Thyroperoxidase, Inhibition

149-30-4

YXIWHUQXZSMYRE-UHFFFAOYSA-N

2-Mercaptobenzothiazole

(2(3H)-Benzothiazolethione) 2(3H)-Benzothiazolethione 1,3-Benzothiazole-2-thiol 1,3-Benzothiazole-2-thione 2,3-Dihydrobenzothiazole-2-thione 2-Benzothiazolethiol 2-Benzothiazolinethione 2-BENZOTHIAZOLTHIOL 2-Benzothiazolyl mercaptan 2-Mercapthobenzothiazole Technical 2-Mercapto-1H-benzothiazole 2-Mercaptobenzthiazole 2-Sulfanylbenzothiazole Accel M Accelerator M Aero Promoter 412 Benz-1,3-thiazolidine-2-thione Benzo[d]thiazole-2-thiol Benzothiazol-2-thiol BENZOTHIAZOLE, 2-MERCAPTO- Benzothiazole-2-thiol Benzothiazole-2-thione Benzothiazolethiol benzotiazol-2-tiol Dermacid Ekagom G Kaptaks Mebetizol Mebetizole Mebithizol MERCAPTOBENZOTHIAZOLE Mercaptobenzthiazole Nocceler M Nocceler M-P Nonflex NB NSC 2041 Perkacit MBT Pneumax MBT Royal MBT Sanceler M Sanceler M-G Soxinol M Thiotax Vulkacit M Vulkacit Mercapto Vulkacit Mercapto MG/C Vulkacit Mercapto/C Vulkacit Mercapto/MG Vulkafil ZN 94TT01 Wobezit M

DTXSID1020807

96-45-7

PDQAZBWRQCGBEV-UHFFFAOYSA-N

Ethylene thiourea

ETU 2-Imidazolidinethione 1,3-Ethylenethiourea 2-Imidazoline-2-thiol 2-Mercapto-2-imidazoline 2-Mercapto-4,5-dihydroimidazole 2-MERCAPTOIMIDAZOLINE 2-Thioimidazolidine 4,5-Dihydro-2-mercaptoimidazole Ethylenethiocarbamide ETHYLENETHIOUREA Imidazolidin-2-thion imidazolidina-2-tiona Imidazolidine-2-thione Imidazolidinethione Imidazoline-2(3H)-thione Imidazoline-2-thiol Mercaptoimidazoline Mercazin I N,N'-AETHYLENTHIOHARNSTOFF N,N'-ETHYLENETHIOUREA Nocceler 22 Pennac CRA Rhenogran ETU Rhodanin S 62 Sanceler 22 Sanceler 22C Sanceler 22S Tetrahydro-2H-imidazole-2-thione Thiourea, N,N'-1,2-ethanediyl- Vulkacit NPV/C Warecure C

DTXSID5020601

60-56-0

PMRYVIKBURPHAH-UHFFFAOYSA-N

Methimazole

2H-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

DTXSID4020820

51-52-5

KNAHARQHSZJURB-UHFFFAOYSA-N

6-Propyl-2-thiouracil

6-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-

DTXSID5021209

108-46-3

GHMLBKRAJCXXBS-UHFFFAOYSA-N

Resorcinol

1,3-Benzenediol 1,3-DIHYDROXYBENZENE 3-Hydroxyphenol C.I. Developer 4 C.I. Oxidation Base 31 Developer O Developer R Developer RS Durafur Developer G Fouramine RS Fourrine 79 Fourrine EW m-Benzenediol m-Dihydroxybenzene m-Hydroquinone m-Hydroxyphenol m-Phenylenediol Nako TGG NSC 1571 Oxidation Base 31 Pelagol Grey RS Pelagol RS PHENOL, 3-HYDROXY- Redimix 401RAP60 Resorcin Resorcinol 80 Rezorsine Rodol RS UN 2876

DTXSID2021238

57583-54-7

OWICEWMBIBPFAH-UHFFFAOYSA-N

Tetraphenyl m-phenylene bis(phosphate)

DTXSID8069197

141-90-2

ZEMGGZBWXRYJHK-UHFFFAOYSA-N

Thiouracil

4(1H)-Pyrimidinone, 2,3-dihydro-2-thioxo- 2,3-Dihydro-2-thioxo-4(1H)-pyrimidinone 2-Mercapto-4-hydroxypyrimidine 2-Mercapto-4-pyrimidinol 2-Mercapto-4-pyrimidinone 2-thiouracil 2-Thiouracile 2-tiouracilo 4-Hydroxy-2-mercaptopyrimidine 4-Hydroxy-2-pyrimidinethiol 6-Hydroxy-2-mercaptopyrimidine Antagothyroil Deracil Nobilen NSC 19473 NSC 290412 NSC 290413 NSC 290414 URACIL, 2-THIO-

DTXSID4021347

61-82-5

KLSJWNVTNUYHDU-UHFFFAOYSA-N

Amitrole

1H-1,2,4-Triazol-3-amine 3-Amino-1,2,4-triazole 3-Aminotriazole 1H-1,2,4-Triazol-3-ylamine 1H-1,2,4-Triazol-5-amine 1H-1,2,4-Triazolamine 1H-1,2,4-Triazole, 3-amino- 2,3,5,6-Tetraazabicyclo[2.1.1]hex-1-ene 2-Amino-1,3,4-triazole 3-Amino-1H-1,2,4-triazole 3-Amino-2H-1,2,4-triazole 3-Amino-s-triazole 5-Amino-1,2,4-triazole 5-Amino-1H-1,2,4-triazole Amitrol Amitrol T Azaplant Cytrole Herbicide, Amino-1H-1,2,4-triazole, 3- Herbidal total Herbizole NSC 34809 NSC 7243 s-Triazole, 3-amino- TRIAZOLE (1,2,4), 3-AMINO-4H Weedazol

DTXSID0020076

131-55-5

WXNRYSGJLQFHBR-UHFFFAOYSA-N

2,2',4,4'-Tetrahydroxybenzophenone

Methanone, bis(2,4-dihydroxyphenyl)- 2,2',4,4'-tetrahidroxibenzofenona 2,2',4,4'-Tetrahydroxy diphenyl ketone 2,2',4,4'-Tetrahydroxybenzophenon 2,4,2',4'-Tetrahydroxybenzophenone Benzophenone 2 BENZOPHENONE, 2,2',4,4'-TETRAHYDROXY- BENZOPHENONE-2 Bis(2,4-dihydroxyphenyl)methanone Dainsorb P 6 NSC 38556 Seesorb 106 Sumisorb 150 Uvinul 3050 Uvinul D 50

DTXSID5041306

486-66-8

ZQSIJRDFPHDXIC-UHFFFAOYSA-N

7,4'-Dihydroxyisoflavone

4',7-Dihydroxyisoflavone 4H-1-Benzopyran-4-one, 7-hydroxy-3-(4-hydroxyphenyl)- 7,4'-Dihydroxyisoflavone 7-hidroxi-3-(4-hidroxifenil)-4-benzopirona 7-Hydroxy-3-(4-hydroxyphenyl)-4-benzopyron 7-hydroxy-3-(4-hydroxyphenyl)-4-benzopyrone 7-Hydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one Daidzeol Isoaurostatin Isoflavone, 4',7-dihydroxy-

DTXSID9022310

446-72-0

TZBJGXHYKVUXJN-UHFFFAOYSA-N

Genistein

GEN 4H-1-Benzopyran-4-one, 5,7-dihydroxy-3-(4-hydroxyphenyl)- 5,7,4'-Trihydroxyisoflavone 5,7-dihidroxi-3-(4-hidroxifenil)-4-benzopirona 5,7-Dihydroxy-3-(4-hydroxyphenyl)-4-benzopyron 5,7-Dihydroxy-3-(4-hydroxyphenyl)-4-benzopyrone Baichanin A Bonistein Genisteol Genisterin Isoflavone, 4',5,7-trihydroxy- NSC 36586 Prunetol Sophoricol 4',5,7-Trihydroxyisoflavone

DTXSID5022308

104-40-5

IGFHQQFPSIBGKE-UHFFFAOYSA-N

4-Nonylphenol

p-Nonylphenol p-NP Phenol, 4-nonyl- 4-n-Nonyl phenol Nonyl phenol Phenol, p-nonyl- p-n-Nonylphenol p-nonilfenol

DTXSID5033836

57-68-1

ASWVTGNCAZCNNR-UHFFFAOYSA-N

Sulfamethazine

Benzenesulfonamide, 4-amino-N-(4,6-dimethyl-2-pyrimidinyl)- 2-(4-Aminobenzenesulfonamido)-4,6-dimethylpyrimidine 2-(4-Aminobenzenesulfonylamino)-4,6-dimethylpyrimidine 2-(p-Aminobenzenesulfonamido)-4,6-dimethylpyrimidine 2-Sulfanilamido-4,6-dimethylpyrimidine 4,6-Dimethyl-2-sulfanilamidopyrimidine 4-Amino-N-(2,6-dimethyl-4-pyrimidinyl)benzenesulfonamide 4-Amino-N-(4,6-dimethyl-2-pyrimidinyl)benzenesulfonamide Azolmetazin Calfspan Calfspan Tablets Cremomethazine DiazilSulfadine Dimezathine Dimidin R Kelametazine Mermeth N-(4,6-Dimethyl-2-pyrimidyl)sulfanilamide N1-(4,6-Dimethyl-2-pyrimidinyl)sulfanilamide N1-(4,6-Dimethyl-2-pyrimidyl)sulfanilamide Neasina Neazina NSC 67457 NSC 683529 Panazin Pirmazin S-Dimidine Spanbolet Sulfadimerazine Sulfadimesin Sulfadimesine Sulfadimethyldiazine Sulfadimethylpyrimidine Sulfadimezin Sulfadimezine Sulfadimidin sulfadimidina Sulfadimidine Sulfadine SULFAMETHAZINE BASE Sulfamethiazine Sulfanilamide, N1-(4,6-dimethyl-2-pyrimidinyl)- SulfaSURE SR Bolus Sulfodimesin Sulfodimezine Sulka K Boluses Sulphadimethylpyrimidine Sulphadimidine Sulphamethasine Sulphamethazine Sulphamezathine Sulphamidine Sulphodimezine Superseptil Superseptyl Sustain III Vertolan

DTXSID6021290

14797-73-0

VLTRZXGMWDSKGL-UHFFFAOYSA-M

Perchlorate

Perchlorate ion Perchlorate ion (ClO41-) Perchlorate ion(1-) Perchlorate(1-) Perchloric acid, ion(1-)

DTXSID6024252

PR:000016584

PR thyroid peroxidase

CHEBI:60311

CHEBI thyroid hormone

CHEBI:30660

CHEBI thyroxine

CHEBI:28774

CHEBI 3,3',5'-triiodothyronine

PCO:0000001

PCO population of organisms

UBERON:0000970

UBERON eye

GO:0004447

GO iodide peroxidase activity

GO:0006590

GO thyroid hormone generation

MP:0005475

MP abnormal circulating thyroxine level

MP:0005473

MP decreased triiodothyronine level

D009026

MESH mortality

PCO:0000008

PCO population growth rate

VT:0002090

VT vision trait

WIKI decreased

WIKI increased

WIKI functional change

2(3H)-Benzothiazolethione

2016-11-29T18:42:08

2-mercaptobenzothiazole

2016-11-29T18:42:08

Ethylene thiourea

2016-11-29T18:42:17

Mercaptobenzothiazole

2016-11-29T18:42:17

Methimazole

2016-11-29T18:42:19

Propylthiouracil

2016-11-29T18:42:22

Resorcinol

2016-11-29T18:42:22

Thiouracil

2016-11-29T18:42:23

Ethylenethiourea

2016-11-29T18:42:23

Amitrole

2016-11-29T18:42:26

131-55-5

2016-11-29T18:42:26

2,2',4,4'-Tetrahydroxybenzophenone

2016-11-29T18:42:26

Daidzein

2016-11-29T18:42:26

Genistein

2016-11-29T18:42:26

4-Nonylphenol

2016-11-29T18:42:26

4-propoxyphenol

2016-11-29T18:42:26

Sulfamethazine

2016-11-29T18:42:26

Perchlorate

2016-11-29T18:42:26

10116

NCBI rat

WCS_9606

common toxicological species humans

9823

NCBI pigs

WCS_8355

common ecological species Xenopus laevis

WCS_9031

common ecological species chicken

WCS_7955

common ecological species zebrafish

WCS_90988

common ecological species fathead minnow

10090

NCBI mouse

WCS_9606

common toxicological species human

9823

NCBI Sus scrofa

WCS_8355

common ecological species African clawed frog

WCS_8022

common ecological species rainbow trout

10095

NCBI mice

WikiUser_28

Vertebrates

WikiUser_22

all species

Thyroperoxidase, Inhibition

Molecular

Thyroperoxidase (TPO) is a heme-containing apical membrane protein within the follicular lumen of thyrocytes that acts as the enzymatic catalyst for thyroid hormone (TH) synthesis. TPO catalyzes several reactions in the thyroid gland, including: the oxidation of iodide; nonspecific iodination of tyrosyl residues of thyroglobulin (Tg); and the coupling of iodotyrosyls to produce Tg-bound monoiodotyrosine (MIT) and diiodotyrosine (DIT) (Divi et al., 1997; Kessler et al., 2008; Ruf et al., 2006; Taurog et al., 1996). The outcome of TPO inhibition is decreased synthesis of thyroxine (T4) and triiodothyronine (T3), a decrease in release of these hormones from the gland into circulation, and unless compensated, a consequent decrease in systemic concentrations of T4, and possibly T3. The primary product of TPO-catalyzed TH synthesis is T4 (Taurog et al., 1996; Zoeller et al., 2007) that would be peripherally or centrally deiodinated to T3. It is important to note that TPO is a complex enzyme that has two catalytic cycles and is capable of iodinating multiple species (Divi et al., 1997). Alterations in all of these events are not covered by some of the commonly used assays that measure “TPO inhibition” (e.g., guaiacol and AmplexUltraRed, see below). Ususally just the first step of this series of events is covered by assays that measure TPO inhibition. Therefore, in the context of this AOP we are using TPO inhibition not in the classical sense, but instead to refer to the empirical data derived from the assays commonly used to investigate environmental chemicals. Therefore, in the context of this AOP we are using TPO inhibition not in the classical sense, but instead to refer to the empirical data derived from the assays commonly used to investigate environmental chemicals. Figure 1      illustrates the enzymatic and nonenzymatic reactions mediated by TPO that result in the synthesis of thyroxine (T4) . <a href="https://aopwiki.org/system/dragonfly/production/2017/04/16/9jyfbzvr2o_Synthesis_figure.jpg"><img alt="" src="https://aopwiki.org/system/dragonfly/production/2017/04/16/9jyfbzvr2o_Synthesis_figure.jpg" style="height:330px; width:604px" /></a> Inhibition of TPO can be reversible, with transient interaction between the enzyme and the chemical, or irreversible, whereby suicide substrates permanently inactivate the enzyme. Reversible and irreversible (isoflavones such as genistein) TPO inhibition may be determined by the chemical structure, may be concentration dependent, or may be influenced by other conditions, including the availability of iodine (Doerge and Chang, 2002). The ontogeny of TPO has been determined using both direct and indirect evidence in mammals.  Available evidence suggests the 11th to 12th fetal week as the beginning of functional TPO in humans. In rodents, TPO function begins late in the second fetal week, with the first evidence of T4 secretion on gestational day 17 (Remy et al., 1980). Thyroid-specific genes appear in the thyroid gland according to a specific temporal pattern; thyroglobulin (Tg), TPO (Tpo), and TSH receptor (Tshr) genes are expressed by gestational day 14 in rats, and the sodium iodide symporter, NIS (Nis), is expressed by gestational day 16 in rats. Maturation to adult function is thought to occur within a few weeks after parturition in rats and mice, and within the first few months in neonatal humans (Santisteban and Bernal, 2005).  Tg is first detected in human fetuses starting at 5th week of gestation and rises throughout gestation (Thorpe-Beeston et al., 1992), but iodine trapping and T4 production does not occur until around 10-12 weeks. Also, the dimerization of Tg, a characteristic of adult TH storage, is not found until much later in human gestation (Pintar, 2000). In rats, Tg immunoreactivity does not appear until day 15 of gestation (Fukiishi et al., 1982; Brown et al., 2000). The vast majority of research and knowledge on Tg is from mammals, although genomic orthologs are known for a variety of other species (Holzer et al., 2016). It is important to note that prior to the onset of fetal thyroid function, THs are still required by the developing fetus which until that time relies solely on maternal sources. Chemical-induced TPO inhibition can affect synthesis in the maternal gland and in the fetal gland. The components of the TH system responsible for TH synthesis are highly conserved across vertebrates. In fish and amphibians TPO and NIS inhibition result in an expected decrease of TH synthesis (Hornung et al., 2010; Tietge et al., 2013; Nelson et al., 2016; Stinckens et al., 2016; Stinckens et al., 2020) like in mammals. Although the TH system is highly conserved across vertebrates, there are some taxon-specific considerations. Zebrafish and fathead minnows are oviparous fish species in which maternal THs are transferred to the eggs and regulate early embryonic developmental processes during external (versus intra-uterine in mammals) development (Power et al., 2001; Campinho et al., 2014; Ruuskanen and Hsu, 2018) until embryonic TH synthesis is initiated. Maternal transfer of THs to the eggs has been demonstrated in zebrafish (Walpita et al., 2007; Chang et al., 2012) and fathead minnows (Crane et al., 2004; Nelson et al., 2016). Inhibition of TPO can only occur after activation of embryonic TH synthesis mediated by TPO. Endogenous transcription profiles of thyroid-related genes in zebrafish and fathead minnow showed that mRNA coding for TPO is maternally transferred in relatively high amounts with subsequent mRNA degradation followed by initiation of embryonic transcription around hatching (Vergauwen et al., 2018).

There are no approved OECD or EPA guideline study protocols for measurement of TPO inhibition. However, there is an OECD scoping document on identification of chemicals that modulate TH signaling that provides details on a TPO assay (OECD, 2017).  From the early 1960's, microsomal fractions prepared from porcine thyroid glands and isolated porcine follicles were used as a source of TPO for inhibition experiments (Taurog, 2005). Microsomes from human goiter samples (Vickers et al., 2012) and rat thyroid glands (Paul et al., 2013; 2014; Paul-Friedman et al., 2016) have also been used as a source of TPO. TPO activity has been measured for decades via indirect assessment by kinetic measurement of the oxidation of guaiacol (Chang & Doerge 2000; Hornung et al., 2010; Schmutzler et al., 2007).  This method is a low-throughput assay due to the very rapid kinetics of the guaiacol oxidation reaction. More recently, higher-throughput methods using commercial fluorescent and luminescent substrates with rodent, porcine, and human microsomal TPO have been developed (Vickers et al., 2012; Paul et al., 2013; 2014; Kaczur et al., 1997). This assay substitutes a pre-fluorescent substrate (Amplex UltraRed) for guaiacol, that when incubated with a source of peroxidase and excess hydrogen peroxidase, results in a stable fluorescent product proportional to TPO activity (Vickers et al., 2012). The stability of the fluorescent reaction product allows this assay to be used in a higher throughput format (Paul-Friedman et al., 2016). This approach is appropriate for high-throughput screening but does not elucidate the specific mechanism by which a chemical may inhibit TPO (Paul-Friedman et al., 2016), and as with most in vitro assays, is subject to various sources of assay interference (Thorne et al., 2010). Recombinant sources of TPO have also been used (e.g. Schmutzler et al., 2007; Dong et al., 2020) HPLC has been used to measure the activity of TPO via formation of the precursors monoiodotyrosine (MIT), diiodotyrosine (DIT), and both T3 and T4, in a reaction mixture containing TPO, or a surrogate enzyme such as lactoperoxidase (Divi & Doerge 1994). The tools and reagents for this method are all available. However, HPLC or other analytical chemistry techniques make this a low throughput assay, depending on the level of automation. A primary advantage of this in vitro method is that it directly informs hypotheses regarding the specific mechanism by which a chemical may impact TH synthesis in vitro.   In fish, increases of TPO mRNA levels are often used as indirect evidence of TPO inhibition in in vivoexperiments (Baumann et al., 2016; Nelson et al., 2016; Wang et al., 2020).

