Key Event Title
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Key Event Components
Key Event Overview
AOPs Including This Key Event
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Key Event Description
T4 (and T3) is actively transported across the cell membrane into target tissues through the action of specific carrier-mediated uptake (simple diffusion probably plays a minor role), where it is T3 that binds to and triggers the nuclear receptors in the target cells (Yen 2001, Zoeller et al 2007). The T3 supply is met via secretion from the thyroid (20%) and through conversion of T4 into T3 (80%) through the action of outer-ring deiodinase enzymes D1 and D3 (Chopra 1996 from Zoeller et al 2007). THs are cleared from serum by the liver following sulfation (via sulfotransferase enzymes) or glucuronidation (via UDP-glucuronosyl transferase enzymes) and ultimately, eliminated in the bile (Hood and Klaasen 2000).
Two major groups of transporters have been identified: organic anionic transport proteins (OATPs) and amino acid transporters (L- and T-type). Several of these transporters have displayed greater affinity and selectivity for T4 and T3 and specific compounds (such as polychlorinated biphenyls and polybrominated diethyl ethers) have been found to bind to the transport proteins either in serum or in various cellular compartments (Zoeller et al 2007)
OATPs transport both iodothyronines as well as sulfated conjugates and the gene family (SLCO) coding for this family of homologous proteins is clustered on human 12p12 (Hagenbuch and Meier 2004). OATP1A2 is expressed in brain, liver and kidney while OATP1B1, -1B2, and -1B3 are expressed in the liver and display high affinity for both T4 and T3 (Friesma et al 2005). OATP1C1 shows binding preference for T4 over T3 and is almost exclusively expressed in brain capillaries, where it is thought to play a role for transport of T4 across the blood brain barrier (Tohyama et al 2004).
There is also evidence that L-type or T-type amino acid transport proteins also play a role in cellular uptake of thyroid hormones. The former transport large neutral branched-chain and aromatic amino acids while the latter are specific to the aromatic amino acids Phe, Tyr and Trp (Visser 2010). The T-type amino acid transport protein TAT1 has been cloned from both rats and humans, is encoded by SLC16A10, and is a member of the monocarboxylate transporter (MCT) family (MCT10)(Kim et al 2002). Both MCT and MCT8 share a high degree of homology and are both highly effective iodothyronine transporters. MCT8 is highly selective for T4 and T, responsible for transporting T3 into neuronal cells and interferes with brain development if absent (Friesma et al 2003, 2006 and 2008). MCT8 is expressed in multiple tissues, including liver, kidney, heart, brain, placenta, thyroid, skeletal muscle and adrenal gland, while MCT10 is also expressed in various tissues, with high expression in muscle, intestine, kidney and pancreas and the former is known to only transport iodothyronine molecules while the latter can also carry aromatic amino acids (Nishimura et al 2008). In terms of transport efficacy, MCT10 appears to be superior to MCT8 for moving T3; however, the reverse is true for T4.
Uptake into hepatocytes is probably mediated through multiple low-affinity/high-capacity and high-affinity/low-capacity processes that can be inhibited by certain molecules, such as fatty acids, bilirubin and indoxyl sulfate (Henneman et al 2001). Km values for these processes are in the micro- to nanomolar range, while the serum concentrations of free T4 and T3 are in the picomolar range.
Accumulation in tissue as well as transport across the placental and blood-brain barrier is dependent on expression level of the various TH membrane transporters, such as those in the MCT and OATP families. MCT8, MCT10, L-type amino acid transporters LAT1 and LAT2, OATP1A2 and OATP4A1 are responsible for transplacental transfer of TH (Loubiere et al 2010), while MCT8 and OATP1C1 are important to transfer across the blood-brain barrier (Roberts et al 2008).
OATP1B1 and OATP1B3 show preference for sulfated THs and are expressed only in the liver
OATP1C1 shows high preference for T4 and almost exclusively expressed in brain capillaries and choroid plexus (Hagenbuch 2007)
LAT1 and LAT2 facilitate bidirectional transport of both T4 and T3 (and aliphatic and aromatic amino acids) across the plasma membrane
MCT8 only transports THs and expressed in choroid plexus, MCT10 also transports aromatic amino acids
Schroder van der Elst et al 1997 injected female rats with synthetic flavonoid [125I]-EMD 49209 and [131I]-T4 (or rats pretreated with EMD 21388), noting rapid clearance of [125I] from serum and rapid uptake of [131I] into tissues. These results show that the flavonoid itself does not cross the blood-brain barrier, despite the fact that they demonstrate displacement of T4 from TTR and temporarily increase the pool of available free T4.
