50-06-6DDBREPKUVSBGFI-UHFFFAOYSA-NDDBREPKUVSBGFI-UHFFFAOYSA-N
Phenobarbital2,4,6(1H,3H,5H)-Pyrimidinetrione, 5-ethyl-5-phenyl-
5-Ethyl-5-phenyl-2,4,6(1H,3H,5H)-pyrimidinetrione
5-Ethyl-5-phenylbarbiturate
5-Ethyl-5-phenylbarbituric acid
5-Phenyl-5-ethylbarbituric acid
Agrypnal
Amylofene
Barbenyl
Barbiphenyl
Barbipil
Barbita
Barbituric acid, 5-ethyl-5-phenyl-
Barbivis
Blu-phen
Cratecil
Dormiral
Doscalun
Duneryl
Eskabarb
Etilfen
Euneryl
Fenemal
Fenemal recip
fenobarbital
Gardenal
Gardepanyl
Hysteps
Lepinal
Lepinaletten
Liquital
Lixophen
Lubergal
Luminal
Neurobarb
NSC 128143
NSC 9848
Phenaemal
Phenemal
Phenobar
Phenobarbitone
Phenobarbituric acid
Phenoluric
Phenonyl
Phenylethylbarbituric acid
Phenylethylmalonylurea
Phenyral
Sedonal
Sedophen
Sevenal
Solfoton
Somonal
Stental Extentabs
Talpheno
Teolaxin
Triphenatol
Versomnal
Aephenal
Aphenylbarbit
Aphenyletten
Austrominal
Barbonal
Barbophen
Bardorm
Bialminal
Cabronal
Calmetten
Calminal
Cardenal
Chinoin
Codibarbita
Coronaletta
Dezibarbitur
EINECS 200-007-0
Elixir of phenobarbital
Ensobarb
Ensodorm
Epidorm
Episedal
Epsylone
5-Ethyl-5-phenyl-2,4,6-(1H,3H,5H)pyrimidinetrione
Fenbital
Fenosed
Fenylettae
Glysoletten
Haplopan
Helional
Hennoletten
Henotal
Hypnaletten
Hypnette
Hypnogen
Hypnolone
Hypnoltol
Hypno-Tablinetten
Lubrokal
Lumesettes
Lumesyn
Lumofridetten
Luphenil
Luramin
Molinal
Nirvonal
Nova-pheno
Parkotal
Pharmetten
Phen-Bar
Phenobarb
Phenobarbitalum
Phenobarbitonum
Phenobarbyl
Phenolurio
Phenomet
Phenoturic
Phenylethyl barbituric acid
Phenyl-ethyl-barbituric acid
Phenyletten
Polcominal
Promptonal
Sedabar
Seda-Tablinen
Sedicat
Sedizorin
Sedofen
Sedonettes
SK-Phenobarbital
Solu-Barb
Sombutol
Somnolens
Somnoletten
Somnosan
Spasepilin
Starifen
Starilettae
Acido 5-fenil-5-etilbarbiturico
Fenobarbitale
UNII-YQE403BP4D
DTXSID5021122117718-60-2YIJZJEYQBAAWRJ-UHFFFAOYSA-NYIJZJEYQBAAWRJ-UHFFFAOYSA-N
ThiazopyrRH-135,680
DTXSID103248851-52-5KNAHARQHSZJURB-UHFFFAOYSA-NKNAHARQHSZJURB-UHFFFAOYSA-N
6-Propyl-2-thiouracil6-Propyl-2 thiouracil (PTU)
4(1H)-Pyrimidinone, 2,3-dihydro-6-propyl-2-thioxo-
2,3-Dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone
2-Mercapto-4-hydroxy-6-n-propylpyrimidine
2-Mercapto-4-hydroxy-6-propylpyrimidine
2-Mercapto-6-propylpyrimidin-4-ol
2-Thio-4-oxo-6-propyl-1,3-pyrimidine
2-Thio-6-propyl-1,3-pyrimidin-4-one
6-n-Propyl-2-thiouracil
6-n-Propylthiouracil
6-Propyl-2-thio-2,4(1H,3H)pyrimidinedione
6-Propylthiouracil
NSC 6498
NSC 70461
Procasil
Propacil
propiltiouracilo
Propycil
Propyl-Thiorist
Propylthiorit
propylthiouracil
Propylthiouracile
Propyl-Thyracil
Prothiucil
Prothiurone
Prothycil
Prothyran
Protiural
Thiuragyl
Thyreostat II
URACIL, 4-PROPYL-2-THIO-
Uracil, 6-propyl-2-thio-
DTXSID502120960-56-0PMRYVIKBURPHAH-UHFFFAOYSA-NPMRYVIKBURPHAH-UHFFFAOYSA-N
Methimazole2H-Imidazole-2-thione, 1,3-dihydro-1-methyl-
1,3-Dihydro-1-methyl-2H-imidazole-2-thione
1-Methyl-1,3-dihydroimidazole-2-thione
1-Methyl-1H-imidazole-2-thiol
1-Methyl-2-mercapto-1H-imidazole
1-Methyl-2-mercaptoimidazole
1-Methyl-4-imidazoline-2-thione
1-Methylimidazole-2(3H)-thione
1-Methylimidazole-2-thiol
1-Methylimidazole-2-thione
2-Mercapto-1-methyl-1H-imidazole
2-Mercapto-1-methylimidazole
2-Mercapto-N-methylimidazole
4-Imidazoline-2-thione, 1-methyl-
Basolan
Danantizol
Favistan
Frentirox
Imidazole-2-thiol, 1-methyl-
Mercaptazole
Mercazole
Mercazolyl
Metazolo
Methimazol
Methylmercaptoimidazole
Metothyrin
Metothyrine
Metotirin
N-Methyl-2-mercaptoimidazole
N-Methylimidazolethiol
NSC 38608
Strumazol
Tapazole
Thacapzol
Thiamazol
thiamazole
Thycapzol
Thymidazol
Thymidazole
tiamazol
DTXSID402082014797-73-0VLTRZXGMWDSKGL-UHFFFAOYSA-MVLTRZXGMWDSKGL-UHFFFAOYSA-M
PerchloratePerchlorate ion
Perchlorate ion (ClO41-)
Perchlorate ion(1-)
Perchlorate(1-)
Perchloric acid, ion(1-)
DTXSID6024252CHEBI:81567Thyroid stimulating hormoneCHEBI:30660thyroxineD000236AdenomaD002277CarcinomaCL:0002258thyroid follicular cellPR:000001325beta-1,3-glucuronyltransferaseMP:0005475abnormal circulating thyroxine levelD006965hyperplasiaGO:0008283cell proliferationD006984hypertrophyGO:0015020glucuronosyltransferase activityGO:0003824catalytic activityGO:0008152metabolic process1increased2decreasedPhenobarbital2016-11-29T18:42:272016-11-29T18:42:27thiazopyr2016-11-29T18:42:272016-11-29T18:42:27Pyrethrins and Pyrethroids2016-11-29T18:42:272016-11-29T18:42:27Propylthiouracil2016-11-29T18:42:222016-11-29T18:42:22Methimazole2016-11-29T18:42:192016-11-29T18:42:19Perchlorate2016-11-29T18:42:262016-11-29T18:42:26WCS_8355African clawed frog10118Rattus