Taxonomic: This KE is plausibly applicable across vertebrates. TPO inhibition is a MIE conserved across taxa, with supporting data from experimental models and human clinical testing. This conservation is likely a function of the high degree of protein sequence similarity in the catalytic domain of mammalian peroxidases (Taurog, 1999). Ample data available for human, rat, and porcine TPO inhibition demonstrate qualitative concordance across these species (Schmultzer et al., 2007; Paul et al., 2013; Hornung et al., 2010). A comparison of rat TPO and pig TPO, bovine lactoperoxidase, and human TPO inhibition by genistein demonstrated good qualitative and quantitative (40–66%) inhibition across species, as indicated by quantification of monoiodotyrosine (MIT) and diiodotyrosine (DIT) production (Doerge and Chang, 2002). Ealey et al. (1984) demonstrated peroxidase activity in guinea pig thyroid tissue using 3,3'-diaminobenzidine tetrahydrochloride (DAB) as a substrate that is oxidized by the peroxidase to form a brown insoluble reaction product. Formation of this reaction product was inhibited by 3-amino-1,2,4-triazole and the TPO inhibitor, methimazole (MMI). A comparative analysis of this action of MMI between rat- and human-derived TPO indicates concordance of qualitative response. Data also suggest an increased quantitative sensitivity to MMI in rats compared to humans (Vickers et al., 2012). Paul et al. (2013) tested 12 chemicals using the guaiacol assay using both porcine and rat thyroid microsomes. The authors concluded that there was an excellent qualitative concordance between rat and porcine TPO inhibition, as all chemicals that inhibited TPO in porcine thyroid microsomes also inhibited TPO in rat thyroid microsomes when tested within the same concentration range. In addition, these authors noted a qualitative concordance that ranged from 1.5 to 50-fold differences estimated by relative potency. Similarly, Takayama et al. (1986) found a very large species difference in potency for sulfamonomethoxine between cynomologus monkeys and rats. Life stage: Applicability to certain life stages may depend on the species and their dependence on maternally transferred THs during the earliest phases of development. 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, TPO inhibition is not expected to decrease TH synthesis during these earliest stages of development. Evidence supporting this hypothesis is obtained from a zebrafish TPO knockout line. In homozygous individuals TPO is inhibited from the embryonic developmental stage onwards, resulting in an abolished T4 production in thyroid follicles with phenotypical abnormalities such as reduced swim bladder inflation and growth retardation appearing at 20 dpf but not before 10 dpf (Fang et al., 2022). 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 and not at 24 hpf but did not analyse time points between 24 and 72 hpf. In fathead minnows, a significant increase of whole body TH 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 TPO inhibition. Sex: This KE is plausibly applicable to both sexes. The molecular components responsible for TH synthesis, including TPO, are identical in both sexes. Therefore inhibition of TPO is not expected to be sex-specific.

UBERON:0005305

UBERON thyroid follicle

CL:0002258

CL thyroid follicular cell

High Female High Male

High

All life stages

High High High High High High High Not Specified

Baumann L, Ros A, Rehberger K, Neuhauss SCF, Segner H. 2016. Thyroid disruption in zebrafish (danio rerio) larvae: Different molecular response patterns lead to impaired eye development and visual functions. Aquatic Toxicology. 172:44-55. Brown RS, Shalhoub V, Coulter S, Alex S, Joris I, De Vito W, Lian J, Stein GS.  Developmental regulation of thyrotropin receptor gene expression in the fetal and neonatal rat thyroid: relation to thyroid morphology and to thyroid-specific gene expression.  Endocrinology. 2000 Jan;141(1):340-5. Brucker-Davis F. 1998. Effects of environmental synthetic chemicals on thyroid function. Thyroid 8:827-856. Campinho MA, Saraiva J, Florindo C, Power DM. 2014. Maternal thyroid hormones are essential for neural development in zebrafish. Molecular Endocrinology. 28(7):1136-1149. Chang, H. C. and D. R. Doerge (2000) Dietary genistein inactivates rat thyroid peroxidase in vivo without an apparent hypothyroid effect. Toxicol Appl Pharmacol. 168:244-252. Chang J, Wang M, Gui W, Zhao Y, Yu L, Zhu G. 2012. Changes in thyroid hormone levels during zebrafish development. Zoological Science. 29(3):181-184. Crane HM, Pickford DB, Hutchinson TH, Brown JA. 2004. Developmental changes of thyroid hormones in the fathead minnow, pimephales promelas. General and Comparative Endocrinology. 139(1):55-60. Divi, R. L., & Doerge, D. R. (1994). Mechanism-based inactivation of lactoperoxidase and thyroid peroxidase by resorcinol derivatives. Biochemistry 33(32), 9668–9674. Divi, R. L., Chang, H. C., & Doerge, D. R. (1997). Anti-Thyroid Isoflavones from Soybean. Biochem. Pharmacol.  54(10), 1087–1096. Doerge DR, Chang HC. Inactivation of thyroid peroxidase by soy isoflavones, in vitro and in vivo. J Chromatogr B Analy Technol Biomed Life Sci. 2002 Sep 25;777(1-2):269-79. Dong, H.Y., Godlewska, M., Wade, M.G., 2020. A rapid assay of human thyroid peroxidase activity. Toxicology in Vitro 62 Ealey PA, Henderson B, Loveridge N.A quantitative study of peroxidase activity in unfixed tissue sections of the guinea-pig thyroid gland. Histochem J. 1984 Feb;16(2):111-22. Fang, Y., Wan, J. P., Zhang, R. J., Sun, F., Yang, L., Zhao, S. X., Dong, M., & Song, H. D. (2022). Tpo knockout in zebrafish partially recapitulates clinical manifestations of congenital hypothyroidism and reveals the involvement of TH in proper development of glucose homeostasis. General and Comparative Endocrinology, 323–324. https://doi.org/10.1016/j.ygcen.2022.114033 Fukiishi Y, Harauchi T, Yoshizaki T, Hasegawa Y, Eguchi Y.  Ontogeny of thyroid peroxidase activity in perinatal rats. Acta Endocrinol (Copenh). 1982 101(3):397-402. Holzer G, Morishita Y, Fini JB, Lorin T, Gillet B, Hughes S, Tohmé M, Deléage G, Demeneix B, Arvan P, Laudet V. Thyroglobulin Represents a Novel Molecular Architecture of Vertebrates. J Biol Chem. 2016 Jun 16. Hornung, M. W., Degitz, S. J., Korte, L. M., Olson, J. M., Kosian, P. a, Linnum, A. L., & Tietge, J. E. (2010). Inhibition of thyroid hormone release from cultured amphibian thyroid glands by methimazole, 6-propylthiouracil, and perchlorate. Toxicol Sci 118(1), 42–51. Hurley PM. 1998. Mode of carcinogenic action of pesticides inducing thyroid follicular cell tumors in rodents. Environ Health Perspect 106:437-445. Kaczur, V., Vereb, G., Molnár, I., Krajczár, G., Kiss, E., Farid, N. R., & Balázs, C. (1997). Effect of anti-thyroid peroxidase (TPO) antibodies on TPO activity measured by chemiluminescence assay. Clin. Chem 43(8 Pt 1), 1392–6. Kessler, J., Obinger, C., Eales, G., 2008. Factors influencing the study of peroxidase- generated iodine species and implications for thyroglobulin synthesis. Thyroid 18, 769–774. Nelson K, Schroeder A, Ankley G, Blackwell B, Blanksma C, Degitz S, Flynn K, Jensen K, Johnson R, Kahl M et al. 2016. Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part i: Fathead minnow. Aquatic Toxicology. 173:192-203. OECD (2017) New Scoping Document on in vitro and ex vivo Assays for the Identification of Modulators of Thyroid Hormone Signalling. Series on Testing and Assessment. No. 207.  ISSN: 20777876 (online) http://dx.doi.org/10.1787/20777876 Opitz R, Maquet E, Zoenen M, Dadhich R, Costagliola S. 2011. Tsh receptor function is required for normal thyroid differentiation in zebrafish. Molecular Endocrinology. 25(9):1579-1599. Paul KB, Hedge JM, Macherla C, Filer DL, Burgess E, Simmons SO, Crofton KM, Hornung MW. Cross-species analysis of thyroperoxidase inhibition by xenobiotics demonstrates conservation of response between pig and rat. Toxicology. 2013. 312:97-107 Paul, K.B., Hedge, J.M., Rotroff, D.M., Hornung, M.W., Crofton, K.M., Simmons, S.O. 2014. Development of a thyroperoxidase inhibition assay for high-throughput screening. Chem.  Res. Toxicol. 27(3), 387-399. Paul-Friedman K, Watt ED, Hornung MW, Hedge JM, Judson RS, Crofton KM, Houck KA, Simmons SO. 2016. Tiered High-Throughput Screening Approach to Identify Thyroperoxidase Inhibitors Within the ToxCast Phase I and II Chemical Libraries.  Toxicol Sci. 151:160-80. Pintar, J.E. (2000) Normal development of the hypothalamic-pituitary-thyroid axis. In. Werner & Ingbar’s The Thyroid. (8th ed), Braverman. L.E. and Utiger, R.D. (eds) Lippincott Williams and Wilkins, Philadelphia. Power DM, Llewellyn L, Faustino M, Nowell MA, Bjornsson BT, Einarsdottir IE, Canario AV, Sweeney GE. 2001. Thyroid hormones in growth and development of fish. Comp Biochem Physiol C Toxicol Pharmacol. 130(4):447-459. Remy L, Michel-Bechet M, Athouel-Haon AM, Magre S. Critical study of endogenous peroxidase activity: its role in the morphofunctional setting of the thyroid follicle in the rat fetus. Acta Histochem. 1980;67(2):159-72. Ruf, J., & Carayon, P. (2006). Structural and functional aspects of thyroid peroxidase. Archives of Biochemistry and Biophysics, 445(2), 269–77. Ruuskanen S, Hsu BY. 2018. Maternal thyroid hormones: An unexplored mechanism underlying maternal effects in an ecological framework. Physiological and Biochemical Zoology. 91(3):904-916. Santisteban P, Bernal J. Thyroid development and effect on the nervous system. Rev Endocr Metab Disord. 2005 Aug;6(3):217-28. Schmutzler, C., Bacinski, A., Gotthardt, I., Huhne, K., Ambrugger, P., Klammer, H., Schlecht, C., Hoang-Vu, C., Gruters, A., Wuttke, W., Jarry, H., Kohrle, J., 2007a. The ultraviolet filter benzophenone 2 interferes with the thyroid hormone axis in rats and is a potent in vitro inhibitor of human recombinant thyroid peroxidase. Endocrinology 148, 2835–2844. Stinckens E, Vergauwen L, Blackwell BR, Anldey GT, Villeneuve DL, Knapen D. 2020. Effect of thyroperoxidase and deiodinase inhibition on anterior swim bladder inflation in the zebrafish. Environmental Science & Technology. 54(10):6213-6223. Stinckens E, Vergauwen L, Schroeder A, Maho W, Blackwell B, Witters H, Blust R, Ankley G, Covaci A, Villeneuve D et al. 2016. Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part ii: Zebrafish. Aquatic Toxicology. 173:204-217. Taurog A. 2005. Hormone synthesis. In: Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text (Braverman LE, Utiger RD, eds). Philadelphia:Lippincott, Williams and Wilkins, 47–81 Taurog, a, Dorris, M. L., & Doerge, D. R. (1996). Mechanism of simultaneous iodination and coupling catalyzed by thyroid peroxidase. Archives of Biochemistry and Biophysics, Taurog A. Molecular evolution of thyroid peroxidase. Biochimie. 1999 May;81(5):557-62 Takayama S, Aihara K, Onodera T, Akimoto T. 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2022-11-04T09:24:35

Thyroid hormone synthesis, Decreased

TH synthesis, Decreased

Cellular

The thyroid hormones (TH), triiodothyronine (T3) and thyroxine (T4) are thyrosine-based hormones. Synthesis of THs is regulated by thyroid-stimulating hormone (TSH) binding to its receptor and thyroidal availability of iodine via the sodium iodide symporter (NIS). Other proteins contributing to TH production in the thyroid gland, including thyroperoxidase (TPO), dual oxidase enzymes (DUOX), and the transport protein pendrin are also necessary for iodothyronine production (Zoeller et al., 2007). The production of THs in the thyroid gland and resulting serum concentrations are controlled by a negatively regulated feedback mechanism. Decreased T4 and T3 serum concentrations activates the hypothalamus-pituitary-thyroid (HPT) axis which upregulates thyroid-stimulating hormone (TSH) that acts to increase production of additional THs (Zoeller and Tan, 2007). This regulatory system includes: 1) the hypothalamic secretion of the thyrotropin-releasing hormone (TRH); 2) the thyroid-stimulating hormone (TSH) secretion from the anterior pituitary; 3) hormonal transport by the plasma binding proteins; 4) cellular uptake mechanisms at the tissue level; 5) intracellular control of TH concentrations by deiodinating mechanisms; 6) transcriptional function of the nuclear TH receptor; and 7) in the fetus, the transplacental passage of T4 and T3 (Zoeller et al., 2007). TRH and the TSH primarily regulate the production of T4, often considered a “pro-hormone,” and to a lesser extent of T3, the transcriptionally active TH. Most of the hormone released from the thyroid gland into circulation is in the form of T4, while peripheral deiodination of T4 is responsible for the majority of circulating T3. Outer ring deiodination of T4 to T3 is catalyzed by the deiodinases 1 and 2 (DIO1 and DIO2), with DIO1 expressed mainly in liver and kidney, and DIO2 expressed in several tissues including the brain (Bianco et al., 2006). Conversion of T4 to T3 takes place mainly in the liver and kidney, but also in other target organs such as in the brain, the anterior pituitary, brown adipose tissue, thyroid and skeletal muscle (Gereben et al., 2008; Larsen, 2009).  In mammals, most evidence for the ontogeny of TH synthesis comes from measurements of serum hormone concentrations. And, importantly, the impact of xenobiotics on fetal hormones must include the influence of the maternal compartment since a majority of fetal THs are derived from maternal blood early in fetal life, with a transition during mid-late gestation to fetal production of THs that is still supplemented by maternal THs. In humans, THs can be found in the fetus as early as gestational weeks 10-12, and concentations rise continuously until birth. At term, fetal T4 is similar to maternal levels, but T3 remains 2-3 fold lower than maternal levels. In rats, THs can be detected in the fetus as early as the second gestational week, but fetal synthesis does not start until gestational day 17 with birth at gestational day 22-23. Maternal THs continue to supplement fetal production until parturition. (see Howdeshell, 2002; Santisteban and Bernal, 2005 for review). Due to the maternal factor, the life stage specific impact of TPO inhibition after exposure to environmental chemicals is complex (Ramhoj et al., 2022). Decreased TH synthesis in the thyroid gland may result from several possible molecular-initiating events (MIEs) including: 1) Disruption of key catalytic enzymes or cofactors needed for TH synthesis, including TPO, NIS, or dietary iodine insufficiency. Theoretically, decreased synthesis of Tg could also affect TH production (Kessler et al., 2008; Yi et al., 1997). Mutations in genes that encode requisite proteins in the thyroid may also lead to impaired TH synthesis, including mutations in pendrin associated with Pendred Syndrome (Dossena et al., 2011), mutations in TPO and Tg (Huang and Jap 2015), and mutations in NIS (Spitzweg and Morris, 2010). 2) Decreased TH synthesis in cases of clinical hypothyroidism may be due to Hashimoto's thyroiditis or other forms of thyroiditis, or physical destruction of the thyroid gland as in radioablation or surgical treatment of thyroid lymphoma. 3) It is possible that TH synthesis may also be reduced subsequent to disruption of the negative feedback mechanism governing TH homeostasis, e.g. pituitary gland dysfunction may result in a decreased TSH signal with concomitant T3 and T4 decreases. 4) More rarely, hypothalamic dysfunction can result in decreased TH synthesis.  Increased fetal TH levels are also possible. Maternal Graves disease, which results in fetal thyrotoxicosis (hyperthyroidism and increased serum T4 levels), has been successfully treated by maternal administration of TPO inhibitors (c.f., Sato et al., 2014).   It should be noted that different species and different life stages store different amounts of TH precursors and iodine within the thyroid gland. Thus, decreased TH synthesis via transient iodine insufficiency or inhibition of TPO may not affect TH release from the thyroid gland until depletion of stored iodinated Tg. Adult humans may store sufficient Tg-DIT residues to serve for several months to a year of TH demand (Greer et al., 2002; Zoeller, 2004). Neonates and infants have a much more limited supply of less than a week. While the TH system is highly conserved across vertebrates, there are some taxon-specific considerations. Zebrafish and fathead minnows are oviparous fish species in which maternal THs are transferred to the eggs and regulate early embryonic developmental processes during external (versus intra-uterine in mammals) development (Power et al., 2001; Campinho et al., 2014; Ruuskanen and Hsu, 2018) until embryonic TH synthesis is initiated. Maternal transfer of THs to the eggs has been demonstrated in zebrafish (Walpita et al., 2007; Chang et al., 2012) and fathead minnows (Crane et al., 2004; Nelson et al., 2016). Decreases in TH synthesis can only occur after initiation of embryonic TH synthesis. The components of the TH system responsible for TH synthesis are highly conserved across vertebrates and therefore interference with the same molecular targets compared to mammals can lead to decreased TH synthesis (TPO, NIS, etc.) in fish. Endogenous transcription profiles of thyroid-related genes in zebrafish and fathead minnow showed that mRNA coding for these genes is also maternally transferred and increasing expression of most transcripts during hatching and embryo-larval transition indicates a fully functional HPT axis in larvae (Vergauwen et al., 2018). Although the HPT axis is highly conserved, there are some differences between fish and mammals (Blanton and Specker, 2007; Deal and Volkoff, 2020). For example, in fish, corticotropin releasing hormone (CRH) often plays a more important role in regulating thyrotropin (TSH) secretion by the pituitary and thus TH synthesis compared to TSH-releasing hormone (TRH). Also, in most fish species thyroid follicles are more diffusely located in the pharyngeal region rather than encapsulated in a gland.

Decreased TH synthesis is often implied by measurement of TPO and NIS inhibition measured clinically and in laboratory models as these enzymes are essential for TH synthesis. Rarely is decreased TH synthesis measured directly, but rather the impact of chemicals on the quantity of T4 produced in the thyroid gland, or the amount of T4 present in serum is used as a marker of decreased T4 release from the thyroid gland (e.g., Romaldini et al., 1988). Methods used to assess TH synthesis include, incorporation of radiolabeled tracer compounds, radioimmunoassay, ELISA, and analytical detection.    Recently, amphibian thyroid explant cultures have been used to demonstrate direct effects of chemicals on TH synthesis, as this model contains all necessary synthesis enzymes including TPO and NIS (Hornung et al., 2010). For this work THs was measured by HPLC/ICP-mass spectometry. Decreased TH synthesis and release, using T4 release as the endpoint, has been shown for thiouracil antihyperthyroidism drugs including MMI, PTU, and the NIS inhibitor perchlorate (Hornung et al., 2010). Techniques for in vivo analysis of TH system disruption among other drug-related effects in fish were reviewed by Raldua and Piña (2014). TIQDT (Thyroxine-immunofluorescence quantitative disruption test) is a method that provides an immunofluorescent based estimate of thyroxine in the gland of zebrafish (Raldua and Babin, 2009; Thienpont et al., 2011; Jomaa et al., 2014; Rehberger et al., 2018).  Thienpont used this method with ~25 xenobiotics (e.g., amitrole, perchlorate, methimazole, PTU, DDT, PCBs). The method detected changes for all chemicals known to directly impact TH synthesis in the thyroid gland (e.g., NIS and TPO inhibitors), but not those that upregulate hepatic catabolism of T4. Rehberger et al. (2018) updated the method to enable simultaneous semi-quantitative visualization of intrafollicular T3 and T4 levels. Most often, whole body TH level measurements in fish early life stages are used as indirect evidence of decreased TH synthesis (Nelson et al., 2016; Stinckens et al., 2016; Stinckens et al., 2020). Analytical determination of TH levels by LC-MS is becoming increasingly available (Hornung et al., 2015). More recently, transgenic zebrafish with fluorescent thyroid follicles are being used to visualize the compensatory proliferation of the thyroid follicles following inhibition of TH synthesis among others (Opitz et al., 2012).