Schroder van der Elst et al 1998 injected pregnant rats at GD 20 with [125I]-EMD 49209 and observed distribution in maternal tissues, intestinal contents and fetal tissues. No flavonoid was detected in the brain but it was found in all fetal tissues examined, including brain.
TRANSPORT ACROSS THE BLOOD-BRAIN BARRIER
Active transport is required for uptake of T3 and T4 across cell membranes (Heuer 2007). Accumulation in tissue as well as transport across the placental and blood-brain barrier (BBB) is dependent on expression level of the various TH membrane transporters, such as those in the MCT and OATP families. MCT8, MCT10, L-type amino acid transporters LAT1 and LAT2, OATP1A2 and OATP4A1 are responsible for transplacental transfer of TH (Loubiere et al 2010), while MCT8 and OATP1C1 are important to transfer across the blood-brain barrier (Roberts et al 2008). Visser et al 2008 proposed that OATP14 is mainly responsible for moving T4 into the brain/CSF, where it is converted into T3 locally and transported into neurons via MCT8.
Schreiber et al 1995; Schreiber 2002
Roberts et al 2008 examined the expression of MCT8 and OATP14 in male Sprague Dawley rats, male CD-1 mice and human brain tissue via qPCR and immunofluorescent staining as well staining and confocal microscopy in isolated cerebral microvessels and choroid plexus (CP) epithelium. They observed that the main transporter at the BBB is OATP14 whereas MCT8 mediates TH uptake into neuronal cells. MCT8 mRNA and proteins were expressed in cerebral microvessels in all species; however, OATP14 mRNA and protein was only enriched in mouse and rat microvessels. In all species, MCT8 is concentrated on the epithelial cell apical surface and OATP14 primarily on the basal-lateral surface of the CP epithelial cells. These data suggested MCT8 plays a role in TH transport across the BBB and this is supported by the pattern of localization of the two transporters.
Kim et al 2015 screened protein transporters in rat serum for the potential to guide nanoparticles across the BBB (via receptor-mediated transcytosis, or RMT) using an in vitro transcytosis assay using rat and human brain microvascular endothelial cells. Eleven (11) proteins were identified as showing potential to penetrate the endothelial cell layer via RMT, including Ttr. Ttr was then incorporated into a quantum dot nanoparticle, administered to male Sprague-Dawley rats via IV and found to cross the BBB in rats via transcytosis, confirmed by in vivo imaging, TEM, ICP-MS and confocal microscopy.
TRANSPORT ACROSS PLACENTA
There is a direct role for maternal TH in the development of the fetal CNS starting with the 1st trimester and this maternal TH must be provided to the fetus via transplacental delivery (Chan et al 2002; de Escobar et al 2004). The placenta responds to TH with both the villous and extravillous trophoblasts (EVTs) expressing specific nuclear receptor isoforms for T3. The primary barrier of cells for maternal-fetal exchange are the syncytiotrophoblasts of placental villi, which are in direct contact with maternal blood, and the cytotrophoblasts, which form an additional inner layer of cells (Benirschke et al 2000). Free T4 is the believed to be the primary TH transported across the placenta and fetal free T4 levels reach ~ 40-50% of maternal concentrations by the early 2nd trimester and peak in the early 3rd trimester, where they remain at levels higher than the corresponding maternal concentration (Calvo et al 2002; Hume et al 2004).
Accumulation in tissue as well as transport across the placental and blood-brain barrier is dependent on expression level of the various TH membrane transporters, such as those in the MCT and OATP families. MCT8, MCT10, L-type amino acid transporters LAT1 and LAT2, OATP1A2 and OATP4A1 are responsible for transplacental transfer of TH (Loubiere et al 2010), while MCT8 and OATP1C1 are important to transfer across the blood-brain barrier (Roberts et al 2008). The MCT8, OATP4A1 and LAT1 are localized at the apical membrane of the syncytiotrophoblasts while MCT10 is localized in the cytotrophoblasts during the 1st trimester (Ritchie and Taylor 2001; Sato et al 2003; Chan et al 2006; Loubiere et al 2010)
Displacement of T4 from transport proteins during the developmental stage could have consequences for both fetal development and later in adulthood (Morse et al 1996). Transfer of maternal TH across the placenta is essential to neurodevelopment and even temporary disruption during the perinatal period can have long-term adverse health effects (Zoeller and Rovet 2004). Animal studies have confirmed that perinatal exposure to PBDEs can adversely affect neurodevelopment of CNS; however, the mechanisms remain elusive and the evidence in humans that hydroxylated metabolites of PBDEs is equivocal (Costa et al 2014).