sp.10090mouseWCS_9606human10116ratWCS_9031chickenWCS_8355Xenopus laevisWCS_7955zebrafishWCS_90988fathead minnow9823Sus scrofa10116Rattus norvegicusIncreased, Thyroid-stimulating hormone (TSH)Increased, Thyroid-stimulating hormone (TSH)TissueUBERON:0001977serumNot SpecifiedNot SpecifiedNot Specified2016-11-29T18:41:282017-09-16T10:17:01 Thyroxine (T4) in serum, DecreasedT4 in serum, DecreasedTissue<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">All iodothyronines are derived from the modification of tyrosine molecules (Taurog, 2000). There are two biologically active thyroid hormones (THs) in serum, triiodothyronine (T3) and T4, and a few less active iodothyronines, reverse T3 (rT3), and 3,3'-Diiodothyronine (3,5-T2). T4 is the predominant TH in circulation, comprising approximately 80% of the TH excreted from the thyroid gland in mammals and is the pool from which the majority of T3 in serum is generated (Zoeller et al., 2007). As such, serum T4 changes usually precede changes in other serum THs. Decreased thyroxine (T4) in serum results from one or more MIEs upstream and is considered a key biomarker of altered TH homeostasis (DeVito et al., 1999).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Serum T4 is used as a biomarker of TH status because the circulatory system serves as the major transport and delivery system for TH delivery to tissues. The majority of THs in the blood are bound to transport proteins (Bartalena and Robbins, 1993). In serum, it is the unbound, or ‘free’ form of the hormone that is thought to be available for transport into tissues. Free hormones are approximately 0.03 and 0.3 percent for T4 and T3, respectively. There are major species differences in the predominant binding proteins and their affinities for THs (see below). However, there is broad agreement that changes in serum concentrations of THs is diagnostic of thyroid disease or chemical-induced disruption of thyroid homeostasis across vertebrates (DeVito et al., 1999; Miller et al., 2009; Zoeller et al., 2007; Carr and Patiño, 2011).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Normal serum T4 reference ranges can be species and lifestage specific. In <strong>rodents</strong>, serum THs are low in the fetal circulation, increasing as the fetal thyroid gland becomes functional on gestational day 17, just a few days prior to birth. After birth serum hormones increase steadily, peaking at two weeks, and falling slightly to adult levels by postnatal day 21 (Walker et al., 1980; Harris et al., 1978; Goldey et al., 1995; Lau et al., 2003). Similarly, in <strong>humans</strong>, adult reference ranges for THs do not reflect the normal ranges for children at different developmental stages, with TH concentrations highest in infants, still increased in childhood, prior to a decline to adult levels coincident with pubertal development (Corcoran et al. 1977; Kapelari et al., 2008).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">In some <strong>frog </strong>species, there is an analogous peak in </span><span style="color:black">THs </span><span style="color:black">in tadpoles that starts around embryonic NF stage 56, peaks at </span><span style="color:black">s</span><span style="color:black">tage 62 and the declines to lower levels by </span><span style="color:black">s</span><span style="color:black">tage 56 (Sternberg et al., 2011; Leloup and Buscaglia, 1977). </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Additionally, ample evidence is available from studies investigating responses to inhibitors of </span><span style="color:black">TH </span><span style="color:black">synthesis in <strong>fish</strong>. For example, Stinckens et al. (2020) showed reduced whole body T4 concentrations in zebrafish larvae exposed to 50 or 100 mg/L methimazole, a potent TPO inhibitor, from immediately after fertilization until 21 or 32 days of age. Exposure to 37 or 111 mg/L propylthiouracil also reduced T4 levels after exposure up to 14, 21 and 32 days in the same study. Walter et al. (2019) showed that propylthiouracil had no effect on T4 levels in 24h old zebrafish, but decreased T4 levels of 72h old zebrafish. This difference is probably due to the onset of embryonic TH production between the age of 24 and 72 hours (Opitz et al., 2011). Stinckens et al. (2016) showed that exposure to 2-mercaptobenzothiazole (MBT), an environmentally relevant TPO inhibitor, decreased whole body T4 levels in continuously exposed 5 and 32 day old zebrafish larvae. A high concentration of MBT also decreased whole body T4 levels in 6 day old fathead minnows, but recovery was observed at the age of 21 days although the fish were kept in the exposure medium (Nelson et al., 2016). Crane et al. (2006) showed decreased T4 levels in 28 day old fathead minnows continuously exposed to 32 or 100 µg/L methimazole.</span></span></span></span></p>