Taxonomic: This KE is plausibly applicable across vertebrates. Decreased TH synthesis resulting from TPO or NIS inhibition is conserved across vertebrate taxa, with in vivo evidence from humans, rats, amphibians, some fish species, and birds, and in vitro evidence from rat and porcine microsomes. Indeed, TPO and NIS mutations result in congenital hypothyroidism in humans (Bakker et al., 2000; Spitzweg and Morris, 2010), demonstrating the essentiality of TPO and NIS function toward maintaining euthyroid status. Though decreased serum T4 is used as a surrogate measure to indicate chemical-mediated decreases in TH synthesis, clinical and veterinary management of hyperthyroidism and Graves’ disease using propylthiouracil and methimazole, known to decrease TH synthesis, indicates strong evidence for chemical inhibition of TPO (Zoeller and Crofton, 2005). Life stage: Applicability to certain life stages may depend on the species and their dependence on maternally transferred THs during the earliest phases of development. The earliest life stages of teleost fish (e.g., fathead minnow, zebrafish) rely on maternally transferred THs to regulate certain developmental processes until embryonic TH synthesis is active (Power et al., 2001). In externally developing fish species, decreases in TH synthesis can only occur after initiation of embryonic TH synthesis. 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. TPO inhibition in a homozygous knockout line abolished the T4 production in thyroid follicles of mutant zebrafish with phenotypic abnormalities occurring from 20 dpf onwards but not before 10 dpf (Fang et al., 2022). Therefore, it is still uncertain when exactly embryonic TH synthesis is activated and thus when exactly this process becomes sensitive to disruption. In fathead minnows, a significant increase of whole body TH 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 currently remains unclear when exactly embryonic TH production is initiated in zebrafish. Sex: The KE is plausibly applicable to both sexes. THs 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 TH levels and the magnitude of the response. In humans, females appear more susceptible to hypothyroidism compared to males when exposed to certain halogenated chemicals (Hernandez‐Mariano et al., 2017; Webster et al., 2014). In adult zebrafish, Liu et al. (2019) showed sex-dependent changes in TH 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.

UBERON:0002046

UBERON thyroid gland

CL:0002258

CL thyroid follicular cell

High Male High Female

High

All life stages

High High Moderate High Moderate High

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Thyroid development and effect on the nervous system. Rev Endocr Metab Disord. 2005 Aug;6(3):217-28. Spitzweg C, Morris JC. 2010. Genetics and phenomics of hypothyroidism and goiter due to NIS mutations. Molecular and cellular endocrinology. 322:56-63. Stinckens E, Vergauwen L, Blackwell BR, Anldey GT, Villeneuve DL, Knapen D. 2020. Effect of thyroperoxidase and deiodinase inhibition on anterior swim bladder inflation in the zebrafish. Environmental Science & Technology. 54(10):6213-6223. Stinckens E, Vergauwen L, Schroeder A, Maho W, Blackwell B, Witters H, Blust R, Ankley G, Covaci A, Villeneuve D et al. 2016. Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part ii: Zebrafish. Aquatic Toxicology. 173:204-217. Thienpont B, Tingaud-Sequeira A, Prats E, Barata C, Babin PJ, Raldúa D.  Zebrafish eleutheroembryos provide a suitable vertebrate model for screening chemicals that impair thyroid hormone synthesis.  Environ Sci Technol. 2011. 45(17):7525-32. Vergauwen L, Cavallin JE, Ankley GT, Bars C, Gabriels IJ, Michiels EDG, Fitzpatrick KR, Periz-Stanacev J, Randolph EC, Robinson SL et al. 2018. Gene transcription ontogeny of hypothalamic-pituitary-thyroid axis development in early-life stage fathead minnow and zebrafish. General and Comparative Endocrinology. 266:87-100. Wabukebunoti MAN, Firling CE. 1983. The prehatching development of the thyroid-gland of the fathead minnow, pimephales-promelas (rafinesque). General and Comparative Endocrinology. 49(2):320-331. Walpita CN, Van der Geyten S, Rurangwa E, Darras VM. 2007. The effect of 3,5,3'-triiodothyronine supplementation on zebrafish (danio rerio) embryonic development and expression of iodothyronine deiodinases and thyroid hormone receptors. Gen Comp Endocrinol. 152(2-3):206-214. Walter KM, Miller GW, Chen XP, Yaghoobi B, Puschner B, Lein PJ. 2019. Effects of thyroid hormone disruption on the ontogenetic expression of thyroid hormone signaling genes in developing zebrafish (danio rerio). General and Comparative Endocrinology. 272:20-32. Webster GM, Venners SA, Mattman A, Martin JW. 2014. Associations between perfluoroalkyl acids (pfass) and maternal thyroid hormones in early pregnancy: A population-based cohort study. Environmental Research. 133:338-347. Yi X, Yamamoto K, Shu L, Katoh R, Kawaoi A. Effects of Propyithiouracil (PTU) Administration on the Synthesis and Secretion of Thyroglobulin in the Rat Thyroid Gland: A Quantitative Immuno-electron Microscopic Study Using Immunogold Technique. Endocr Pathol. 1997 Winter;8(4):315-325. Zoeller RT, Crofton KM. 2005.  Mode of action: developmental thyroid hormone insufficiency--neurological abnormalities resulting from exposure to propylthiouracil. Crit Rev Toxicol. 35:771-81 Zoeller RT, Tan SW, Tyl RW. 2007. General background on the hypothalamic-pituitary-thyroid (HPT) axis. Critical reviews in toxicology.  37:11-53. Zoeller RT.  Interspecies differences in susceptibility to perturbation of thyroid hormone homeostasis requires a definition of "sensitivity" that is informative for risk analysis. Regul Toxicol Pharmacol. 2004 Dec;40(3):380.   AOPWiki 2016-11-29T18:41:23

2022-11-04T09:25:39

Thyroxine (T4) in serum, Decreased

T4 in serum, Decreased

Tissue

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). 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). Normal serum T4 reference ranges can be species and lifestage specific. In rodents, 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 humans, 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). In some frog species, there is an analogous peak in THs in tadpoles that starts around embryonic NF stage 56, peaks at stage 62 and the declines to lower levels by stage 56 (Sternberg et al., 2011; Leloup and Buscaglia, 1977).  Additionally, ample evidence is available from studies investigating responses to inhibitors of TH synthesis in fish. 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.

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). 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.

Taxonomic: 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). Their 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 THs 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, extrapolation regarding TH action across species and developmental stages should be done with caution. 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- 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. Life stage: 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 TH 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 system disruptors. Sex: The KE is plausibly applicable to both sexes. THs 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 TH levels and the magnitude of the response. In humans, females appear more susceptible to hypothyroidism compared to males when exposed to certain halogenated chemicals (Hernandez‐Mariano et al., 2017; Webster et al., 2014). In adult zebrafish, Liu et al. (2019) showed sex-dependent changes in TH 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.

UBERON:0001977

UBERON serum

High Female High Male

High

All life stages

High High High Moderate Moderate High High High

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. Baret A. and Fert V.  T4 and ultrasensitive TSH immunoassays using luminescent enhanced xanthine oxidase assay. J Biolumin Chemilumin. 1989. 4(1):149-153 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. Capen CC. Mechanistic data and risk assessment of selected toxic end points of the thyroid gland. Toxicol Pathol. 1997 25(1):39-48. 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. Chang J, Wang M, Gui W, Zhao Y, Yu L, Zhu G. 2012. Changes in thyroid hormone levels during zebrafish development. Zoological Science. 29(3):181-184. Cope RB, Kacew S, Dourson M. A reproductive, developmental and neurobehavioral study following oral exposure of tetrabromobisphenol A on Sprague-Dawley rats. Toxicology. 2015 329:49-59. Corcoran JM, Eastman CJ, Carter JN, Lazarus L. (1977). Circulating thyroid hormone levels in children. Arch Dis Child. 52: 716-720. Crane HM, Pickford DB, Hutchinson TH, Brown JA. 2006. The effects of methimazole on development of the fathead minnow, pimephales promelas, from embryo to adult. Toxicological Sciences. 93(2):278-285. Crofton KM. Developmental disruption of thyroid hormone: correlations with hearing dysfunction in rats. Risk Anal. 2004 Dec;24(6):1665-71. DeVito M, Biegel L, Brouwer A, Brown S, Brucker-Davis F, Cheek AO, Christensen R, Colborn T, Cooke P, Crissman J, Crofton K, Doerge D, Gray E, Hauser P, Hurley P, Kohn M, Lazar J, McMaster S, McClain M, McConnell E, Meier C, Miller R, Tietge J, Tyl R. (1999). Screening methods for thyroid hormone disruptors. Environ Health Perspect. 107:407-415. 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. Eales JG. (1997). Iodine metabolism and thyroid related functions in organisms lacking thyroid follicles: Are thyroid hormones also vitaminsProc Soc Exp Biol Med. 214:302-317. Furlow JD, Neff ES. (2006). A developmental switch induced by thyroid hormone: Xenopus laevis metamorphosis. Trends Endocrinol Metab. 17:40–47. Goldey ES, Crofton KM. Thyroxine replacement attenuates hypothyroxinemia, hearing loss, and motor deficits following developmental exposure to Aroclor 1254 in rats. Toxicol Sci. 1998 45(1):94-10 Goldey ES, Kehn LS, Lau C, Rehnberg GL, Crofton KM.  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. Harris AR, Fang SL, Prosky J, Braverman LE, Vagenakis AG.  Decreased outer ring monodeiodination of thyroxine and reverse triiodothyronine in the fetal and neonatal rat.  Endocrinology. 1978 Dec;103(6):2216-22 Hernandez-Mariano JA, Torres-Sanchez L, Bassol-Mayagoitia S, Escamilla-Nunez M, Cebrian ME, Villeda-Gutierrez EA, Lopez-Rodriguez G, Felix-Arellano EE, Blanco-Munoz J. 2017. Effect of exposure to p,p '-dde during the first half of pregnancy in the maternal thyroid profile of female residents in a mexican floriculture area. Environmental Research. 156:597-604. Heyland A, Hodin J. (2004). Heterochronic developmental shift caused by thyroid hormone in larval sand dollars and its implications for phenotypic plasticity and the evolution of non-feeding development. Evolution. 58: 524-538. Heyland A, Moroz LL. (2005). Cross-kingdom hormonal signaling: an insight from thyroid hormone functions in marine larvae. J Exp Biol. 208:4355-4361. Hill RN, Crisp TM, Hurley PM, Rosenthal SL, Singh DV. Risk assessment of thyroid follicular cell tumors.  Environ Health Perspect. 1998 Aug;106(8):447-57. Hornung MW, Kosian P, Haselman J, Korte J, Challis K, Macherla C, Nevalainen E, Degitz S (2015) In vitro, ex vivo and in vivo determination of thyroid hormone modulating activity of benzothiazoles. Toxicol Sci 146:254-264. Hulbert AJ. Thyroid hormones and their effects: a new perspective. Biol Rev Camb Philos Soc. 2000 Nov;75(4):519-631. Review. Kapelari K, Kirchlechner C, Högler W, Schweitzer K, Virgolini I, Moncayo R. 2008. Pediatric reference intervals for thyroid hormone levels from birth to adulthood: a retrospective study. BMC Endocr Disord. 8: 15. Lau C, Thibodeaux JR, Hanson RG, Rogers JM, Grey BE, Stanton ME, Butenhoff JL, Stevenson LA.  Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse. II: postnatal evaluation.  Toxicol Sci. 2003 Aug;74(2):382-92. Leloup, J., and M. Buscaglia. La triiodothyronine: hormone de la métamorphose des amphibiens. CR Acad Sci 284 (1977): 2261-2263. Liu J, Liu Y, Barter RA, Klaassen CD.: Alteration of thyroid homeostasis by UDP-glucuronosyltransferase inducers in rats: a dose-response study. J Pharmacol Exp Ther 273, 977-85, 1994 Liu XS, Cai Y, Wang Y, Xu SH, Ji K, Choi K. 2019. Effects of tris(1,3-dichloro-2-propyl) phosphate (tdcpp) and triphenyl phosphate (tpp) on sex-dependent alterations of thyroid hormones in adult zebrafish. Ecotoxicology and Environmental Safety. 170:25-32. Liu YW, Chan WK. 2002. Thyroid hormones are important for embryonic to larval transitory phase in zebrafish. Differentiation. 70(1):36-45. Manzon RG, Youson JH. (1997). The effects of exogenous thyroxine (T4) or triiodothyronine (T3), in the presence and absence of potassium perchlorate, on the incidence of metamorphosis and on serum T4 and T3 concentrations in larval sea lampreys (Petromyzon marinus L.). Gen Comp Endocrinol. 106:211-220.  McClain RM. Mechanistic considerations for the relevance of animal data on thyroid neoplasia to human risk assessment. Mutat Res. 1995 Dec;333(1-2):131-42 Miller MD, Crofton KM, Rice DC, Zoeller RT.  Thyroid-disrupting chemicals: interpreting upstream biomarkers of adverse outcomes. Environ Health Perspect. 2009 117(7):1033-41 Morse DC, Wehler EK, Wesseling W, Koeman JH, Brouwer A. Alterations in rat brain thyroid hormone status following pre- and postnatal exposure to polychlorinated biphenyls (Aroclor 1254). Toxicol Appl Pharmacol. 1996 Feb;136(2):269-79. Nelson K, Schroeder A, Ankley G, Blackwell B, Blanksma C, Degitz S, Flynn K, Jensen K, Johnson R, Kahl M et al. 2016. Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part i: Fathead minnow. Aquatic Toxicology. 173:192-203. NTP National Toxicology Program.: NTP toxicology and carcinogenesis studies of 3,3'-dimethylbenzidine dihydrochloride (CAS no. 612-82-8) in F344/N rats (drinking water studies). Natl Toxicol Program Tech Rep Ser 390, 1-238, 1991. O'Connor, J. C., J. C. Cook, et al. (1998). "An ongoing validation of a Tier I screening battery for detecting endocrine-active compounds (EACs)." Toxicol Sci 46(1): 45-60. O'Connor, J. C., L. G. Davis, et al. (2000). "Detection of dopaminergic modulators in a tier I screening battery for identifying endocrine-active compounds (EACs)." Reprod Toxicol 14(3): 193-205. Opitz R, Maquet E, Zoenen M, Dadhich R, Costagliola S. 2011. Tsh receptor function is required for normal thyroid differentiation in zebrafish. Molecular Endocrinology. 25(9):1579-1599. Power DM, Llewellyn L, Faustino M, Nowell MA, Bjornsson BT, Einarsdottir IE, Canario AV, Sweeney GE. 2001. Thyroid hormones in growth and development of fish. Comp Biochem Physiol C Toxicol Pharmacol. 130(4):447-459. Rathmann D, Rijntjes E, Lietzow J, Köhrle J. (2015) Quantitative Analysis of Thyroid Hormone Metabolites in Cell Culture Samples Using LC-MS/MS. Eur Thyroid J. Sep;4(Suppl 1):51-8. Rouaze-Romet M, Savu L, Vranckx R, Bleiberg-Daniel F, Le Moullac B, Gouache P, Nunez EA. 1992. Reexpression of thyroxine-binding globulin in postweaning rats during protein or energy malnutrition. Acta Endocrinol (Copenh).127:441-448. Samanidou VF, Kourti PV. (2009) Rapid HPLC method for the simultaneous monitoring of duloxetine, venlaflaxine, fluoxetine and paroxetine in biofluids. Bioanalysis. 2009 Aug;1(5):905-17. Savu L, Vranckx R, Maya M, Gripois D, Blouquit MF, Nunez EA. 1989. Thyroxine-binding globulin and thyroxinebinding prealbumin in hypothyroid and hyperthyroid developing rats. BiochimBiophys Acta. 992:379-384. Schneider S, Kaufmann W, Strauss V, van Ravenzwaay B.    Vinclozolin: a feasibility and sensitivity study of the ILSI-HESI F1-extended one-generation rat reproduction protocol. Regul Toxicol Pharmacol. 2011 Feb;59(1):91-100. Schussler, G.C. (2000). The thyroxine-binding proteins. Thyroid 10:141–149. Spencer, CA. (2013). Assay of thyroid hormone and related substances. In De Groot, LJ et al. (Eds). Endotext. South Dartmouth, MA Sternberg RM, Thoemke KR, Korte JJ, Moen SM, Olson JM, Korte L, Tietge JE, Degitz SJ Jr. Control of pituitary thyroid-stimulating hormone synthesis and secretion by thyroid hormones during Xenopus metamorphosis. Gen Comp Endocrinol. 2011. 173(3):428-37 Stinckens E, Vergauwen L, Blackwell BR, Anldey GT, Villeneuve DL, Knapen D. 2020. Effect of thyroperoxidase and deiodinase inhibition on anterior swim bladder inflation in the zebrafish. Environmental Science & Technology. 54(10):6213-6223. Stinckens E, Vergauwen L, Schroeder A, Maho W, Blackwell B, Witters H, Blust R, Ankley G, Covaci A, Villeneuve D et al. 2016. Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part ii: Zebrafish. Aquatic Toxicology. 173:204-217. Taurog A. 2005. Hormone synthesis. In: Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text (Braverman LE, Utiger RD, eds). Philadelphia:Lippincott, Williams and Wilkins, 47–81Walker P, Dubois JD, Dussault JH.  Free thyroid hormone concentrations during postnatal development in the rat.  Pediatr Res. 1980 Mar;14(3):247-9. Thienpont B, Tingaud-Sequeira A, Prats E, Barata C, Babin PJ, Raldúa D. Zebrafish eleutheroembryos provide a suitable vertebrate model for screening chemicals that impair thyroid hormone synthesis. Environ Sci Technol. 2011 Sep 1;45(17):7525-32. Wabukebunoti MAN, Firling CE. 1983. The prehatching development of the thyroid-gland of the fathead minnow, pimephales-promelas (rafinesque). General and Comparative Endocrinology. 49(2):320-331. Walter KM, Miller GW, Chen XP, Yaghoobi B, Puschner B, Lein PJ. 2019. Effects of thyroid hormone disruption on the ontogenetic expression of thyroid hormone signaling genes in developing zebrafish (danio rerio). General and Comparative Endocrinology. 272:20-32. Webster GM, Venners SA, Mattman A, Martin JW. 2014. Associations between perfluoroalkyl acids (pfass) and maternal thyroid hormones in early pregnancy: A population-based cohort study. Environmental Research. 133:338-347. Yamauchi K1, Ishihara A. Evolutionary changes to transthyretin: developmentally regulated and tissue-specific gene expression. FEBS J. 2009. 276(19):5357-66. Yaoita Y, Brown DD. (1990). A correlation of thyroid hormone receptor gene expression with amphibian metamorphosis. Genes Dev. 4:1917-1924. Yen PM. (2001). Physiological and molecular basis of thyroid hormone action. Physiol Rev. 81:1097-1142. Zoeller RT, Tan SW, Tyl RW. General background on the hypothalamic-pituitary-thyroid (HPT) axis. Crit Rev Toxicol. 2007 Jan-Feb;37(1-2):11-53 Zoeller, R. T., R. Bansal, et al. (2005). "Bisphenol-A, an environmental contaminant that acts as a thyroid hormone receptor antagonist in vitro, increases serum thyroxine, and alters RC3/neurogranin expression in the developing rat brain." Endocrinology 146(2): 607-612. AOPWiki 2016-11-29T18:41:23

2022-10-10T08:52:30

Decreased, Triiodothyronine (T3)