TTR mediates transport through the placenta and the hydroxylated metabolites of PCBs and PBDEs have been found to more potent than the natural ligand T4 and thus, competitive binders. The presence of these compounds in maternal and infant blood have been associated with changes in TH, developmental endpoints and fertility in humans (Chevrier et al 2010, Harley et al 2010, Koopman-Esseboom et al 1994). Several studies have demonstrated links between decreased T4 levels and neurodevelopmental and neurobehavioral adverse outcomes in mice exposed specifically to BDE-99 (Branchi et al 2002; Viberg et al 2002).
Darnerud et al 1996 treated pregnant C57BL and NMRI mice on GD 13 with a single gavage at two doses of [14C]-labelled 3,3’,4,4’-tetraCB (PCB 77) and experiment was terminated after 4 days, measuring radioactivity and TH in maternal and fetal liver and plasma. Competitive binding assay was also done with [125I]-T4 complex from samples of fetal and maternal plasma. Dose-dependent uptake of [14C] were noted in both maternal and fetal plasma and liver, with fetal plasma radioactivity levels being 4- to 9-fold higher than maternal levels and corresponded to a single metabolite (4-OH-tetraCB). Gel electrophoresis confirmed the [14C] was bound to fetal serum TTR and the fetal sera samples at the top dose (10 mg/kg) showed 50% TTR binding relative to controls, along with significant decrease in free and total serum T4.
Morse et al 1996 (also see Morse et al 1993) treated Wistar rats with Aroclor 1254 at 2 doses via daily oral exposure from GD 10 to 16, with blood and tissue (brain, liver) collected from dams and fetuses on GD 20 with pups reared until PND Day 21 (with blood and tissue collected at PND 4 and 21). The biological samples were analyzed for TH, type II deiodinase activity and levels of PCBs and metabolites. Maternal exposure to Aroclor 1254 significantly reduced both free and total T4 in the serum of fetus and neonate (Day 4) in a dose-dependent manner (but less pronounced at PND 21 and absent at Day 90). At GD 20, levels of T4 in fetal forebrain and cerebellum, and at PND 21 female weanlings at the high dose (25 mg/kg) still had significantly decreased forebrain T4. In the fetus, deiodination (T4 to T3) was significantly increased in forebrain and in the female weanling, only at the low dose was deiodination significantly decreased. Similarly, glucuronidation was significantly decreased in the fetus and significantly increased in the female weanling. Accumulation of mainly one metabolite (2,3,3’,4’,5-pentachloro-4-biphenylol, or 4-OH-pentaCB; possibly from PCB 118 or PCB 126) was noted in fetal serum and forebrain as well as neonatal and weanling plasma and the concentrations of the metabolite in plasma relative to the more persistent parent congeners (PCB 153) were increased all the way to 90 days (and the plasma levels of the offspring exceeded that of dam all the way to 90 days). These data show that maternal exposure to PCBs can result in accumulation of hydroxylated metabolites in fetal plasma that reduces T4 and, as a result, reduces brain levels of T4 with a compensatory increase in brain deiodination to maintain brain T3 concentration.
Pedraza et al 1996 treated pregnant Wistar rats first with methimazole (to block hormone synthesis) and then continuous infusion of EMD 21388 and T4 from GD 11 to 21, noting decreased total T4, increased free T4 and decreased T3 in maternal serum, increase of T3 in placenta and led to measurable amounts of parent compound in fetal serum along with decreased total T4 and increased T3.
Schroder van der Elst et al 1998 injected pregnant rats at GD 20 with [125I]-EMD 49209 and observed distribution in maternal tissues, intestinal contents and fetal tissues. No flavonoid was detected in the maternal brain but it was found in all fetal tissues examined, including brain. It should be noted though that TTR is the principal carrier in the fetal rat and the EMD flavonoids were designed as T4 analogs and only bind to TTR (and not to albumin or TBG). Shortly after birth, TTR production decreases to nearly zero and thus, interference with TTR-T4 during certain developmental windows might impact availability of thyroid hormone in certain tissues at critical time periods.