<p><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Serum T3 and T4 can be measured as free (unbound) or total (bound + unbound). Free hormone concentrations are clinically considered more direct indicators of T4 and T3 activities in the body, but in animal studies, total T3 and T4 are typically measured. Historically, the most widely used method in toxicology is the radioimmunoassay (RIA). The method is routinely used in rodent endocrine and toxicity studies. The ELISA method is commonly used as a human clinical test method. Analytical determination of iodothyronines (T3, T4, rT3, T2) and their conjugates, through methods employing HPLC, liquid chromatography, immuno luminescence, and mass spectrometry are less common, but are becoming increasingly available (Hornung et al., 2015; DeVito et al., 1999; Baret and Fert, 1989; Spencer, 2013; Samanidou V.F et al., 2000; Rathmann D. et al., 2015 ). In fish early life stages most evidence for the ontogeny of thyroid hormone synthesis comes from measurements of whole body thyroid hormone levels using LC-MS techniques (Hornung et al., 2015) which are increasingly used to accurately quantify whole body thyroid hormone levels as a proxy for serum thyroid hormone levels (Nelson et al., 2016; Stinckens et al., 2016; Stinckens et al., 2020). It is important to note that thyroid hormones concentrations can be influenced by a number of intrinsic and extrinsic factors (e.g., circadian rhythms, stress, food intake, housing, noise) (see for example, Döhler et al., 1979).</span></span></span></span></p>
<p><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Any of these measurements should be evaluated for the relationship to the actual endpoint of interest, repeatability, reproducibility, and lower limits of quantification using a fit-for-purpose approach. This is of particular significance when assessing the very low levels of TH present in fetal serum. Detection limits of the assay must be compatible with the levels in the biological sample. All three of the methods summarized above would be fit-for-purpose, depending on the number of samples to be evaluated and the associated costs of each method. Both RIA and ELISA measure THs by an indirect methodology, whereas analytical determination is the most direct measurement available. All these methods, particularly RIA, are repeatable and reproducible.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Taxonomic</span></strong><span style="color:black">: This KE is plausibly applicable across vertebrates and the overall evidence supporting taxonomic applicability is strong. THs are evolutionarily conserved molecules present in all vertebrate species (Hulbert, 2000; Yen, 2001). Moreover, their crucial role in zebrafish development, embryo-to-larval transition and larval-to-juvenile transition (Thienpont et al., 2011; Liu and Chan, 2002), and amphibian and lamprey metamorphoses is well established (Manzon and Youson, 1997; Yaoita and Brown, 1990; Furlow and Neff, 2006). </span><span style="color:black">T</span><span style="color:black">heir role as environmental messenger via exogenous routes in echinoderms confirms the hypothesis that these molecules are widely distributed among the living organisms (Heyland and Hodin, 2004). However, the role of TH</span><span style="color:black">s</span><span style="color:black"> in the different species depends on the expression and function of specific proteins (e.g receptors or enzymes) under TH control and may vary across species and tissues. As such</span><span style="color:black">,</span><span style="color:black"> extrapolation regarding TH action across species and developmental stages should be done with caution.