Tissue

There are two biologically active thyroid hormones (THs), triiodothyronine (T3) and thyroxine (T4), and a few less active iodothyronines (rT3, 3,5-T2), which are all derived from the modification of tyrosine molecules (Hulbert, 2000). However, the plasma concentrations of the other iodothyronines are significantly lower than those of T3 and T4. The different iodothyronines are formed by the sequential outer or inner ring monodeiodination of T4 and T3 by the deiodinating enzymes, Dio1, Dio2, and Dio3 (Gereben et al., 2008). Deiodinase structure is considered to be unique, as THs are the only molecules in the body that incorporate iodide. The circulatory system serves as the major transport and delivery system for THs from synthesis in the gland to delivery to tissues. The majority of THs in the blood are bound to transport proteins (Bartalena and Robbins, 1993). In humans, the major transport proteins are TBG (thyroxine binding globulin), TTR (transthyretin) and albumin. The percent bound to these proteins in adult humans is about 75, 15 and 10 percent, respectively (Schussler 2000). Unbound (free) hormones are approximately 0.03 and 0.3 percent for T4 and T3, respectively. In serum, it is the free form of the hormone that is active. There are major species differences in the predominant binding proteins and their affinities for THs (see section below on Taxonomic applicability). However, there is broad agreement that changes in concentrations of THs is diagnostic of thyroid disease or chemical-induced disruption of thyroid homeostasis (Zoeller et al., 2007). It is notable that the changes measured in the free TH concentration reflect mainly the changes in the serum transport proteins rather than changes in the thyroid status. These thyroid-binding proteins serve as hormonal storage which ensures their even and constant distribution in the different tissues, while they protect the most sensitive ones in the case of severe changes in thyroid availability, like in thyroidectomies (Obregon et al., 1981). Initially, it was believed that all of the effects of TH were mediated by the binding of T3 to the thyroid nuclear receptors (TRa and TRb), a notion which is now questionable due to the increasing evidence that support the non-genomic action of TH (Davis et al., 2010, Moeller et al., 2006). Many non-nuclear TH binding sites have been identified to date and they usually lead to rapid cellular response in TH-effects (Bassett et al., 2003). Four types of thyroid hormone signaling have been defined (Anyetei-Anum et al., 2018): type 1 is the canonical pathway in which liganded TR binds directly to DNA; type 2 describes liganded TR tethered to chromatin-associated proteins, but not bound to DNA directly; type 3 suggests that liganded TR can exert its function without recruitment to chromatin in either the nucleus or cytoplasm; and type 4 proposes that thyroid hormone acts at the plasma membrane or in the cytoplasm without binding TR, a mechanism of action that is emerging as a key component of thyroid hormone signaling. The production of THs in the thyroid gland and the circulation levels in the bloodstream are self-controlled by an efficiently regulated feedback mechanism across the Hypothalamus-Pituitary-Thyroid (HPT) axis. TH levels are regulated, not only in the plasma level, but also in the individual cell level, to maintain homeostasis. This is succeeded by the efficient regulatory mechanism of the thyroid hormone axis which consists of the following: (1) the hypothalamic secretion of the thyrotropin-releasing hormone (TRH), (2) the thyroid-stimulating hormone (TSH) secretion from the anterior pituitary, (3) hormonal transport by the plasma binding proteins, (4) cellular uptake mechanisms in the cell level, (5) intracellular control of TH concentration by the deiodinating mechanism (6) transcriptional function of the nuclear thyroid hormone receptor and (7) in the fetus, the transplacental passage of T4 and T3 (Cheng et al., 2010). In regards to the brain, the TH concentration involves also an additional level of regulation, namely the hormonal transport through the Blood Brain Barrier (BBB) (Williams, 2008). The TRH and the TSH regulate the production of thyroid hormones. Less T3 (the biologically more active TH) than T4 is produced by the thyroid gland. The rest of the required amount of T3 is produced by outer ring deiodination of T4 by the deiodinating enzymes D1 and D2 (Bianco et al., 2006), a process which takes place mainly in liver and kidneys but also in other target organs such as in the brain, the anterior pituitary, brown adipose tissue, thyroid and skeletal muscle (Gereben et al., 2008; Larsen, 2009). Both hormones exert their action in almost all tissues of mammals and they are acting intracellularly, and thus the uptake of T3 and T4 by the target cells is a crucial step of the overall pathway. The trans-membrane transport of TH is performed mainly through transporters that differ depending on the cell type (Hennemann et al., 2001; Friesema et al., 2005; Visser et al., 2008). Many transporter proteins have been identified to date. The monocarboxylate transporters (Mct8, Mct10) and the anion-transporting polypeptide (OATP1c1) show the highest degree of affinity towards TH (Jansen et al., 2005) and mutations in these genes have pathophysiological effects in humans (Bernal et al., 2015). Unlike humans with an MCT8 deficiency, MCT8 knockout mice do not have neurological impairment. One explanation for this discrepancy could be differences in expression of the T4 transporter OATP1C1 in the blood–brain barrier. This shows that cross-species differences in the importance of specific transporters may occur. T3 and T4 have significant effects on normal development, neural differentiation, growth rate and metabolism (Yen, 2001; Brent, 2012; Williams, 2008), with the most prominent ones to occur during the fetal development and early childhood. The clinical features of hypothyroidism and hyperthyroidism emphasize the pleiotropic effects of these hormones on many different pathways and target organs. The thyroidal actions though are not only restricted to mammals, as their high significance has been identified also for other vertebrates, with the most well-studied to be the amphibian metamorphosis (Furlow and Neff, 2006). The importance of the thyroid-regulated pathways becomes more apparent in iodine deficient areas of the world, where a higher rate of cretinism and growth retardation has been observed and linked to decreased TH levels (Gilbert et al., 2012). Another very common cause of severe hypothyroidism in human is the congenital hypothyroidism, but the manifestation of these effects is only detectable in the lack of adequate treatment and is mainly related to neurological impairment and growth retardation (Glinoer, 2001), emphasizing the role of TH in neurodevelopment in all above cases. In adults, the thyroid-related effects are mainly linked to metabolic activities, such as deficiencies in oxygen consumption, and in the metabolism of the vitamin, proteins, lipids and carbohydrates, but these defects are subtle and reversible (Oetting and Yen, 2007). Blood tests to detect the amount of thyroid hormone (T4) and thyroid stimulating hormone (TSH) are routinely done for newborn babies for the diagnosis of congenital hypothyroidism at the earliest stage possible. Although the components of the thyroid hormone system as well as thyroid hormone synthesis and action are highly conserved across vertebrates, there are some taxon-specific considerations. Although the HPT axis is highly conserved, there are some differences between fish and mammals (Blanton and Specker, 2007; Deal and Volkoff, 2020). For example, in fish, corticotropin releasing hormone (CRH) often plays a more important role in regulating thyrotropin (TSH) secretion by the pituitary and thus thyroid hormone synthesis compared to TSH-releasing hormone (TRH). TTRs from fish have low sequence identity with human TTR, for example seabream TTR has 54% sequence identity with human TTR but the only amino acid difference within the thyroxine-binding site is the conservative substitution of Ser117 in human TTR to Thr117 in seabream TTR (Santos and Power, 1999; Yamauchi et al., 1999; Eneqvist et al., 2004). In vitro binding experiments showed that TH system disrupting chemicals bind with equal or weaker affinity to seabream TTR than to the human TTR with polar TH disrupting chemicals, in particular, showing a more than 500-fold lower affinity for seabream TTR compared to human TTR (Zhang et al., 2018). Zebrafish and fathead minnow are oviparous fish species in which maternal thyroid hormones are transferred to the eggs and regulate early embryonic developmental processes during external (versus intra-uterine in mammals) development (Power et al., 2001; Campinho et al., 2014; Ruuskanen and Hsu, 2018) until embryonic thyroid hormone synthesis is initiated. Maternal transfer of thyroid hormones, both T4 and T3, to the eggs has been demonstrated in zebrafish (Walpita et al., 2007; Chang et al., 2012) and fathead minnows (Crane et al., 2004; Nelson et al., 2016). Several studies have reported evidence of T3 decreases after exposure to TPO inhibitors and deiodinase inhibitors in early life stages of zebrafish (Stinckens et al., 2016; Stinckens et al., 2020; Wang et al., 2020) and fathead minnow (Nelson et al., 2016; Cavallin et al., 2017).

T3 and T4 can be measured as free (unbound) or total (bound + unbound) in serum, or in tissues. Free hormones are considered more direct indicators of T4 and T3 activities in the body. The majority of T3 and T4 measurements are made using either RIA or ELISA kits. In animal studies, total T3 and T4 are typically measured as the concentrations of free hormone are very low and difficult to detect. Historically, the most widely used method in toxicology is RIA. The method is routinely used in rodent endocrine and toxicity studies. The ELISA method has become more routine in rodent studies. The ELISA method is commonly used as a human clinical test method. Recently, analytical determination of iodothyronines (T3, T4, rT3, T2) and their conjugates through methods employing HPLC and mass spectrometry have become more common (DeVito et al., 1999; Miller et al., 2009; Hornung et al., 2015; Nelson et al., 2016; Stinckens et al., 2016). Any of these measurements should be evaluated for fit-for-purpose, relationship to the actual endpoint of interest, repeatability, and reproducibility. 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 a an indirect methodology, whereas analytical determination is the most direct measurement available. All of these methods, particularly RIA, are repeatable and reproducible. In fish early life stages most evidence for the ontogeny of TH synthesis comes from measurements of whole-body TH levels and using LC-MS techniques (Hornung et al., 2015) are increasingly used to accurately quantify whole-body TH levels (Nelson et al., 2016; Stinckens et al., 2016, 2020).

Taxonomic: The overall evidence supporting taxonomic applicability is strong. With few exceptions vertebrate species have T3 and T4 that are mostly bound to transport proteins in blood as well as T3 and T4 in tissues. Therefore, the current key event is plausibly applicable to vertebrates in general. Clear species differences exist in transport proteins (Yamauchi and Isihara, 2009). Specifically, the majority of supporting data for TH decreases come from rat studies and have been measured mostly in serum. The predominant iodothyronine binding protein in rat serum is transthyretin (TTR). TTR demonstrates a reduced binding affinity for T4 when compared with thyroxine binding globulin (TBG), the predominant serum binding protein for T4 in humans. This difference in serum binding protein affinity for THs is thought to modulate serum half-life for T4; the half-life of T4 in rats is 12-24 hr, whereas the half-life in humans is 5-9 days (Capen, 1997). While these species differences impact hormone half-life, possibly regulatory feedback mechanisms, and quantitative dose-response relationships, measurement of decreased THs is still regarded as a measurable key event causatively linked to downstream adverse outcomes. Several studies have reported evidence of T3 decreases after exposure to TPO inhibitors and deiodinase inhibitors in early life stages of zebrafish (Stinckens et al., 2016; Stinckens et al., 2020; Wang et al., 2020) and fathead minnow (Nelson et al., 2016; Cavallin et al., 2017). Such measurements in fish early life stages are usually based on whole animal samples and do not allow for distinguishing between systemic and tissue TH alterations. THs are evolutionarily conserved molecules present in all vertebrate species (Hulbert, 2000; Yen, 2001). Moreover, their crucial role in amphibian and lamprey metamorphoses (Manzon and Youson, 1997; Yaoita and Brown, 1990) as well as fish development, embryo-to-larval transition and larval-to-juvenile transition (Thienpont et al., 2011; Liu and Chan, 2002) is well established. Their 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 in the different species may differ depending on the expression or function of specific proteins (e.g., receptors or enzymes) that are related to TH function, and therefore extrapolation between species should be done with caution. Life stage: THs are essential in all life stages, but decreases of TH levels are not applicable to all developmental phases. 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. However, T3 levels are expected to decrease upon exposure to deiodinase inhibitors in any life stage, since maternal T4 needs to be activated to T3 by deiodinases similar to embryonically synthesized T4. Sex: The KE is plausibly applicable to both sexes. THs 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 TH levels and the magnitude of the response. In humans, females appear more susceptible to hypothyroidism compared to males when exposed to certain halogenated chemicals (Hernandez‐Mariano et al., 2017; Webster et al., 2014). In adult zebrafish, Liu et al. (2019) showed sex-dependent changes in TH 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.

Moderate Unspecific

High

All life stages

High High High

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2022-10-07T08:26:15

Altered, Photoreceptor patterning

Cellular

Photoreceptors in the retina of vertebrates and invertebrates are the cells that are responsible for phototransduction. The main groups of photoreceptor cells are rods, active at very low light levels, and cones, active at higher light levels and responsible for color vision. Photoreceptor subtypes are characterized by different opsins (light-sensitive proteins) that respond to light with different wavelengths. The opsin characterizing rods is rhodopsin. Cones are further divided in several subtypes. The opsins characterizing these subtypes are generally grouped in S-opsins (short wavelength-sensitive), M-opsins (medium wavelength-sensitive) and L-opsins (long wavelength-sensitive). The occurrence of different opsins is species-specific (see Taxonomic applicability).  The distribution of photoreceptor subtypes within the retina is also referred to as photoreceptor patterning and has a quantitative component (typical ratios of photoreceptor subtypes) as well as a spatial component (organization of photoreceptor subtypes). Depending on the species, the spatial organization is stochastic/regionalized (human, fruit fly), regionalized (mouse), or ordered (zebrafish). During early development, photoreceptor subtypes differentiate from retinal progenitor cells. In a later stage of embryo or juvenile development, already differentiated cone photoreceptors can also switch opsin expression to a different opsin type. In general, this opsin switch is characterized by a switch in opsin expression from short to longer wavelength-sensitive opsins. An opsin switch is part of normal eye development and has been documented mostly in fish species (Shand et al., 2002; Cheng et al., 2006; Cheng and Flamarique, 2007; Matsumoto and Ishibashi, 2016; Mackin et al., 2019), and also in rodents (Lukats et al., 2005).  Under some circumstances, photoreceptor patterning and opsin switching can be altered. This can manifest itself as altered numbers of photoreceptor subtypes leading to an altered ratio of photoreceptor subtypes and/or altered spatial organization (Raymond et al., 2014).

In general, photoreceptor cell types are quantified and/or localized based on their opsin expression. The target for measurement therefore are the opsins. They can be measured either on the mRNA or on the protein level. Altered opsin expression patterns indicative of altered ratios of photoreceptor subtypes are often detected by relative quantification of mRNA coding for the specific opsins expressed in the photoreceptor subtypes using qPCR (quantitative polymerase chain reaction) (Allison et al., 2006; Mackin et al., 2019). This is a straightforward technique that many laboratories have available. Several methods can be used to obtain information on spatial patterning and to count photoreceptor types.  <ul> <li dir="ltr"> Immunohistochemistry allows for labelling specific opsins (protein level) with antibodies, mostly through the use of primary antibodies specific to the target and secondary antibodies that bind to the primary antibodies and are conjugated to e.g., a fluorescent label or alkaline phosphatase that produces a measurable product (Allison et al., 2006; DuVal et al., 2014; Houbrechts et al., 2016; DuVal and Allison, 2018). This is typically performed on retinal wholemounts or cryosections.  </li> <li dir="ltr"> In situ hybridization is used to label opsin mRNA using complementary oligonucleotide probes on retinal sections (Allison et al., 2006; Gan and Flamarique, 2010; Glaschke et al., 2010; DuVal et al., 2014; Karagic et al., 2018; Mackin et al., 2019). </li> <li dir="ltr"> Zebrafish transgenic lines expressing fluorescent reporters in specific photoreceptor types (again associated with opsin expression) have also been successfully used to analyse photoreceptor counts, spatial patterning and opsin switches (Raymond et al., 2014; Mackin et al., 2019). Examples include lines reporting rhodopsin, blue  cone or UV cone expression (Raymond et al., 2014). </li> </ul>

Based on available evidence, it seems plausible that this key event is applicable across all life stages and for a wide variety of taxa including vertebrates and invertebrates. <ol> <li dir="ltr"> Taxonomic applicability </li> </ol> Rod and cone pigments all diverged from a common ancestor through a series of duplication events (Nathans et al., 1986). These duplication events gave rise to important taxonomic differences in opsin genes. As an example, humans have three cone photoreceptor types expressing long (L, red), medium (M, green), or short (S, blue) wavelength‐specific opsins (Nathans et al., 1986), while the zebrafish genome has two red (LWS-1 and LWS-2), four green (RH2-1, RH2-2, RH2-3, and RH2-4), and single blue (SWS2) and ultraviolet (SWS1) opsin genes (Chinen et al., 2003). Suzuki et al. (2013) further discuss that some species have pure cone types that express a single opsin, while others have mixed cone types expressing different opsins simultaneously. The authors suggested that expression of thrbeta2 in progenitor cells results in pure L-opsin cones in zebrafish. This is opposed to expression of thrbeta2 in later in postmitotic cells resulting in mixed cones in mice. The importance of normal ratios of photoreceptor types and the concept of photoreceptor patterning however seems to be applicable to a wide range of species, including vertebrates and invertebrates. Retinal patterning of different taxa can be stochastic/regionalized (human, fruit fly), regionalized (mouse), or ordered (zebrafish) and has evolved to suit different environments and behaviors (Raymond et al., 2014; Viets et al., 2016). Since normal patterning differs among taxa, changes in patterning should be considered within species. During early development, photoreceptor subtypes differentiate from retinal progenitor cells. In a later stage of embryo or juvenile development, already differentiated cone photoreceptors can also switch opsin expression to a different opsin type. Such opsin switch is part of normal eye development and has been documented mostly in fish (Shand et al., 2002; Cheng et al., 2006; Cheng and Flamarique, 2007; Matsumoto and Ishibashi, 2016), and also in rodents (Lukats et al., 2005) and humans (Cornish et al., 2004). This opsin switch is characterized by a switch in opsin expression from short to longer wavelength-sensitive opsins. For example, in salmonids, single cones express ultraviolet (SWS-1) opsin during embryonic development and switch to blue (SWS-2) opsin as the fish grow (Gan and Flamarique, 2010). In zebrafish a switch occurs from LWS-2 to the longer wavelength LWS-1 opsin (Tsujimura et al., 2010; Mitchell et al., 2015; Mackin et al., 2019). Mitchell et al. (2015) and Mackin et al. (2019) even confirmed opsin switching in real time using developing transgenic zebrafish. In rodents and humans, the opsin switch involves a switch from S to M opsins. Teleost fish and salamanders are capable of regenerating the retina following injury, while mammals do not have this innate capacity to regenerate the retina (Mader and Cameron, 2004; Lamba et al., 2008; Van Gelder and Kaur, 2015). Studies have shown however that opsin expression in terminally differentiated mammalian cones also remains subject to alterations (Glaschke et al., 2011). Therefore, in addition to alterations during development, alterations of photoreceptor patterning in the adult retina are also expected to be relevant across taxa. <ol start="2"> <li dir="ltr"> Life-stage applicability </li> </ol> Normal photoreceptor patterning is established during development and this process can be altered by various circumstances (Mackin et al., 2019). Therefore, this key event is applicable to early life stages in which the retina is under development. Juvenile zebrafish show some plasticity in opsin expression (Mackin et al., 2019). This type of phenotypic plasticity appears common among fish as a result of changes in habitats.  Since teleosts and salamanders can regenerate the retina after injury, the process of restoring photoreceptor patterning can also be affected in the adult life stage (Mader and Cameron, 2006).  In adult mice and rats, the normal pattern of opsin expression and distribution can be reversibly altered, suggesting that opsin expression in terminally differentiated mammalian cones also remains subject to alterations (Glaschke et al., 2011).  Taken together, there is good evidence that this key event is applicable across all life stages. <ol start="3"> <li dir="ltr"> Sex applicability </li> </ol> Zebrafish are undifferentiated gonochorists since both sexes initially develop an immature ovary (Maack and Segner, 2003). Immature ovary development progresses until approximately the onset of the third week. Later, in female fish immature ovaries continue to develop further, while male fish undergo transformation of ovaries into testes. Final transformation into testes varies among male individuals, however finishes usually around 6 weeks post fertilization. Establishment of photoreceptor patterning during early development is therefore expected to be independent of sex. A few studies have shown that sex hormones can regulate spectral sensitivity, and this is probably related to the importance of perceiving breeding coloration. In sexually mature male sticklebacks, androgen is a key factor in enhancing sensitivity to red light via regulation of opsin gene expression (Shao et al., 2014). This is in line with the need to detect the red breeding color of males during the breeding season. Lizards also regulate opsin expression seasonally, and this appears to be related to evaluation of the coloration of potential mates. Tseng et al. (2018) showed that testosterone regulates opsin expression in a sexually dimorphic lizard and that males and females show opposite shifts in opsin expression during the breeding season. In mammals, medium (green) and long (red) wavelength-sensitive opsin genes are located on the X chromosome, leading to sex-linked color vision deficiencies where male individuals are more susceptible (Jacobs, 2009).  Studies have shown sexual dimorphism of photoreceptor patterning in Arthropoda such as the fruitfly and the small white butterfly (Arikawa et al., 2005; Hilbrant et al., 2014). The crustacean Euphilomedes carcharodonta exhibits radical sexual dimorphism of the lateral eyes. Females have only a tiny, simple lateral eye while males have elaborate ommatidial eyes. This coincides with differences in the expression of genes related to eye development and phototransduction (Sajuthi et al., 2015).  Alterations in normal photoreceptor patterning can be expected to occur across sexes. Based on the general evidence of sexual dimorphism in terms of spectral sensitivity, sex specific alterations may occur in sexually mature organisms.