Sinjari and Darnerud (1998) injected C57BL mice on GD 16 with 5 doses of [14C]-labelled metabolites of PCB 77 (4-OH-tetraCB, two different 4-OH-pentaCB metabolites of PCB105), sacrificed 24 hours later, plasma and tissues collected from dam and fetus and analyzed for [14C], total T4 and liver microsomes. Partial dose dependency was found for both maternal and fetal decreased total T4 for 4-OH-tetraCB and one of the pentaCBs. Also, placental transfer to fetal plasma was dose dependent and, at lower doses (less than 5 mg/kg), fetal serum levels of 4-OH-tetraCB were 2-fold higher than maternal serum levels. The authors conclude that doses in excess of 5 mg/kg saturate ligand binding, as effects measured at concentrations higher than this are not dose-related (however, there was extensive biliary excretion of 4-OH-tetraCB at the highest doses (20 and 50 µmol/kg). These results suggest that hydroxylated metabolites of PCBs are transferred to fetus upon maternal exposure, but did not induce a CYP1A1 or CYP1A2 response in the dam and competitive binding with T4 may not be the only mechanism behind noted adverse fetal effects from T4 modulation.
Meerts et al 2002 treated pregnant rats with 5 mg/kg of 4-OH-CB107 (radiolabeled and non-labelled) on GD 10 to 16, noting accumulation in the fetal compartment. The complex between TTR and [14C]-4-OH-CB107 was detected in serum in both dam and fetus. Total and free serum T4 were reduced in fetus at GD 17 and 20. T4 concentration in fetal forebrain homogenate was reduced at GD20 and deiodination of T4 to T3 was increased at GD 17. No changes were noted in maternal or fetal hepatic UDP-UGT activity, type 1 deiodination, or EROD activity. These data show that TTR-mediated transport of xenobiotics, like the metabolites of PCB 107, can result in transfer from mother to fetus and can result in reduced fetal T4 (although it should be noted that fetal T3 remained unaffected). Furthermore, there was significant increase of fetal TSH at GD20, indicating stimulation of the HPT axis.
Inoue et al 2004 reported that PFOS can cross the placental barrier in humans
McKinnon et al 2005
Morse et al 2005 injected pregnant Wistar rats on GD 13 with single dose of [14C]-labelled 3,3’,4,4’-tetraCB (PCB 77) and tracked metabolism for 7 days. The main metabolite was 4-OH-CB77 was found in maternal liver and plasma, placental tissue and fetal plasma, with 4-OH-CB77 accumulating 100-fold in fetus over the observation period with levels in fetal plasma being 14-fold higher than maternal plasma on GD 20. Similarly, while maternal serum T4 was initially significantly reduced and recovered by GD 20, the fetal plasma T4 was found to be significantly reduced relative to maternal T4 on GD 20. These data show that exposure to PCBs during pregnancy can result on transfer of metabolites to fetus (and these are competitive with T4 at the TTR binding site).
Riu et al 2008 fed pregnant Wistar rats with [14C]-decabromodiphenyl ether (DBDE) over 96 hr of late gestation (GD 16 to 19) and tissues analyzed via HPLC. More than 19% of the administered dose was recovered, with 2/3 of this eliminated via feces, and results in accordance with past findings in Fisher and Sprague Dawley rats. Small amounts were found to cross both the blood-brain and placental barriers and hydroxylated octaBDE was found in all tissues and fetus.
Dalliare et al 2009a looked at the relationship between TH status TBG 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. This confirmed previous findings of Sandau et al 2002, but has conflicted with other study populations and published reports; however, has biological plausibility as PCP has been reported to have a binding affinity twice that of the natural ligand for TTR (van den Berg 1990).
Loubiere et al 2010 described the ontogeny of TH transporters MCT8, MCT10, LAT1, LAT2, OATP1A2 and OATP4A1 in over 100 placenta samples collected across gestation via RNA extraction and qRT-PCR. These mRNA data showed increasing expression of MCT8, MCT10, OATP1A2 and LAT1 throughout gestation, while OATP4A1 and CD98 (associated with LAT activity) mRNA fell to a nadir in the late 1st and early 2nd trimester. Immunohistochemistry data localized MCT10 and OATP1A2 for the first time to EVTs as well as syncytiotrophoblasts.
How It Is Measured or Detected
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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