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">With few exceptions, vertebrate species have circulating T4 (and T3) that are bound to transport proteins in blood. Clear species differences exist in serum transport proteins (Dohler et al., 1979; Yamauchi and Isihara, 2009). There are three major transport proteins in mammals; thyroid binding globulin (TBG), transthyretin (TTR), and albumin. In adult humans, the percent bound to these proteins is about 75, 15 and 10 percent, respectively (Schussler 2000). In contrast, in adult rats the majority of THs are bound to TTR. Thyroid</span><span style="color:black">-</span> <span style="color:black">binding proteins are developmentally regulated in rats. TBG is expressed in rats until approximately postnatal day (PND) 60, with peak expression occurring during weaning (Savu et al., 1989). However, low levels of TBG persist into adult ages in rats and can be experimentally induced by hypothyroidism, malnutrition, or caloric restriction (Rouaze-Romet et al., 1992). While these species differences impact TH half-life (Capen, 1997) and possibly regulatory feedback mechanisms, there is little information on quantitative dose-response relationships of binding proteins and serum hormones during development across different species. Serum THs are still regarded as the most robust measurable key event causally linked to downstream adverse outcomes.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Life stage</span></strong><span style="color:black">: The earliest life stages of teleost fish rely on maternally transferred THs to regulate certain developmental processes until embryonic TH synthesis is active (Power et al., 2001). As a result, T4 levels are not expected to decrease in response to exposure to inhibitors of TH synthesis during these earliest stages of development. In zebrafish, Opitz et al. (2011) showed the formation of a first thyroid follicle at 55 hours post fertilization (hpf), Chang et al. (2012) showed a first significant TH increase at 120 hpf and Walter et al. (2019) showed clear TH production already at 72 hpf but did not analyse time points between 24 and 72 hpf. In fathead minnows, a significant increase of whole body </span><span style="color:black">TH </span><span style="color:black">levels was already observed between 1 and 2 dpf, which corresponds to the appearance of the thyroid anlage at 35 hpf prior to the first observation of thyroid follicles at 58 hpf (Wabuke-Bunoti and Firling, 1983). It is still uncertain when exactly embryonic TH synthesis is activated and how this determines sensitivity to TH </span><span style="color:black">system </span><span style="color:black">disruptors.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Sex</span></strong><span style="color:black">: The KE is plausibly applicable to both sexes. </span><span style="color:black">THs</span> <span style="color:black">are essential in both sexes and the components of the HPT-axis are identical in both sexes. There can however be sex-dependent differences in the sensitivity to the disruption of </span><span style="color:black">TH</span> <span style="color:black">levels and the magnitude of the response. In humans, females appear more susceptible to hypothyroidism compared to males when exposed to certain halogenated chemicals (HernandezāMariano et al., 2017; Webster et al., 2014). In adult zebrafish, Liu et al. (2019) showed sex-dependent changes in </span><span style="color:black">TH</span> <span style="color:black">levels and mRNA expression of regulatory genes including corticotropin releasing hormone (crh), thyroid stimulating hormone (tsh) and deiodinase 2 after exposure to organophosphate flame retardants. The underlying mechanism of any sex-related differences remains unclear.</span></span></span></span></p>
UBERON:0001977serumHighFemaleHighMaleHighAll life stagesHighHighHighModerateModerateHighHighHigh<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Axelrad DA, Baetcke K, Dockins C, Griffiths CW, Hill RN, Murphy PA, Owens N, Simon NB, Teuschler LK. Risk assessment for benefits analysis: framework for analysis of a thyroid-disrupting chemical. J Toxicol Environ Health A. 2005 68(11-12):837-55.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Baret A. and Fert V. T4 and ultrasensitive TSH immunoassays using luminescent enhanced xanthine oxidase assay. J Biolumin Chemilumin. 1989. 4(1):149-153</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Bartalena L, Robbins J. Thyroid hormone transport proteins. Clin Lab Med. 1993 Sep;13(3):583-98. Bassett JH, Harvey CB, Williams GR. (2003). Mechanisms of thyroid hormone receptor-specific nuclear and extra nuclear actions. Mol Cell Endocrinol. 213:1-11.</span></span></span></span></p>
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<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Carr JA, Patino R. 2011. The hypothalamus-pituitary-thyroid axis in teleosts and amphibians: Endocrine disruption and its consequences to natural populations. General and Comparative Endocrinology. 170(2):299-312.</span></span></span></span></p>