UBERON:0000966

UBERON retina

Moderate Male Not Specified Female

Moderate

Embryo

Moderate

Juvenile

Moderate

Larvae

High

All life stages

High Moderate Not Specified Not Specified Moderate Allison, W.T., Dann, S.G., Veldhoen, K.M., Hawryshyn, C.W., 2006. Degeneration and regeneration of ultraviolet cone photoreceptors during development in rainbow trout. Journal of Comparative Neurology 499, 702-715. Arikawa, K., Wakakuwa, M., Qiu, X.D., Kurasawa, M., Stavenga, D.G., 2005. Sexual dimorphism of short-wavelength photoreceptors in the small white butterfly, Pieris rapae crucivora. Journal of Neuroscience 25, 5935-5942. Cheng, C.L., Flamarique, I.N., 2007. Chromatic organization of cone photoreceptors in the retina of rainbow trout: single cones irreversibly switch from UV (SWS1) to blue (SWS2) light sensitive opsin during natural development. Journal of Experimental Biology 210, 4123-4135. Cheng, C.L., Flamarique, I.N., Harosi, F.I., Rickers-Haunerland, J., Haunerland, N.H., 2006. Photoreceptor layer of salmonid fishes: Transformation and loss of single cones in juvenile fish. Journal of Comparative Neurology 495, 213-235. Chinen, A., Hamaoka, T., Yamada, Y., Kawamura, S., 2003. Gene duplication and spectral diversification of cone visual pigments of zebrafish. Genetics 163, 663-675. Cornish, E.E., Xiao, M., Yang, Z.T., Provis, J.M., Hendrickson, A.E., 2004. The role of opsin expression and apoptosis in determination of cone types in human retina. Experimental Eye Research 78, 1143-1154. DuVal, M.G., Allison, W.T., 2018. Photoreceptor Progenitors Depend Upon Coordination of gdf6a, thr beta, and tbx2b to Generate Precise Populations of Cone Photoreceptor Subtypes. Investigative Ophthalmology & Visual Science 59, 6089-6101. DuVal, M.G., Oel, A.P., Allison, W.T., 2014. gdf6a Is Required for Cone Photoreceptor Subtype Differentiation and for the Actions of tbx2b in Determining Rod Versus Cone Photoreceptor Fate. Plos One 9. Gan, K.J., Flamarique, I.N., 2010. Thyroid Hormone Accelerates Opsin Expression During Early Photoreceptor Differentiation and Induces Opsin Switching in Differentiated TR alpha-Expressing Cones of the Salmonid Retina. Developmental Dynamics 239, 2700-2713. Glaschke, A., Glosmann, M., Peichl, L., 2010. Developmental Changes of Cone Opsin Expression but Not Retinal Morphology in the Hypothyroid Pax8 Knockout Mouse. Investigative Ophthalmology & Visual Science 51, 1719-1727. Glaschke, A., Weiland, J., Del Turco, D., Steiner, M., Peichl, L., Glosmann, M., 2011. Thyroid Hormone Controls Cone Opsin Expression in the Retina of Adult Rodents. Journal of Neuroscience 31, 4844-4851. Hilbrant, M., Almudi, I., Leite, D.J., Kuncheria, L., Posnien, N., Nunes, M.D.S., McGregor, A.P., 2014. Sexual dimorphism and natural variation within and among species in the Drosophila retinal mosaic. Bmc Evolutionary Biology 14. Houbrechts, A.M., Vergauwen, L., Bagci, E., Van Houcke, J., Heijlen, M., Kulemeka, B., Hyde, D.R., Knapen, D., Darras, V.M., 2016. Deiodinase knockdown affects zebrafish eye development at the level of gene expression, morphology and function. Molecular and Cellular Endocrinology 424, 81-93. Jacobs, G.H., 2009. Evolution of colour vision in mammals. Philosophical Transactions of the Royal Society B-Biological Sciences 364, 2957-2967. Karagic, N., Harer, A., Meyer, A., Torres-Dowdall, J., 2018. Heterochronic opsin expression due to early light deprivation results in drastically shifted visual sensitivity in a cichlid fish: Possible role of thyroid hormone signaling. Journal of Experimental Zoology Part B-Molecular and Developmental Evolution 330, 202-214. Lamba, D., Karl, M., Rehl, T., 2008. Neural regeneration and cell replacement: A view from the eye. Cell Stem Cell 2, 538-549. Lukats, A., Szabo, A., Rohlich, P., Vigh, B., Szel, A., 2005. Photopigment coexpression in mammals: comparative and developmental aspects. Histology and Histopathology 20, 551-574. Maack, G., Segner, H., 2003. Morphological development of the gonads in zebrafish. Journal of Fish Biology 62, 895-906. Mackin, R.D., Frey, R.A., Gutierrez, C., Farre, A.A., Kawamura, S., Mitchell, D.M., Stenkamp, D.L., 2019. Endocrine regulation of multichromatic color vision. Proceedings of the National Academy of Sciences of the United States of America 116, 16882-16891. Mader, M., Cameron, D., 2006. Effects of induced systemic hypothyroidism upon the retina: Regulation of thyroid hormone receptor alpha and photoreceptor production. Molecular Vision 12, 915-930. Mader, M.M., Cameron, D.A., 2004. Photoreceptor differentiation during retinal development, growth, and regeneration in a metamorphic vertebrate. Journal of Neuroscience 24, 11463-11472. Matsumoto, T., Ishibashi, Y., 2016. Sequence analysis and expression patterns of opsin genes in the longtooth grouper Epinephelus bruneus. Fisheries Science 82, 17-27. Mitchell, D.M., Stevens, C.B., Frey, R.A., Hunter, S.S., Ashino, R., Kawamura, S., Stenkamp, D.L., 2015. Retinoic Acid Signaling Regulates Differential Expression of the Tandemly-Duplicated Long Wavelength-Sensitive Cone Opsin Genes in Zebrafish. Plos Genetics 11. Nathans, J., Thomas, D., Hogness, D.S., 1986. MOLECULAR-GENETICS OF HUMAN COLOR-VISION - THE GENES ENCODING BLUE, GREEN, AND RED PIGMENTS. Science 232, 193-202. Raymond, P.A., Colvin, S.M., Jabeen, Z., Nagashima, M., Barthel, L.K., Hadidjojo, J., Popova, L., Pejaver, V.R., Lubensky, D.K., 2014. Patterning the Cone Mosaic Array in Zebrafish Retina Requires Specification of Ultraviolet-Sensitive Cones. Plos One 9. Sajuthi, A., Carrillo-Zazueta, B., Hu, B., Wang, A., Brodnansky, L., Mayberry, J., Rivera, A.S., 2015. Sexually dimorphic gene expression in the lateral eyes of Euphilomedes carcharodonta (Ostracoda, Pancrustacea). Evodevo 6. Shand, J., Hart, N.S., Thomas, N., Partridge, J.C., 2002. Developmental changes in the cone visual pigments of black bream Acanthopagrus butcheri. Journal of Experimental Biology 205, 3661-3667. Shao, Y.T., Wang, F.Y., Fu, W.C., Yan, H.Y., Anraku, K., Chen, I.S., Borg, B., 2014. Androgens Increase Iws Opsin Expression and Red Sensitivity in Male Three-Spined Sticklebacks. Plos One 9. Tseng, W.H., Lin, J.W., Lou, C.H., Lee, K.H., Wu, L.S., Wang, T.Y., Wang, F.Y., Irschick, D.J., Lin, S.M., 2018. Opsin gene expression regulated by testosterone level in a sexually dimorphic lizard. Scientific Reports 8. Tsujimura, T., Hosoya, T., Kawamura, S., 2010. A Single Enhancer Regulating the Differential Expression of Duplicated Red-Sensitive Opsin Genes in Zebrafish. Plos Genetics 6. Van Gelder, R.N., Kaur, K., 2015. Vision Science: Can Rhodopsin Cure Blindness? Current Biology 25, R713-R715. Viets, K., Eldred, K.C., Johnston, R.J., 2016. Mechanisms of Photoreceptor Patterning in Vertebrates and Invertebrates. Trends in Genetics 32, 638-659.   AOPWiki 2019-05-22T05:06:40

2021-06-16T06:56:20

Increased Mortality

Population

Increased mortality refers to an increase in the number of individuals dying in an experimental replicate group or in a population over a specific period of time.

Mortality of animals is generally observed as cessation of the heart beat, breathing (gill or lung movement) and locomotory movements. Mortality is typically measured by observation. Depending on the size of the organism, instruments such as microscopes may be used. The reported metric is mostly the mortality rate: the number of deaths in a given area or period, or from a particular cause. Depending on the species and the study setup, mortality can be measured: <ul> <li>in the lab by recording mortality during exposure experiments</li> <li>in dedicated setups simulating a realistic situation such as mesocosms or drainable ponds for aquatic species</li> <li>in the field, for example by determining age structure after one capture, or by capture-mark-recapture efforts. The latter is a method commonly used in ecology to estimate an animal population's size where it is impractical to count every individual.</li> </ul>

All living things are susceptible to mortality.

Moderate Unspecific

High

All life stages

High

AOPWiki 2016-11-29T18:41:24

2022-07-08T07:32:26

Decrease, Population growth rate

Population

A population can be defined as a group of interbreeding organisms, all of the same species, occupying a specific space during a specific time (Vandermeer and Goldberg 2003, Gotelli 2008).  As the population is the biological level of organization that is often the focus of ecological risk assessments, population growth rate (and hence population size over time) is important to consider within the context of applied conservation practices. If N is the size of the population and t is time, then the population growth rate (dN/dt) is proportional to the instantaneous rate of increase, r, which measures the per capita rate of population increase over a short time interval. Therefore, r, is a difference between the instantaneous birth rate (number of births per individual per unit of time; b) and the instantaneous death rate (number of deaths per individual per unit of time; d) [Equation 1]. Because  r is an instantaneous rate, its units can be changed via division.  For example, as there are 24 hours in a day, an r of 24 individuals/(individual x day) is equal to an r of 1 individual/(individual/hour) (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020).  Equation 1:  r = b - d This key event refers to scenarios where r < 0 (instantaneous death rate exceeds instantaneous birth rate). Examining r in the context of population growth rate: ● A population will decrease to extinction when the instantaneous death rate exceeds the instantaneous birth rate (r < 0).              ● The smaller the value of r below 1, the faster the population will decrease to zero.   ● A population will increase when resources are available and the instantaneous birth rate exceeds the instantaneous death rate (r > 0)            ● The larger the value that r exceeds 1, the faster the population can increase over time       ● A population will neither increase or decrease when the population growth rate equals 0 (either due to N = 0, or if the per capita birth and death rates are exactly balanced).  For example, the per capita birth and death rates could become exactly balanced due to density dependence and/or to the effect of a stressor that reduces survival and/or reproduction (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020).      Effects incurred on a population from a chemical or non-chemical stressor could have an impact directly upon birth rate (reproduction) and/or death rate (survival), thereby causing a decline in population growth rate.   ● Example of direct effect on r:  Exposure to 17b-trenbolone reduced reproduction (i.e., reduced b) in the fathead minnow over 21 days at water concentrations ranging from 0.0015 to about 41 mg/L (Ankley et al. 2001; Miller and Ankley 2004).              Alternatively, a stressor could indirectly impact survival and/or reproduction.   ● Example of indirect effect on r:  Exposure of non-sexually differentiated early life stage fathead minnow to the fungicide prochloraz has been shown to produce male-biased sex ratios based on gonad differentiation, and resulted in projected change in population growth rate (decrease in reproduction due to a decrease in females and thus recruitment) using a population model. (Holbech et al., 2012; Miller et al. 2022) Density dependence can be an important consideration: ● The effect of density dependence depends upon the quantity of resources present within a landscape.  A change in available resources could increase or decrease the effect of density dependence and therefore cause a change in population growth rate via indirectly impacting survival and/or reproduction.   ● This concept could be thought of in terms of community level interactions whereby one species is not impacted but a competitor species is impacted by a chemical stressor resulting in a greater availability of resources for the unimpacted species.  In this scenario, the impacted species would experience a decline in population growth rate. The unimpacted species would experience an increase in population growth rate (due to a smaller density dependent effect upon population growth rate for that species).        Closed versus open systems: ● The above discussion relates to closed systems (there is no movement of individuals between population sites) and thus a declining population growth rate cannot be augmented by immigration.   ● When individuals depart (emigrate out of a population) the loss will diminish population growth rate.   Population growth rate applies to all organisms, both sexes, and all life stages.

Population growth rate (instantaneous growth rate) can be measured by sampling a population over an interval of time (i.e. from time t = 0 to time t = 1).  The interval of time should be selected to correspond to the life history of the species of interest (i.e. will be different for rapidly growing versus slow growing populations). The population growth rate, r, can be determined by taking the difference (subtracting) between the initial population size, Nt=0 (population size at time t=0), and the population size at the end of the interval, Nt=1 (population size at time t = 1), and then subsequently dividing by the initial population size.  Equation 2:  r = (Nt=1 - Nt=0) / Nt=0 The diversity of forms, sizes, and life histories among species has led to the development of a vast number of field techniques for estimation of population size and thus population growth over time (Bookhout 1994, McComb et al. 2021).   ● For stationary species an observational strategy may involve dividing a habitat into units. After setting up the units, samples are performed throughout the habitat at a select number of units (determined using a statistical sampling design) over a time interval (at time t = 0 and again at time t = 1), and the total number of organisms within each unit are counted. The numbers recorded are assumed to be representative for the habitat overall, and can be used to estimate the population growth rate within the entire habitat over the time interval.   ● For species that are mobile throughout a large range, a strategy such as using a mark-recapture method may be employed (i.e. tags, bands, transmitters) to determine a count over a time interval (at time = 0 and again at time =1).    Population growth rate can also be estimated using mathematical model constructs (for example, ranging from simple differential equations to complex age or stage structured matrix projection models and individual based modeling approaches), and may assume a linear or nonlinear population increase over time (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020). The AOP framework can be used to support the translation of pathway-specific mechanistic data into responses relevant to population models and output from the population models, such as changing (declining) population growth rate, can be used to assess and manage risks of chemicals (Kramer et al. 2011). As such, this translational capability can increase the capacity and efficiency of safety assessments both for single chemicals and chemical mixtures (Kramer et al. 2011).   Some examples of modeling constructs used to investigate population growth rate: ● A modeling construct could be based upon laboratory toxicity tests to determine effect(s) that are then linked to the population model and used to estimate decline in population growth rate.  Miller et al. (2007) used concentration–response data from short term reproductive assays with fathead minnow (Pimephales promelas) exposed to endocrine disrupting chemicals in combination with a population model to examine projected alterations in population growth rate.   ● A model construct could be based upon a combination of effects-based monitoring at field sites (informed by an AOP) and a population model.  Miller et al. (2015) applied a population model informed by an AOP to project declines in population growth rate for white suckers (Catostomus commersoni) using observed changes in sex steroid synthesis in fish exposed to a complex pulp and paper mill effluent in Jackfish Bay, Ontario, Canada. Furthermore, a model construct could be comprised of a series of quantitative models using KERs that culminates in the estimation of change (decline) in population growth rate.   ● A quantitative adverse outcome pathway (qAOP) has been defined as a mathematical construct that models the dose–response or response–response relationships of all KERs described in an AOP (Conolly et al. 2017, Perkins et al. 2019). Conolly et al. (2017) developed a qAOP using data generated with the aromatase inhibitor fadrozole as a stressor and then used it to predict potential population‐level impacts (including decline in population growth rate). The qAOP modeled aromatase inhibition (the molecular initiating event) leading to reproductive dysfunction in fathead minnow (Pimephales promelas) using 3 computational models: a hypothalamus–pituitary–gonadal axis model (based on ordinary differential equations) of aromatase inhibition leading to decreased vitellogenin production (Cheng et al. 2016), a stochastic model of oocyte growth dynamics relating vitellogenin levels to clutch size and spawning intervals (Watanabe et al. 2016), and a population model (Miller et al. 2007). ● Dynamic energy budget (DEB) models offer a methodology that reverse engineers stressor effects on growth, reproduction, and/or survival into modular characterizations related to the acquisition and processing of energy resources (Nisbet et al. 2000, Nisbet et al. 2011).  Murphy et al. (2018) developed a conceptual model to link DEB and AOP models by interpreting AOP key events as measures of damage-inducing processes affecting DEB variables and rates. ● Endogenous Lifecycle Models (ELMs), capture the endogenous lifecycle processes of growth, development, survival, and reproduction and integrate these to estimate and predict expected fitness (Etterson and Ankley, 2021).  AOPs can be used to inform ELMs of effects of chemical stressors on the vital rates that determine fitness, and to decide what hierarchical models of endogenous systems should be included within an ELM (Etterson and Ankley, 2021).

Consideration of population size and changes in population size over time is potentially relevant to all living organisms.

