of OH-PBDEs.
How It Is Measured or Detected
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?
Thyroid hormone uptake into human tissues has been measured by analyzing the rate of disappearance of radiolabeled TH from plasma into rapidly and slowly equilibrating tissue compartments (Visser 2010).
Measuring the rate of T4 glucuronidation and sulfation as well as biliary excretion informs the mechanism of action of thyroid system modulation. Studies involving knock/out mice and thyroidectomized rats also inform this mechanism.
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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