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<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Döhler KD, Wong CC, von zur Mühlen A (1979). The rat as model for the study of drug effects on thyroid function: consideration of methodological problems. Pharmacol Ther B. 5:305-18.</span></span></span></span></p>
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<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Goldey ES, Kehn LS, Lau C, Rehnberg GL, Crofton KM. </span><span style="color:black">Developmental exposure to polychlorinated biphenyls (Aroclor 1254) reduces circulating thyroid hormone concentrations and causes hearing deficits in rats. Tox Appl Pharmacol. 1995 135(1):77-88.</span></span></span></span></p>
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2016-11-29T18:41:232022-10-10T08:52:30Increase, Adenomas/carcinomas (follicular cell)Increase, Adenomas/carcinomas (follicular cell)TissueUBERON:0002046thyroid glandNot SpecifiedNot Specified2016-11-29T18:41:262017-09-16T10:16:08Increase, Hyperplasia (follicular cells)Increase, Hyperplasia (follicular cells)CellularCL:0002258thyroid follicular cellNot SpecifiedNot Specified2016-11-29T18:41:262017-09-16T10:16:07Increase, Hypertrophy and proliferation (follicular cell)Increase, Hypertrophy and proliferation (follicular cell)CellularCL:0002258thyroid follicular cellNot SpecifiedNot Specified2016-11-29T18:41:262017-09-16T10:16:07Induction, Upregulation of glucuronyltransferase activityInduction, Upregulation of glucuronyltransferase activityMolecularCL:0000255eukaryotic cellNot SpecifiedNot Specified2016-11-29T18:41:232017-09-16T10:14:22Increased, Clearance of thyroxine from serumIncreased, Clearance of thyroxine from serumTissue<p>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).</p>
<p>Deiodination:</p>
<p>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.</p>
<p>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).</p>
<p>Conjugation:</p>
<p>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.</p>
<p>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).</p>
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<p>Data in animals for PCBs</p>
<p>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)</p>
<p>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.</p>
<p>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). </p>
<p>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 <em>in vitro</em> 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). </p>
<p>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.</p>
<p>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 [<sup>125</sup>I]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[<sup>125</sup>I]T4 accumulated following treatment.</p>
<p>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 [<sup>125</sup>I]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 [<sup>125</sup>I]T4 from serum relative to controls and serum pharmacokinetic data were estimated, along with tissue-to-serum (K<sub>p</sub> value) concentration ratios and [<sup>125</sup>I]T4 tissue distribution levels. These data imply that 4-OH-CB187 inhibits formation of the [<sup>125</sup>I]T4-TTR complex, which may lead to a change in tissue distribution, with accumulation in the liver and kidney mainly.</p>
<p>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 [<sup>125</sup>I]T4 clearance from serum and accumulation in tissues. Treatment with pentaCB resulted in decrease of [<sup>125</sup>I]T4-TTR and increase in [<sup>125</sup>I]T4-albumin and [<sup>125</sup>I]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).</p>
<p>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 [<sup>125</sup>I]T4 complexes with TBG, albumin and TTR were only observed in C57BL/6 mice (and not DBA/2), despite [<sup>125</sup>I]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).</p>
<p>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).</p>
<p>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).</p>
<p>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 [<sup>125</sup>I]T4 and collection of urine, blood, bile and urine. No treatments increased urinary excretion of [<sup>125</sup>I]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 [<sup>125</sup>I]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. </p>
<p>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.</p>
<p> </p>