Not Specified Unspecific

Not Specified

All life stages

High

<ul> <li>Ankley GT, Jensen KM, Makynen EA, Kahl MD, Korte JJ, Hornung MW, Henry TR, Denny JS, Leino RL, Wilson VS, Cardon MD, Hartig PC, Gray LE. 2003. Effects of the androgenic growth promoter 17b-trenbolone on fecundity and reproductive endocrinology of the fathead minnow. Environ. Toxicol. Chem. 22: 1350–1360.</li> <li>Bookhout TA. 1994. Research and management techniques for wildlife and habitats. The Wildlife Society, Bethesda, Maryland. 740 pp.</li> <li>Caswell H. 2001. Matrix Population Models. Sinauer Associates, Inc., Sunderland, MA, USA</li> <li>Cheng WY, Zhang Q, Schroeder A, Villeneuve DL, Ankley GT, Conolly R.  2016.  Computational modeling of plasma vitellogenin alterations in response to aromatase inhibition in fathead minnows. Toxicol Sci 154: 78–89.</li> <li>Conolly RB, Ankley GT, Cheng W-Y, Mayo ML, Miller DH, Perkins EJ, Villeneuve DL, Watanabe KH. 2017. Quantitative adverse outcome pathways and their application to predictive toxicology. Environ. Sci. Technol. 51:  4661-4672.</li> <li>Etterson MA, Ankley GT.  2021.  Endogenous Lifecycle Models for Chemical Risk Assessment. Environ. Sci. Technol. 55:  15596-15608. </li> <li>Gotelli NJ, 2008. A Primer of Ecology. Sinauer Associates, Inc., Sunderland, MA, USA.</li> <li>Holbech H, Kinnberg KL, Brande-Lavridsen N, Bjerregaard P, Petersen GI, Norrgren L, Orn S, Braunbeck T, Baumann L, Bomke C, Dorgerloh M, Bruns E, Ruehl-Fehlert C, Green JW, Springer TA, Gourmelon A. 2012 Comparison of zebrafish (Danio rerio) and fathead minnow (Pimephales promelas) as test species in the Fish Sexual Development Test (FSDT). Comp. Biochem. Physiol. C Toxicol. Pharmacol. 155:  407–415.</li> <li>Kramer VJ, Etterson MA, Hecker M, Murphy CA, Roesijadi G, Spade DJ, Stromberg JA, Wang M, Ankley GT.  2011.  Adverse outcome pathways and risk assessment: Bridging to population level effects.  Environ. Toxicol. Chem. 30, 64-76.</li> <li>McComb B, Zuckerberg B, Vesely D, Jordan C.  2021.  Monitoring Animal Populations and their Habitats: A Practitioner's Guide.  Pressbooks, Oregon State University, Corvallis, OR Version 1.13, 296 pp. </li> <li>Miller DH, Villeneuve DL, Santana Rodriguez KJ, Ankley GT. 2022.  A multidimensional matrix model for predicting the effect of male biased sex ratios on fish populations. Environmental Toxicology and Chemistry 41(4): 1066-1077.</li> <li>Miller DH, Tietge JE, McMaster ME, Munkittrick KR, Xia X, Griesmer DA, Ankley GT. 2015. Linking mechanistic toxicology to population models in forecasting recovery from chemical stress: A case study from Jackfish Bay, Ontario, Canada. Environmental Toxicology and Chemistry 34(7):  1623-1633.</li> <li>Miller DH, Jensen KM, Villeneuve DE, Kahl MD, Makynen EA, Durhan EJ, Ankley GT. 2007. Linkage of biochemical responses to population-level effects: A case study with vitellogenin in the fathead minnow (Pimephales promelas). Environ Toxicol Chem 26:  521–527.</li> <li>Miller DH, Ankley GT. 2004. Modeling impacts on populations: Fathead minnow (Pimephales promelas) exposure to the endocrine disruptor 17b-trenbolone as a case study. Ecotox Environ Saf 59: 1–9.</li> <li>Murphy CA, Nisbet RM, Antczak P, Garcia-Reyero N, Gergs A, Lika K, Mathews T, Muller EB, Nacci D, Peace A, Remien CH, Schultz IR, Stevenson LM, Watanabe KH.  2018.  Incorporating suborganismal processes into dynamic energy budget models for ecological risk assessment.  Integrated Environmental Assessment and Management 14(5):  615–624.</li> <li>Murray DL, Sandercock BK (editors).  2020.  Population ecology in practice.  Wiley-Blackwell, Oxford UK, 448 pp.</li> <li>Nisbet RM, Jusup M, Klanjscek T, Pecquerie L.  2011.  Integrating dynamic energy budget (DEB) theory with traditional bioenergetic models.  The Journal of Experimental Biology 215: 892-902.</li> <li>Nisbet RM, Muller EB, Lika K, Kooijman SALM. 2000. From molecules to ecosystems through dynamic energy budgets. J Anim Ecol 69:  913–926.</li> <li>Perkins EJ,  Ashauer R, Burgoon L, Conolly R, Landesmann B,, Mackay C, Murphy CA, Pollesch N, Wheeler JR, Zupanic A, Scholzk S.  2019.  Building and applying quantitative adverse outcome pathway models for chemical hazard and risk assessment.  Environmental Toxicology and Chemistry 38(9): 1850–1865. </li> <li>Vandermeer JH, Goldberg DE. 2003.  Population ecology: first principles.  Princeton University Press, Princeton NJ, 304 pp.</li> <li>Villeneuve DL, Crump D, Garcia-Reyero N, Hecker M, Hutchinson TH, LaLone CA, Landesmann B, Lattieri T, Munn S, Nepelska M, Ottinger MA, Vergauwen L, Whelan M. Adverse outcome pathway (AOP) development 1: Strategies and principles. Toxicol Sci. 2014: 142:312–320</li> <li>Watanabe KH, Mayo M, Jensen KM, Villeneuve DL, Ankley GT, Perkins EJ.  2016.  Predicting fecundity of fathead minnows (Pimephales promelas) exposed to endocrine‐disrupting chemicals using a MATLAB(R)‐based model of oocyte growth dynamics. PLoS One 11:  e0146594.</li> </ul> AOPWiki 2016-11-29T18:41:24

2023-01-03T09:09:06

Altered, Visual function

Organ

The decrease in visual function can have different aspects, such as loss of chromatic vision, changes in eye movements, differences in sensitivity to light, but also changes in the retinal pigment epithelium (RPE) that may be related to a decrease in visual function (Strauss, 2005). The visual system is highly variable from one species to another, and this variability is a key factor influencing animal behaviour (Corral-López et al., 2017). Decreases in these visual functions can have a strong impact on behaviour, leading to changes in individual response and abilities in the environment, including, for example, perception of food or avoidance of predators. Variation in the visual system can also influence learning tasks when visual stimuli are used (Corral-López et al., 2017). Studies have detected visual impairments in fish at different temperatures (Babkiewicz et al., 2020) after treatment with the endocrine disruptor propylthiouracil (Baumann et al 2016 ), after chronic dietary selenomethionine exposure (Raine et al 2016), exposure to PCBs (Zhang et al, 2015) or deiodinase knockdown (Houbrechts et al 2016, Vancamp et al 2018).

Measurements of visual function can be performed at the level of neuronal activity: <ul> <li>Electroretinography (Chrispell et al., 2015)</li> <li>Analysis of neural activity in the optic tectum can be quantified as the ratio of phosphorylated extracellular signal–regulated kinase (ERK)      to total ERK in the optic tectum using immunofluorescent antibodies (Randlett et al., 2015, Dehnert et al., 2019).</li> <li>Babkiewicz et al. (2020) used an advanced technique to display an artificial prey on a miniature OLED screen and use functional calcium imaging with light sheet microscopy to visualize a neural response in the optic tectum.</li> </ul> Other measurements are performed at the level of the eyes: <ul> <li>Opto Kinetic response, OKR (similar protocol for Rat/mice (Segura et al., 2018), fish (Zou et al., 2010) and humans (Kang and Wildsoet, 2016)). The OKR is a visually-mediated assay in which an individual will respond to alternating black and white stripes by exhibiting eye saccades, eye movements without coordinated body movements, in the same direction as rotating stripes. An eye saccade relies on the ability to rapidly move the eye from focusing on one external target to the next in a repeated manner (Magnuson et al., 2020). Optokinetic tracking has a robust performance and does not require training the animal, allowing for the quick assessment (and at earlier ages) of visual features such as visual acuity (VA) and contrast sensitivity (CS)11–14.      </li> </ul> Yet other studies use assessment of vision-related behaviours:  <ul> <li>Opto Motor Reponses, OMR. OMR tracks the ability of fish to swim in the direction of a perceived motion when presented with a whole-field stimulus (Neuhauss, 2003), (Gould et al., 2017)).</li> <li>Light-dark transition or vision startle response: reaction to change in light intensity (light sensitivity) (Brastrom et al., 2019)</li> <li>Black-white preference test (Baumann et al., 2016)</li> </ul> <ul> <li>Diverse Mobility assay including Tracking, touch-evoked escape-response assays, Swirl assays, locomotion assay, swimming activity, phototactic swimming activity assay, induced locomotor response (LLR) (Baumann et al., 2016; Gao et al., 2015; Zhao et al., 2014, Dehnert et al., 2019).</li> </ul>

Taxonomic applicability: Visual function decrease can be evaluated in a wide range of species including mammals, amphibians, fish and humans. Evaluation of these visual function modifications change according to the species and its environment. Life-stage applicability: Vision plays a crucial role in the early life stages of most species, as timing of eye development and establishment of functional vision is essential for perception of food or avoidance of predators for example (Carvalho et al., 2002). The first visual responses based on retinal functionality appear around 70 hpf in zebrafish (Schmitt and Dowling 1999). It is plausible to assume that alterations of the eye structure would result in altered visual function across all life stages, but such alterations are most likely to occur during the development of the normal eye structure, which occurs in the embryo-eleutheroembryo phase. Some studies have also shown a decrease in vision related to age (Brastrom et al., 2019; Martínez-Roda et al., 2016; Segura et al., 2018) including on visual acuity, visual fields, colour vision and dark adaptation, are well documented (Hennelly et al, 1998). Sex applicability: Sex does not seem relevant for most of the visual function decreases observed in different studies. Differences according to the sex of the individuals have however been reported concerning the basic visual capacities (e.g. color perception, contrast sensitivity, visual acuity, motion perception,...) but also concerning the frequency of certain diseases influencing these diminished visual functions, notably in humans (Vanston and Strother, 2017).

UBERON:0000970

UBERON eye

Moderate Unspecific

High

Embryo

Moderate

Juvenile

High

Larvae

High

Baumann, L., Ros, A., Rehberger, K., Neuhauss, S. C. F., & Segner, H. (2016). Thyroid disruption in zebrafish (Danio rerio) larvae: Different molecular response patterns lead to impaired eye development and visual functions. Aquatic Toxicology, 172, 44–55. https://doi.org/10.1016/j.aquatox.2015.12.015 Babkiewicz, E., Bazała, M., Urban, P., Maszczyk, P., Markowska, M., & Maciej Gliwicz, Z. (2020). The effects of temperature on the proxies of visual detection of Danio rerio larvae: observations from the optic tectum. Biology Open, 9(7). https://doi.org/10.1242/BIO.047779 Brastrom, L.K., Scott, C.A., Dawson, D. V., Slusarski, D.C., 2019. A High-Throughput Assay for Congenital and Age-Related Eye Diseases in Zebrafish. Biomedicines 7, 28. https://doi.org/10.3390/biomedicines7020028 Carvalho, P.S.M., Noltie, D.B., Tillitt, D.E., 2002. Ontogenetic improvement of visual function in the medaka Oryzias latipes based on an optomotor testing system for larval and adult fish. Anim. Behav. 64, 1–10. https://doi.org/10.1006/anbe.2002.3028 Chrispell JD, Rebrik TI, Weiss ER. 2015. Electroretinogram Analysis of the Visual Response in Zebrafish Larvae. Jove-Journal of Visualized Experiments(97). Corral-López, A., Garate-Olaizola, M., Buechel, S.D., Kolm, N., Kotrschal, A., 2017. On the role of body size, brain size, and eye size in visual acuity. Behav. Ecol. Sociobiol. 71. https://doi.org/10.1007/s00265-017-2408-z Dehnert GK, Karasov WH, Wolman MA. 2019. 2,4-Dichlorophenoxyacetic acid containing herbicide impairs essential visually guided behaviors of larval fish. Aquatic Toxicology 209:1-12. Gao, D., Wu, M., Wang, C., Wang, Y., Zuo, Z., 2015. Chronic exposure to low benzo[a]pyrene level causes neurodegenerative disease-like syndromes in zebrafish (Danio rerio). Aquat. Toxicol. Gould, C. J., Wiegand, J. L., & Connaughton, V. P. (2017). Acute developmental exposure to 4-hydroxyandrostenedione has a long-term effect on visually-guided behaviors. Neurotoxicology and Teratology, 64, 45–49. https://doi.org/10.1016/j.ntt<a href="https://doi.org/10.1016/j.ntt.2017.10.003">.</a>2017.10.003 Hennelly, M. L., Barbur, J. L., Edgar, D. F., & Woodward, E. G. (1998). The effect of age on the light scattering characteristics of the eye. Ophthalmic and Physiological Optics, 18(2), 197–203. https://doi.org/10.1046/j.1475-1313.1998.00333.x Houbrechts, A. M., Vergauwen, L., Bagci, E., Van houcke, J., Heijlen, M., Kulemeka, B., Hyde, D. R., Knapen, D., & Darras, V. M. (2016). Deiodinase knockdown affects zebrafish eye development at the level of gene expression, morphology and function. Molecular and Cellular Endocrinology, 424, 81–93.      https://doi.org/10.1016/j.mce.2016.01.018 Kang, P., & Wildsoet, C. F. (2016). Acute and short-term changes in visual function with multifocal soft contact lens wear in young adults. Contact Lens and Anterior Eye, 39(2), 133–140. https://doi.org/10.1016/j.clae.2015.09.004 Magnuson, J., Bautista, N., Lucero, J., Lund, A., Xu, E. G., Schlenk, D., Burggren, W., & Roberts, A. P. (2020). Exposure to crude oil induces retinal apoptosis and impairs visual function in fish. Environmental Science & Technology. https://doi.org/10.1021/acs.est.9b07658 Martínez-Roda, J. A., Vilaseca, M., Ondategui, J. C., Aguirre, M., & Pujol, J. (2016). Effects of aging on optical quality and visual function. Clinical and Experimental Optometry, 99(6), 518–525. https://doi.org/10.1111/cxo.12369 Neuhauss, S. C. F. (2003). Behavioral genetic approaches to visual system development and function in zebrafish. Journal of Neurobiology, 54(1), 148–160. https://doi.org/10.1002/neu.10165 Raine, J. C., Lallemand, L., Pettem, C. M., & Janz, D. M. (2016). Effects of Chronic Dietary Selenomethionine Exposure on the Visual System of Adult and F1 Generation Zebrafish (Danio rerio). Bulletin of Environmental Contamination and Toxicology, 97(3), 331–336. https://doi.org/10.1007/s00128-016-1849-9 Randlett O, Wee CL, Naumann EA, Nnaemeka O, Schoppik D, Fitzgerald JE, Portugues R, Lacoste AMB, Riegler C, Engert F et al. . 2015. Whole-brain activity mapping onto a zebrafish brain atlas. Nature Methods 12(11):1039-1046. Schmitt, E. A., & Dowling, J. E. (1994). Early‐eye morphogenesis in the zebrafish, Brachydanio rerio. Journal of Comparative Neurology, 344(4), 532–542. https://doi.org/10.1002/cne.903440404 Segura, F., Arines, J., Sánchez-Cano, A., Perdices, L., Orduna-Hospital, E., Fuentes-Broto, L., & Pinilla, I. (2018). Development of optokinetic tracking software for objective evaluation of visual function in rodents. Scientific Reports, 8(1), 1–11. https://doi.org/10.1038/s41598-018-28394-x Strauss, O. (2005). The retinal pigment epithelium in visual function. Physiological Reviews, 85(3), 845–881.https://doi.org/10.1152/physrev.00021.2004 Vancamp, P., Bourgeois, N. M. A., Houbrechts, A. M., & Darras, V. M. (2019). Knockdown of the thyroid hormone transporter MCT8 in chicken retinal precursor cells hampers early retinal development and results in a shift towards more UV/blue cones at the expense of green/red cones. Experimental Eye Research,178(September 2018), 135–147. https://doi.org/10.1016/j.exer.2018.09.018 Zhang, X., Hong, Q., Yang, L., Zhang, M., Guo, X., Chi, X., & Tong, M. (2015). PCB1254 exposure contributes to the abnormalities of optomotor responses and influence of the photoreceptor cell development in zebrafish larvae. Ecotoxicology and Environmental Safety, 118, 133–138. https://doi.org/10.1016/j.ecoenv.2015.04.026 Zhao, J., Xu, T., & Yin, D. Q. (2014). Locomotor activity changes on zebrafish larvae with different 2,2’,4,4’-tetrabromodiphenyl ether (PBDE-47) embryonic exposure modes. Chemosphere, 94, 53–61. https://doi.org/10.1016/j.chemosphere.2013.09.010 Zou, S. Q., Yin, W., Zhang, M. J., Hu, C. R., Huang, Y. bin, & Hu, B. (2010). Using the optokinetic response to study visual function of zebrafish. Journal of Visualized Experiments, 36, 5–8. https://doi.org/10.3791/1742 AOPWiki 2019-05-22T05:12:28

2022-07-08T07:30:59

<upstream-id>b7ed89cc-e531-4532-a5eb-a9ca41eaf971</upstream-id> <downstream-id>7f524501-9f40-4756-a949-0db5167dd510</downstream-id> Thyroperoxidase (TPO) is a heme-containing apical membrane protein within the follicular lumen of thyrocytes that acts as the enzymatic catalyst for thyroid hormone (TH) synthesis (Taurog, 2005) across vertebrates. Two commonly used reference chemicals, propylthiouracil (PTU) and methimazole (MMI), are drugs that inhibit the ability of TPO to: a) activate iodine and transfer it to thyroglobulin (Tg) (Davidson et al., 1978); and, b) couple thyroglobulin (Tg)-bound iodotyrosyls to produce Tg-bound thyroxine (T4) and triiodothyronine (T3) (Taurog, 2005).

The weight of evidence supporting a direct linkage between the MIE, TPO inhibition, and the KE of decreased TH synthesis, is strong and supported by more than three decades of research in animals, including humans (Cooper et al., 1982; Cooper et al.,1983; Divi and Doerge, 1994; Fang et al., 2022).

The biological plausibility for this KER is rated Strong. TPO is the only enzyme capable of de novo synthesis of TH. TPO catalyzes several reactions, including the oxidation of iodide, nonspecific iodination of tyrosyl residues of thyroglobulin (Tg) to form monoiodotyrosyl (MIT) or diiodotyrosyl (DIT) residues, and the coupling of these Tg-bound iodotyrosyls to produce Tg-bound T3 and T4 (Divi and Doerge, 1994; Kessler et al., 2008; Ruf et al., 2006; Taurog et al., 1996, 2005). Therefore, inhibition of TPO activity is widely accepted to directly impact TH synthesis.

Empirical support for this KER is strong. There are several papers that have measured alterations in TPO and subsequent effects on TH synthesis across vertebrates. Taurog et al. (1996) showed decreased guicaol activity, decreased bound I125, and subsequent decreases in newly formed T3 and T4 per molecule of Tg, following exposure to PTU, MMI and some antibiotics.  There is important evidence in mammals. Following in vivo exposure to PTU in rats (Cooper et al., 1982; 1983), there are concentration and time-dependent decreases in thyroid protein bound iodine and serum T4 and T3 that recovered one month after cessation of PTU exposure.  In addition, measures of thyroidal iodine content were highly correlated with intra-thyroidal PTU concentration. Vickers et al. (2012) demonstrated dose- and time- dependent inhibition of TPO activity in both human and rat thyroid homogenates exposed to MMI. Hassan et al. (2017, 2020) and Handa et al. (2021) predicted the level of THs in serum after treatment with PTU and MMI in rats. They developed a quantitative model by comparing dose- response data.  Tietge et al (2010) showed decreases in thyroidal T4 following MMI exposure in Xenopus.  Also in Xenopus, Haselman et al (2020) showed decreases in thyroidal iodotyrosines (MIT/DIT) and iodothyronines (T4/T3) following exposure to MMI. Doerge et al (1998) showed that a tryphenylmethane dye, malachite green, inhibited TPO and lowered thyroxine production. A recent paper used a series of benzothiazoles and showed TPO inhibition (guicaol assay) and inhibition of TSH stimulated thyroxine release from Xenopus thyroid gland explant cultures (Hornung et al., 2015).  Additionally, evidence is available from studies investigating responses to TPO inhibitors in fish. 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. Several other studies have also shown that chemically induced Inhibition of TPO results in reduced TH synthesis in zebrafish (Van der Ven et al., 2006; Raldua and Babin, 2009; Liu et al., 2011; Thienpont et al., 2011; Rehberger et al., 2018). Using a TPO knockout line Fang et al. (2022) showed that TPO inhibition abolished the T4 synthesis in 7 dpf zebrafish mutants. 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. Temporal Evidence: In mammals, the temporal nature of this KER is applicable to all life stages, including development (Seed et al., 2005). The impact of decreased TPO activity on TH synthesis is similar across all ages in mammals. Good evidence for the temporal relationship of the KER comes from thyroid system modeling (e.g., Degon et al., 2008; Fisher et al., 2013) using data from studies of iodine deficiency and chemicals that inhibit NIS. In addition, there is ample evidence of the temporal impacts of TPO inhibition on TH synthesis, using ex vivo and in vitro measures that demonstrate the time course of inhibition following chemical exposures, including some data from human thyroid microsomes and ex vivo thyroid slices (Vickers et al., 2012). Future work is needed that measures both TPO inhibition and TH production during development.  In oviparous fish such as zebrafish and fathead minnow, the nature of this KER depends on the life stage since the earliest stages of embryonic development rely on maternal THs transferred to the eggs. Embryonic TH synthesis is activated later during embryo-larval development. (See Domain of applicability) Dose-Response Evidence: Dose-response data is available from a number of studies in mammals that correlate TPO inhibition with decreased TH production measured using a variety of endpoints including iodine organification (e.g., Taurog et al., 1996), inhibition of guicaol oxidation in thyroid microsomes (e.g., Doerge and Chang, 2002), and direct measure of thyroid gland T4 concentrations (e.g., Hornung et al., 2015). However, there is a lack of dose-response data from developmental studies showing direct linkages from TPO inhibition to thyroidal TH synthesis.

While it is clear that TPO inhibition will lead to altered TH synthesis, there is a need for data that will inform quantitative modeling of the relationship between TPO inhibition and the magnitude of effects on TH synthesis. Data from studies on genistein highlight this uncertainty. Doerge and colleagues have demonstrated that for this compound up to 80% TPO inhibition did not result in decreased serum T4 in rats (Doerge and Chang, 2002). This is not consistent with other prototypical TPO inhibitors (e.g., PTU, MMI). Genistein is however a well-known phytoestrogen and the observed inconsistency may be the result of feedback mechanisms resulting from its estrogenic effect.

Iodine availability will impact the ability of TPO to iodinate tyrosine residues on thyroglobulin. Iodine availability to TPO can be impacted in a number of ways. First, environmental availability of iodine can vary greatly depending on whether and how much iodine exists in surface waters for aquatic organisms (gill respirators) and in the diets of both terrestrial and aquatic organisms. Second, somewhat regardless of iodine availability through environmental uptake (i.e., barring extremely high iodine exposure), iodine is actively transported into the thyroid follicular cell from the blood via sodium-iodide symporter (NIS), which has been shown to be susceptible to inhibition by, for example, perchlorate. As such, iodine availability to TPO is mediated by functional NIS. Finally, iodine is not fully available to TPO on the apical surface of the thyroid follicular cell until it is transported through the apical membrane by pendrin, an anion exchange protein - mutations or inhibition of pendrin could affect iodine availability to TPO. Hydrogen peroxide is also needed by TPO to mediate the oxidation of iodide, which is produced locally by dual oxidase (DUOX). A mutation or inhibition of DUOX will impact local production of H2O2 leading to lower oxidizing potential of TPO and less organification of iodide.

In Xenopus laevis, Haselman et al.(2020) demonstrated temporal profiles of thyroidal iodotyrosines (MIT/DIT) and iodothyronines (T4/T3), the products of TPO activity, following exposure to three different model TPO inhibitors (MMI, PTU, MBT) at multiple concentrations. This study established that, in Xenopus, measurable decreases in the products of TPO activity can occur as early as 2 days of exposure during pro-metamorphosis. However, despite consistent profiles of some iodo-species across chemicals, other iodo-species showed inconsistent profiles across chemicals. This highlights the multiple mechanisms of TPO (iodination and coupling) and differential susceptibility to inhibition of those mechanisms depending on the chemical's type of interaction with TPO. The most consistent concentration-response relationship across chemicals and over time was demonstrated by thyroidal T4, which is the most relevant product to subsequent key events. At the highest concentrations tested for each chemical, thyroidal T4 was below detection by 7 days of exposure across all three TPO inhibitors. Keeping in mind that the thyroid gland has follicular lumen space where thyroglobulin/T4 is stored until proteolysis and release to the blood, full inhibition of TPO would result in a delayed measurable response due to the time it takes to deplete stored hormones. Regardless of the delay, the results from this study imply full inhibition of TPO by each of these three chemicals at the highest test concentrations, but would require chemical residue analysis and/or toxicokinetic modeling to relate cellular/tissue concentrations at the site of TPO catalysis to levels of inhibition via Michaelis-Menten kinetic descriptions. Profiles of thyroidal iodinated species demonstrated by Haselman et al. (2020) across three different TPO inhibitors suggests that a high level of TPO inhibition must occur in order to elicit responses in subsequent key events. Although the level of TPO inhibition is not directly quantifiable from this study, these data suggest that at least 90-100% inhibition was occurring since circulating T4 was not detectable at 10 days of exposure to the highest concentrations of MMI and MBT. However, additional efforts would be necessary to determine the minimum level of TPO inhibition that leads to a measurable decrease in thyroidal T4 and subsequently circulating T4.  Furthermore, Hassan et al. (2017, 2020) and Handa et al. (2021) predicted the level of THs in serum after treatment with PTU and MMI in rats. They developed a quantitative model by comparing dose- response data.

There are only a limited number of studies where both TPO inhibition and iodine organification have been measured in vivo, and there is not enough data available to make any definitive quantitative correlations. One in vivo study in rats exposed to the TPO inhibitor genistein found no in vivo impact on serum TH concentrations, even when TPO was inhibited up to 80% (Chang and Doerge, 2000). Genistein is however a well-known phytoestrogen and the observed inconsistency may be the result of feedback mechanisms resulting from its estrogenic effect. Given that this is an MIE to KE relationship, there is only one response to evaluate in the relationship. Decreased TH synthesis, as measured by responses of iodinated species in the thyroid gland, is the result of TPO inhibition, which cannot be measured directly in vivo.

In vivo, evaluations of TPO inhibition are limited to evaluation of the iodinated species, or products of TPO activity, present in the thyroid gland at a particular time. However, as stated previously, any measurable response in these iodinated species is not a discreet assessment of TPO activity given that the gland maintains storage of hormone in the follicular lumen space and any alteration of TPO activity would be detected once the stores begin to be depleted. In Xenopus laevis, Haselman et al. (2020) showed a decrease in thyroidal iodinated species after only 2 days of exposure to potent TPO inhibitor MMI during thyroid-mediated metamorphosis and within 4 days for PTU and MBT, both model TPO inhibitors. In zebrafish, Walter et al. (2019) reported a similar time frame, namely a decrease in T4 levels at 72 hpf after starting the exposure to PTU at 0-2 hpf. It should be noted that the time-scale is probably depending on the developmental stage and whether the embryo is capable of thyroid hormone synthesis, rather than on the exposure duration.

Thyroid stimulating hormone (TSH) released from the pituitary positively regulates the synthesis and release of thyroid hormones from the thyroid gland. As such, when TPO is inhibited and thyroid hormone synthesis is decreased, lower systemic levels of hormone cause feedback from the pituitary via TSH to upregulate a number of processes in the thyroid gland as a means of compensation, including (but not limited to) enhanced gene expression of NIS and thyrocyte cell proliferation (Tietge et al., 2010; Haselman et al., 2020).

High Male High Female

High

All life stages

High High High High Low

Taxonomic: This KER is plausibly applicable across vertebrates. Inhibition of TPO activity is widely accepted to directly impact TH synthesis. This is true for both rats and humans, as well as some fishes, frogs and birds. Most of the data supporting a causative relationship between TPO inhibition and altered TH synthesis is derived from animal studies, in vitro thyroid microsomes from rats or pigs, and a limited number of human ex vivo (Nagasaka and Hidaka, 1976; Vickers et al., 2012) and clinical studies. There are data to support that gene mutations in TPO result in congenital hypothyroidism, underscoring the essential role of TPO in human TH synthesis. Life stage: Applicability to certain life stages may depend on the species and their dependence on maternally transferred THs during the earliest phases of development. 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, TPO inhibition is not expected to decrease TH synthesis during these earliest stages of development. Evidence supporting this hypothesis is obtained from a zebrafish TPO knockout line. In homozygous individuals TPO is inhibited from the embryonic developmental stage onwards, resulting in an abolished T4 production in thyroid follicles with phenotypical abnormalities such as reduced swim bladder inflation and growth retardation appearing at 20 dpf but not before 10 dpf (Fang et al., 2022). 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 minnow, a significant increase of whole body TH 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 system disruptors. Sex: The KE is plausibly applicable to both sexes. Thyroid hormones 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 thyroid hormone levels and the magnitude of the response. In humans, females appear more susceptible to hypothyroidism compared to males when exposed to certain halogenated chemicals (Hernandez‐Mariano et al., 2017; Webster et al., 2014). In adult zebrafish, Liu et al. (2019) showed sex-dependent changes in thyroid hormone 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.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430aedcbc8> AOPWiki 2016-11-29T18:41:33

2022-11-04T09:27:29

<upstream-id>7f524501-9f40-4756-a949-0db5167dd510</upstream-id> <downstream-id>184aa0de-37e3-4562-a777-40290d2f5d57</downstream-id> Thyroid hormones (THs), thyroxine (T4) and triiodothyronine (T3) are synthesized by NIS and TPO in the thyroid gland as iodinated thyroglobulin (Tg) and stored in the colloid of thyroid follicles across vertebrates. Secretion from the follicle into serum is a multi-step process. The first involves thyroid stimulating hormone (TSH) stimulation of the separation of the peptide linkage between Tg and TH. The next steps involve endocytosis of colloid, fusion of the endosome with the basolateral membrane of the thyrocyte, and finally release of TH into blood. More detailed descriptions of this process can be found in reviews by Braverman and Utiger (2012) and Zoeller et al. (2007).

The weight of evidence linking these two KEs of decreased TH synthesis and decreased T4 in serum is strong. It is commonly accepted dogma that decreased synthesis in the thyroid gland will result in decreased circulating TH (serum T4).

The biological relationship between two KEs in this KER is well understood and documented fact within the scientific community.

It is widely accepted that TPO inhibition leads to declines in serum T4 levels in adult mammals. This is due to the fact that the sole source for circulating T4 derives from hormone synthesis in the thyroid gland. Indeed, it has been known for decades that insufficient dietary iodine will lead to decreased serum TH concentrations due to inadequate synthesis. Strong qualitative and quantitative relationships exist between reduced TH synthesis and reduced serum T4 (Ekerot et al., 2013; Degon et al., 2008; Cooper et al., 1982; 1983; Leonard et al., 2016; Zoeller and Tan, 2007).  There is more limited evidence supporting the relationship between decreased TH synthesis and lowered circulating hormone levels during development.  Lu and Anderson (1994) followed the time course of TH synthesis, measured as thyroxine secretion rate, in non-treated pregnant rats and correlated it with serum T4 levels. Modeling of TH in the rat fetus demonstrates the quantitative relationship between TH synthesis and serum T4 concentrations (Hassan et al., 2017, 2020; Handa et al., 2021). Furthermore, a wide variety of drugs and chemicals that inhibit TPO are known to result in decreased release of TH from the thyroid gland, as well as decreased circulating TH concentrations. This is evidenced by a very large number of studies that employed a wide variety of techniques, including thyroid gland explant cultures, tracing organification of 131-I and in vivo treatment of a variety of animal species with known TPO inhibitors (King and May,1984; Atterwill et al., 1990; Brown et al., 1986; Brucker-Davis, 1998; Haselman et al., 2020; Hornung et al., 2010; Hurley et al., 1998; Kohrle, 2008; Tietge et al., 2010). Additionally, evidence is available from studies investigating responses to TPO inhibitors in fish. 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. Several other studies have also shown that chemically induced Inhibition of TPO results in reduced TH synthesis in zebrafish (Van der Ven et al., 2006; Raldua and Babin, 2009; Liu et al., 2011; Thienpont et al., 2011; Rehberger et al., 2018). 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. Temporal Evidence: In mammals, the temporal nature of this KER is applicable to all life stages, including development (Seed et al., 2005).  There are currently no studies that measured both TPO synthesis and TH production during development. However, the impact of decreased TH synthesis on serum hormones is similar across all ages in mammals. Good evidence for the temporal relationship comes from thyroid system modeling of the impacts of iodine deficiency and NIS inhibition (e.g., Degon et al., 2008; Fisher et al., 2013). In addition, recovery experiments have demonstrated that serum thyroid hormones recovered in athyroid mice following grafting of in-vitro derived follicles (Antonica et al., 2012). In Xenopus, it has been shown that depression of TH synthesis in the thyroid gland precedes depression of circulating TH within 7 days of exposure during pro-metamorphosis (Haselman et al., 2020).    In oviparous fish such as zebrafish and fathead minnow, the nature of this KER depends on the life stage since the earliest stages of embryonic development rely on maternal THs transferred to the eggs. Embryonic TH synthesis is activated later during embryo-larval development. (See Domain of applicability) Dose-response Evidence: Dose-response data is lacking from studies that include concurrent measures of both TH synthesis and serum TH concentrations. However, data is available demonstrating correlations between thyroidal TH and serum TH concentrations during gestation and lactation during development (Gilbert et al., 2013). This data was used to develop a rat quantitative biologically-based dose-response model for iodine deficiency (Fisher et al., 2013). In Xenopus, dose-responses were demonstrated in both thyroidal T4 and circulating T4 following exposure to three TPO inhibitors (Haselman et al., 2020).

There are no inconsistencies in this KER, but there are some uncertainties. The first uncertainty stems from the paucity of data for quantitative modeling of the relationship between the degree of synthesis decrease and resulting changes in circulating T4 concentrations. In addition, most of the data supporting this KER comes from inhibition of TPO, and there are a number of other processes (e.g., endocytosis, lysosomal fusion, basolateral fusion and release) that are not as well studied. For example, Kim et al. (2015) investigated the adverse effects of Triphenyl phosphate (TPP), a substance that disrupts the thyroid system. Therefore, Rat pituitary (GH3) and thyroid follicular cell lines (FRTL-5) were studied. In the GH3 cells, TPP led to an upregulation of the expression of important thyroid genes (tsh, tr alpha and tr beta) while T3, a positive control, downregulated the expression of these genes. In FRTL-5 cells, the expression of nis and tpo genes was significantly upregulated, suggesting that TPP stimulates TH synthesis in the thyroid gland. In zebrafish larvae at the age of 7 days post-fertilisation (dpf), TPP exposure resulted in a significant increase in T3 and T4 concentrations and the expression of genes involved in thyroid hormone synthesis. Exposure to TPP also significantly regulated the expression of genes involved in the metabolism (dio1), transport (ttr) and excretion (ugt1ab) of THs. The down-regulation of the crh and tsh genes in the zebrafish larvae suggests the activation of a central regulatory feedback mechanism that is triggered by the increased T3 levels in vivo. Taken together, these observations indicate that TPP increases TH concentrations in early life stages of zebrafish by disrupting central regulatory and hormone synthesis pathways.

During Xenopus metamorphosis, circulating T4 steadily increases to peak levels at metamorphic climax. Therefore, during Xenopus metamorphosis, this KER is operable at an increased rate as compared to a system that is maintaining steady circulating T4 levels through homeostatic control. In this case, developmental status is a modulating factor for the rates and trajectories of these KEs.

In rats, Hassan et al. (2020) demonstrated in vitro: ex vivo correlations of TPO inhibition using PTU and MMI and constructed a quantitative model relating level of TPO inhibition with changes in circulating T4 levels. They determined that 30% inhibition of TPO was sufficient to decrease circulating T4 levels by 20%. This is further supported by studies of Hassan et al. (2017) and Handa et al. (2021) In Xenopus, Haselman et al. (2020) collected temporal and dose-response data for both thyroidal and circulating T4 which showed strong qualitative concordance of the response-response relationship. A quantitative relationship exists there in, but is yet to be demonstrated mathematically in this species.

Fisher et al. (2013) published a quantitative biologically-based dose-response model for iodine deficiency in the rat. This model provides quantitative relationships for thyroidal T4 synthesis (iodine organification) and predictions of serum T4 concentrations in developing rats. There are other computational models that include thyroid hormone synthesis. Ekerot et al. (2012) modeled TPO, T3, T4 and TSH in dogs and humans based on exposure to myeloperoxidase inhibitors that also inhibit TPO.  This model was recently adapted for rats(Leonard et al., 2016) and Hassan et al (2017) have extended it to include the pregnant rat dam in response to TPO inhibition induced by PTU. While the original model predicted serum TH and TSH levels as a function of oral dose, it was not used to explicitly predict the relationship between serum hormones and TPO inhibition, or TH synthesis. Leonard et al. (2016) recently incorporated TPO inhibition into the model. Degon et al (2008) developed a human thyroid model that includes TPO, but does not make quantitative prediction of organification changes due to inhibition of the TPO enzyme. Further empirical support for the response-response relationship has been demonstrated in the amphibian model, Xenopus laevis, exposed to TPO inhibitors during pro-metamorphosis (Haselman et al., 2020) wherein temporal profiles were measured for both thyroidal and circulating T4.

Given that the thyroid gland contains follicular lumen space filled with stored thyroglobulin/T4, complete inhibition of thyroid hormone synthesis at a given point in time will not result in an instantaneous decrease in circulating T4. The system will be capable of maintaining sufficient circulating T4 levels until the gland stores are depleted. The time it takes to deplete stored hormone will greatly depend on species, developmental status and numerous other factors. In Xenopus, Haselman et al. (2020) demonstrated an approximately 5 day difference between a significant decrease in thyroidal T4 preceding a significant decrease in circulating T4 while exposed to a potent TPO inhibitor (MMI) continuously during pro-metamorphosis.

This KER is entirely influenced by the feedback loop between circulating T4 originating from the thyroid gland and circulating TSH originating from the pituitary. Intermediate biochemical processes exist within the hypothalamus to affirm feedback and coordinately release TSH from the pituitary. However, quantitative representations of these feedback processes are limited to models discussed previously. In Xenopus, circulating levels of T4 increase through pro-metamorphosis indicating a "release" of feedback to allow circulating levels of T4 to increase and drive metamorphic changes (Sternberg et al., 2011). This provides evidence that homeostatic control of feedback can be developmentally dependent, and likely species dependent.

High Male High Female

High

All life stages

High High High High Low Low

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430af3b470> AOPWiki 2016-11-29T18:41:33

2022-10-10T08:56:38

<upstream-id>184aa0de-37e3-4562-a777-40290d2f5d57</upstream-id> <downstream-id>4893e0a5-dd50-4e56-a439-9ca3fc1a53d2</downstream-id> When serum thyroxine (T4) levels are decreased, less T4 is available for conversion to the more biologically active triiodothyronine (T3). While some thyroid hormone (TH) disrupting mechanisms can immediately affect T3 levels, including deiodinase inhibition, other mechanisms reduce T4 levels, for example through inhibition of TH synthesis, leading to decreased T3 levels. Since in fish early life stages TH are typically measured on a whole-body level, it is currently uncertain whether TH levels changes occur at the serum and/or tissue level. Pending more dedicated studies, whole-body TH levels are often considered a proxy for serum TH levels. This key event relationship is not always evident. This could be due to feedback/compensatory mechanisms that in some cases seem to be able to maintain T3 levels even though T4 levels are reduced, for example through increased conversion of T4 to T3 by deiodinases.

When serum thyroxine (T4) levels are decreased, less T4 is available for conversion to the more biologically active triiodothyronine (T3). It is plausible to assume that while some thyroid hormone (TH) disrupting mechanisms can immediately affect T3 levels, including deiodinase inhibition, other mechanisms reduce T4 levels, for example through inhibition of TH synthesis, leading to decreased T3 levels.