<p>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).</p>
<p>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.</p>
<p><em>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? </em></p>
<p>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).</p>
<p>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.</p>
<p> </p>
<p>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).</p>
<p>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.</p>
<p>Measuring displacement of T4 from serum transport proteins is done mainly via one of three <em>in vitro</em> methods: radioligand binding assay, plasmon resonance-based biosensor, or fluorescence displacement.</p>
<p>Radioligand binding assays, using [<sup>125</sup>I]-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 [<sup>125</sup>I]-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).</p>
<p>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.</p>
<p>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.</p>
<p>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.</p>
<p>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 IC<sub>50</sub> values. Cao et al 2011 developed a fluorescent microtiter method for pTTR and TBG tested with bisphenol A.</p>
<p>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).</p>
<p>Aqai et al 2012 described a rapid and isotope-free (<sup>13</sup>C<sub>6</sub>-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.</p>
<p>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).</p>
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2016-11-29T18:41:282021-01-26T10:41:197f4b8f3d-1641-40ab-bbda-753eef0dda4376250e5d-a80d-4a9a-85e1-7c6996023200Not SpecifiedNot SpecifiedNot Specified2021-09-10T08:32:292021-09-10T08:32:2976250e5d-a80d-4a9a-85e1-7c69960232004e8618da-4012-466f-95ce-eebacb6d8bd6Not SpecifiedNot SpecifiedNot Specified2021-01-26T10:42:592021-01-26T10:42:594e8618da-4012-466f-95ce-eebacb6d8bd609e9c3a0-f3b7-4f3a-8ecd-4b3d19e63e92Not Specified2021-07-07T09:49:072021-07-07T09:49:0709e9c3a0-f3b7-4f3a-8ecd-4b3d19e63e92dbd1a732-1396-4f61-bdbf-823451ba4e74Not Specified2021-07-07T10:17:352021-07-07T10:17:35dbd1a732-1396-4f61-bdbf-823451ba4e74a5a09344-0aba-48ae-9a7b-769abab24180Not SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:00a5a09344-0aba-48ae-9a7b-769abab24180f2891e25-e368-4201-91ae-f6fbd36a8e8eNot SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:00Enhanced hepatic clearance of thyroid hormones leading to thyroid follicular cell adenomas and carcinomas in the rat and mousethyroid follicular cell adenomas and carcinomas<p>Cancer AOP Workgroup. National Health and Environmental Effects Research Laboratory, Office of Research and Development, Integrated Systems Toxicology Division, US Environmental Protection Agency, Research Triangle Park, NC. Corresponding author for wiki entry (wood.charles@epa.gov)</p>
Under Development: Contributions and Comments WelcomeUnder Development1.29<p>This putative adverse outcome pathway (AOP) outlines potential key events leading to a tumor outcome in standard carcinogenicity models. This information is based largely on modes of action described previously in cited literature sources and is intended as a resource template for AOP development and data organization. Presentation in this Wiki does not indicate EPA acceptance of a particular pathway for a given reference agent, only that the information has been proposed in some manner. In addition, this putative AOP relates to the model species indicated and does not directly address issues of human relevance.</p>
adjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedHighModerateNot SpecifiedNot SpecifiedNot Specified<p>1. Dellarco, V. L., McGregor, D., Berry, S. C., Cohen, S. M., and Boobis, A. R. (2006). Thiazopyr and thyroid disruption: case study within the context of the 2006 IPCS Human Relevance Framework for analysis of a cancer mode of action. Critical reviews in toxicology 36(10), 793-801, 10.1080/10408440600975242.</p>
<p>2. Finch, J. M., Osimitz, T. G., Gabriel, K. L., Martin, T., Henderson, W. J., Capen, C. C., Butler, W. H., and Lake, B. G. (2006). A mode of action for induction of thyroid gland tumors by Pyrethrins in the rat. Toxicology and applied pharmacology 214(3), 253-62, 10.1016/j.taap.2006.01.009.</p>
<p>3. Hurley, P. M. (1998). Mode of carcinogenic action of pesticides inducing thyroid follicular cell tumors in rodents. Environmental health perspectives 106(8), 437-45.</p>
<p> </p>
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