<ul> <li>A decrease in whole-body T4 and T3 was observed in zebrafish exposed to methimazole from fertilization until the age of 21 and 32 days and to propylthiouracil until the age of 14, 21 and 32 days (Stinckens et al., 2020). Additionally, a strong correlation was observed between T4 and T3 levels. Both compounds are TPO inhibitors expected to inhibit TH synthesis.</li> <li>A dose-dependent decrease in whole-body T4 and T3 was observed in zebrafish exposed to perfluorooctanoic acid and perfluoropolyether carboxylic acids from fertilization until the age of 5 days (Wang et al., 2020). The exact mechanisms by which PFAS disrupt the TH system remain uncertain.</li> <li>While T4 measurements could not be acquired in fathead minnows exposed to 1 mg/L 2-mercaptobenzothiazole, a TPO inhibitor, for 14 days, a significant decrease in T3 was observed (Nelson et al., 2016). The decreased T3 levels were likely the result of reduced T4 synthesis.</li> <li>Besson et al. (2020) showed both decreased T4 levels and decreased T3 levels in metamorphosing convict surgeonfish exposed to chlorpyrifos.</li> </ul>

<ul> <li>Since in fish early life stages THs are typically measured on a whole body level, it is currently uncertain whether TH level changes occur at the serum and/or tissue level. Pending more dedicated studies, whole body TH levels are considered a proxy for serum TH levels.</li> <li>This key event relationship is not always evident. This could be due to feedback/compensatory mechanisms that in some cases seem to be able to maintain T3 levels even though T4 levels are reduced, for example through increased conversion of T4 to T3 by deiodinases. Examples of studies showing reduced T4 levels in the absence of reduced T3 levels: <ul style="list-style-type:circle"> <li>Zebrafish exposed to 0.35 mg/L 2-mercaptobenzothiazole, a TPO inhibitor, through 32 dpf showed decreased whole-body T4, but T3 levels showed particularly large variation and overall were not significantly decreased (Stinckens et al., 2016).</li> <li>Although T4 content of 28 dpf larval fathead minnows exposed to 32 or 100 µg/l methimazole, a TPO inhibitor, was reduced, these fish showed no change in whole body T3 content (Crane et al., 2006). Significantly higher T3/T4 ratios in fish held in 100 µg/l methimazole suggest an increased conversion of T4 to T3 or reduced degradation and conjugation during continued exposure to methimazole</li> </ul> </li> </ul>

Stinckens et al. (2020, supplementary information) showed a significant linear relationship between whole body T3 and T4 concentrations at 21 and 32 days post fertilization after continuous exposure of zebrafish to methimazole and propylthiouracil, two inhibitors of TH synthesis.

This key event relationship is not always evident. This could be due to feedback/compensatory mechanisms that in some cases seem to be able to maintain T3 levels even though T4 levels are reduced, for example through increased conversion of T4 to T3 by deiodinases. Examples of studies showing reduced T4 levels in the absence of reduced T3 levels: <ul> <li>Zebrafish exposed to 0.35 mg/L 2-mercaptobenzothiazole, a TPO inhibitor, through 32 dpf showed decreased whole-body T4, but T3 levels showed particularly large variation and overall were not significantly decreased (Stinckens et al., 2016).</li> <li>Although T4 content of 28 dpf larval fathead minnows exposed to 32 or 100 µg/l methimazole, a TPO inhibitor, was reduced, these fish showed no change in whole body T3 content (Crane et al., 2006). Significantly higher T3/T4 ratios in fish held in 100 µg/l methimazole suggest an increased conversion of T4 to T3 or reduced degradation and conjugation during continued exposure to methimazole</li> </ul> This relationship depends on the MIE that is causing the decrease in T3. For example, deiodinase inhibition results in reduced activation of T4 to T3 and thus in reduced T3 levels; increased T4 levels have been observed, probably as a compensatory mechanism in response to the lower T3 levels. For example, Cavallin et al. (2017) exposed fathead minnows to iopanoic acid, a deiodinase inhibitor, and observed T4 increases together with T3 decreases.

Moderate Unspecific

Moderate

Juvenile

Moderate

Larvae

High Moderate

Taxonomic: Thyroid follicles mainly produce T4 and to a lesser extent T3 across vertebrates. When serum T4 levels are decreased, less T4 is available for conversion to the more biologically active T3. This key event relationship is not always evident. This could be due to feedback/compensatory mechanisms that in some cases seem to be able to maintain T3 levels even though T4 levels are reduced, for example through increased conversion of T4 to T3 by deiodinases. These feedback mechanisms can also differ across species. Therefore, although this KER is plausibly applicable across vertebrates, variation can be expected. In zebrafish and fathead minnow, several studies reported evidence for a relationship between whole body T4 and T3 levels (Nelson et al., 2016; Stinckens et al., 2020, Wang et al., 2020). Life stage: This key event relationship is applicable to late larvae and juveniles rather than to embryos, because of the presence of maternal TH in embryos. Uncertainties during embryonic life stage: <ul> <li>A decrease in whole body T4 was observed in fathead minnows exposed to 1 mg/L 2-mercaptobenzothiazole (MBT), a TPO inhibitor, until 6 dpf (Nelson et al., 2016). In contrast, there was no observed effect on T3 in fathead minnows exposed to MBT until 6 dpf. Comparably, zebrafish exposed to 0.4 or 0.7 mg/L MBT thruntilough 120 hpf showed decreased whole body T4 but not T3 (Stinckens et al., 2016). During this early larval life stage, T3 may have been derived from maternal T4. In addition, it could be produced from further depletion of any T4 still produced by the thyroid gland (as TPO may not have been fully inhibited at the tested exposure concentrations).</li> <li>Since exposure to PFAS did result in decreased whole-body T4 and T3 in 5 day old zebrafish, the life-stage specificity possibly depends on the mechanism that lies at the basis of the TH changes (Wang et al., 2020). The exact mechanisms by which PFAS disrupt the TH system remain uncertain. Compounds that directly reduce T3 levels (e.g., deiodinase inhibitors) in addition to reducing T4 levels via another mechanism can be expected to result in decreased T4 and T3 levels.</li> </ul> Sex: The KE is plausibly applicable to both sexes. Thyroid hormones 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 thyroid hormone levels and the magnitude of the response. In humans, females appear more susceptible to hypothyroidism compared to males when exposed to certain halogenated chemicals (Hernandez‐Mariano et al., 2017; Webster et al., 2014). In adult zebrafish, Liu et al. (2019) showed sex-dependent changes in thyroid hormone 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.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430af7bd68> AOPWiki 2020-02-19T09:39:46

2022-10-10T09:02:24

<upstream-id>4893e0a5-dd50-4e56-a439-9ca3fc1a53d2</upstream-id> <downstream-id>1ad59a43-d7dc-46b3-821b-653cd96ab260</downstream-id> Thyroid hormone signaling coordinates cell fate of photoreceptors in the visual system, especially during development and growth. Although different taxonomic groups differ in their photoreceptor subtypes, in general across species, thyroid hormone action promotes a shift of spectral sensitivity of opsins toward longer wavelengths. Decreased serum levels of triiodothyronine (T3), the more biologically active thyroid hormone, can alter photoreceptor patterning.

It is widely accepted that thyroid hormones play a role in the development of the visual system, and specifically in the development of the normal photoreceptor pattern in the retina. It follows that decreased availability of T3 in serum disrupts the normal photoreceptor pattern.

There is ample evidence across species that thyroid hormones (TH) promote a switch/shift to photoreceptors with opsins sensitive to longer wavelengths: <ul> <li dir="ltr"> Thyroid hormone action is known to be required for M-opsin identity in mice (and rats) <ul> <li dir="ltr"> Using thrb2 knockout mice, Ng et al. (2001) showed that TH reduces S (short wavelength opsin) cones and promotes M (medium wavelength opsin) cones. </li> <li dir="ltr"> Roberts et al. (2006) also showed that exogenous TH inhibits S-opsin expression, but activates M-opsin expression via thrbeta2 action. Furthermore, they found a spatial TH gradient with more TH in the dorsal retina, that corresponded to the spatial pattern of more M-opsin in the dorsal retina, confirming that THs determine spatial patterning of photoreceptors. </li> <li dir="ltr"> Ng et al. (2011) concluded that in mice photoreceptor diversity originates in a common precursor with default S cone properties and differentiation is a two-step process where neural retina leucine zipper factor (NRL) first promotes differentiation of a fraction of precursor cells to rods and thrbeta2 secondly promotes differentiation of another fraction to M cones. </li> <li dir="ltr"> Glaschke et al. (2010) showed that a postnatal decrease in serum thyroid hormone resulted in upregulation of S opsin was upregulated in all cones, whereas M opsin was downregulated throughout the retina. </li> <li dir="ltr"> Glaschke et al. (2011) showed that TH also controls adult cone opsin expression. Methimazole-induced suppression of serum TH in adult mice and rats yielded no changes in cone numbers but reversibly altered cone patterns by activating the expression of S-cone opsin and repressing the expression of M-cone opsin. Treatment of athyroid mice with TH restored a wild-type pattern of cone opsin expression that reverted back to the mutant S-opsin-dominated pattern after termination of treatment. No evidence for cone death or the generation of new cones from retinal progenitors was found in retinas that shifted opsin expression patterns. </li> <li dir="ltr">   Gamborino et al. () found a delay in photoreceptor outer segment morphogenesis (in relation to retarded disc formation) and significantly lower values for ganglion cell nuclear volumes (p > 0.001) and nuclear pore density (p > 0.01)  in the TH deficient rats </li> <li dir="ltr"> Ma Ding (2016) found out that treatment with thyroid hormone triiodothyronine (T3) or induction of high T3 by deleting the hormone-inactivating enzyme type 3 iodothyronine deiodinase (DIO3) causes cone death in mice. </li> </ul> </li> <li dir="ltr"> Salmonids undergo indirect development with an intermediate metamorphosis. In salmonids, this includes a switch from UV cones to blue cones (Cheng et al., 2006). Thyroid hormone action is known to be required for this opsin switch: <ul> <li dir="ltr"> Allison et al. (2006) showed that increasing thyroid hormone (TH) levels led to UVS cone degeneration in rainbow trout, which is part of metamorphosis that prepares them for deeper/marine waters. After the cessation of TH treatment, UVS cones regenerated in the retina. Labeling demonstrated that UVS cone degeneration occurs via programmed cell death.  </li> <li dir="ltr"> Cheng et al. (2006): Thyroid hormone induced a reversible UV-to-blue opsin switch in differentiated single cones of juvenile salmonids (alevin and parr stages), but did not have a similar effect on the retina of older fish (smolt stage). </li> <li dir="ltr"> Gan and Flamarique (2010) showed that thyroid hormone accelerated opsin expression in differentiating cones and induced the opsin switch (from UV sensitive cones to blue cones sensitive to longer wavelengths) in differentiated single cones, whereas propylthiouracil (PTU) repressed the opsin switch in the salmonid retina. TRalpha spatial expression patterns paralleled the progression of the opsin switch.  </li> <li dir="ltr"> Suliman and Novales Flamarique (2014): In both alevins and smolt (large juvenile rainbow trout) of rainbow trout, thyroid hormone treatment significantly increased the wavelength of maximum absorbance of the M and L visual pigments. While in alevins this was accompanied by a switch of S-opsin expression from UV to blue opsin, opsin expression in smolt remained unchanged. </li> <li dir="ltr"> Duval and Allison (2018): TH promotes red cones and restricts UV cones via thrb during early development of zebrafish. During later development it additionally restricts blue cones. </li> </ul> </li> <li dir="ltr"> Thyroid hormone action is known to be required for long-wavelength-sensitive cone identity in zebrafish. <ul> <li dir="ltr"> Suzuki et al. (2013): Thyroid hormone receptor β2 expression in cone precursors is required to produce pure red cones.  </li> <li dir="ltr"> Houbrechts et al. (2016): Knockdown of deiodinase 1 and 2 in zebrafish embryos (expected to result in decreased levels of T3) decreased expression of opsins and decreased the numbers of each cone type.   </li> <li dir="ltr"> Van Camp et al. (2019) showed that deiodinase 2 knockout in zebrafish (expected to result in decreased levels of T3) reduced the numbers of red (long-wavelength-sensitive)/green (medium-wavelength-sensitive) cones and rods. </li> <li dir="ltr"> Mackin et al. (2019):  <ul> <li dir="ltr"> Fluorescent lws reporters permitted direct visualization of individual cones switching expression from lws2 to lws1 (with longer wavelength sensitivity) in zebrafish treated with TH.  </li> <li dir="ltr"> Athyroidism increased lws2 and reduced lws1, except within a small ventral domain of lws1 that was likely sustained by retinoic acid signaling.  </li> <li dir="ltr"> Changes in lws abundance and distribution in athyroid zebrafish were rescued by TH, demonstrating essentiality of decreased TH levels for the downstream effect of altered photoreceptor patterning, and demonstrating plasticity of cone phenotype.  </li> <li dir="ltr"> The intracellular presence of T3 was consistent with the fraction of LWS cones that switch from lws2 to lws1 expression, supporting the importance of T3. </li> <li dir="ltr"> In juvenile zebrafish treated with T4, transcript abundance of both short-wavelength-sensitive opsins sws1 (UV opsin) and sws2 (blue opsin) was reduced. </li> <li dir="ltr"> TH treatment also regulated the rh2 (medium-wavelength-sensitive, green cone) array, with athyroidism reducing abundance of distal members that are sensitive to longer wavelengths. </li> </ul> </li> </ul> </li> <li dir="ltr"> winter flounder, a species that undergoes metamorphosis: <ul> <li dir="ltr"> Mader and Cameron (2006): TH signaling significantly affects, in a targeted manner, the photoreceptor pattern during retinal growth and regeneration. More specifically, evidence suggests that TH is required for specification of rods (i.e. manifestation of the rod as opposed to cone photoreceptor lineage), while TH influences the differentiation (i.e., expression of particular opsins), but perhaps not specification, of cone photoreceptors. </li> </ul> </li> </ul>

<ul> <li dir="ltr"> Mackin et al. (2019): All 4 cone opsins are regulated by T4. However, in athyroid juvenile zebrafish, sws1 and sws2 levels were not different compared to controls, findings which are not consistent with endogenous functions for TH signaling in regulation of these genes in juvenile zebrafish. </li> <li dir="ltr"> Some studies show that TH can still alter opsin expression in later life stages after retinal development, while other studies report that opsin expression remains unaltered but the wavelength where maximal absorbance occurs increases. </li> </ul>

Not Specified

<ul> <li dir="ltr"> Taxonomic applicability </li> <li dir="ltr"> The function of thyroid hormones in regulating eye development including photoreceptor patterning is highly conserved across vertebrates (Viets et al., 2016) </li> <li dir="ltr"> Species that undergo noticeable metamorphosis seem to have more plasticity in opsin expression both at the embryonic stage and when the retina is fully differentiated (Suliman and Flamarique, 2014). </li> <li dir="ltr"> Life-stage applicability </li> <li dir="ltr"> Mackin et al. (2019): Lws and Rh2 differential Expression Remains Plastic to the Effects of TH Signaling through Juvenile Growth. </li> <li dir="ltr"> Mackin et al. (2019): components of the zebrafish rh2 opsin gene array can also be regulated by exogenous T3 in larval zebrafish. </li> <li dir="ltr"> Sex applicability </li> <li dir="ltr"> Zebrafish are undifferentiated gonochorists since both sexes initially develop an immature ovary (Maack and Segner, 2003). Immature ovary development progresses until approximately the onset of the third week. Later, in female fish immature ovaries continue to develop further, while male fish undergo transformation of ovaries into testes. Final transformation into testes varies among male individuals, however finishes usually around 6 weeks post fertilization. Effects on photoreceptor patterning resulting from altered T3 levels during early development are therefore expected to be independent of sex. </li>   <li> </li> <li> </li> <li> </li> <li dir="ltr"> Glaschke et al. (2011) showed that TH also controls adult cone opsin expression in mice and rats. </li> <li dir="ltr"> Mader and Cameron (2006): Premetamorphic winter flounder express only RH2 opsin. During metamorphosis they develop a new repertoire of opsins (RH1, SWS2, RH2, and LWS). the phenotypic organization of the premetamorphic retina, which is produced during low TH conditions, is consistent with the premetamorphic-like retina produced by the growing postmetamorphic retina during induced hypothyroidic conditions. Additionally, a similar effect of TH upon photoreceptor production was observed for regenerating postmetamorphic retina. This suggests that regeneration of the adult vertebrate retina involves a recapitulation of the mechanisms that drive and direct cytogenesis during normal development and growth </li> <li dir="ltr"> While in early life stages during retinal development, TH alters opsin expression and photoreceptor fate, during later stages TH treatment does not always result in altered opsin expression: <ul> <li dir="ltr"> Allison et al. (2004) showed that thyroid hormone treatment increases the wavelength of maximum absorbance of photoreceptors in adult zebrafish, and this could not be explained by changes in opsin expression. </li> <li dir="ltr"> Suliman and Novales Flamarique (2014): Opsin expression did not change in young juveniles of zebrafish or killifish treated with TH. </li> </ul> </li> </ul>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430af9e2c8> AOPWiki 2021-05-11T05:45:51

2021-10-17T16:34:17

<upstream-id>1ad59a43-d7dc-46b3-821b-653cd96ab260</upstream-id> <downstream-id>a99ad392-6e7e-4f96-87d2-db5cd9d42ae3</downstream-id> Photoreceptors in the retina of vertebrates and invertebrates are the cells that are responsible for phototransduction. Photoreceptor subtypes are characterized by different opsins (light-sensitive proteins) that respond to light with different wavelengths. The pattern of photoreceptors in the eyes therefore determines visual function. Alterations in photoreceptor patterning could include altered numbers of photoreceptor subtypes leading to an altered ratio of photoreceptor subtypes and/or altered spatial organization.

Since different photoreceptor subtypes have different opsins that allow for perceiving light of different wavelengths, it is plausible to assume that alterations in photoreceptor patterning such as altered ratios of photoreceptor subtypes affect normal visual function.

<ul> <li dir="ltr"> Flamarique et al. (2013) used thyroid hormone treatment to transform the UV cones of young rainbow trout into blue cones and showed that this reduced the distances and angles at which prey were located (variables that are known indicators of foraging performance). Using optical measurements and photon-catch calculations, the study showed that control rainbow trouts perceived Daphnia with greater contrast compared to thyroid-hormone-treated fish, demonstrating that the presence of UV cones enhances foraging performance of young rainbow trout. </li> <li dir="ltr"> Houbrechts et al. (2016) used a knockdown of deiodinase 1 and 2 in zebrafish embryos to induce transient hypothyroidism and observed decreased levels of mRNA coding for rod and cone opsins (at 3 dpf, days post fertilization) and a strong transient reduction in rods and all four cone types (at 3 dpf but no longer at 7 dpf) together with a transiently reduced response (increase of swimming activity) to light (4 dpf, but no longer at 7 dpf). </li> <li dir="ltr"> Van Camp et al. (2019) showed that permanent deiodinase 2 deficiency resulted in a reduction of the number of R/G cones and rods that persisted through 7 dpf together with a reduced response to light (observed at 6 dpf).   </li> <li dir="ltr"> Frau et al. (2020) studied the consequences of differences in photoreceptor patterning across fish species. They concluded that species that are primarily nocturnal or live in low light environments such as the common sole and Senegalese sole have a less ordered mosaic cone pattern. A study of different fish species reveiled that lattice-like patterning of the cone mosaic seems to improve visual acuity. Fish taxa that live in low light environments generally do not possess lattice-like cone mosaics. </li> </ul>

Not Specified

<ol> <li dir="ltr"> Taxonomic </li> </ol> Although there are important taxonomic differences in opsin genes and in photoreceptor patterning across taxa, it is plausible to assume that the importance of proper photoreceptor patterning for normal visual function is applicable across all vertebrates and invertebrates that have eyes. <ol start="2"> <li dir="ltr"> Life stage </li> </ol> It is plausible to assume that alterations of photoreceptor patterning would result in altered visual function across all life stages, but such alterations are most likely to occur during the development of the normal photoreceptor pattern, which occurs in the embryonic phase.  <ol start="3"> <li dir="ltr"> Sex </li> </ol> Zebrafish are undifferentiated gonochorists since both sexes initially develop an immature ovary (Maack and Segner, 2003). Immature ovary development progresses until approximately the onset of the third week. Later, in female fish immature ovaries continue to develop further, while male fish undergo transformation of ovaries into testes. Final transformation into testes varies among male individuals, however finishes usually around 6 weeks post fertilization. Effects on visual function resulting from altered photoreceptor patterning during early development are therefore expected to be independent of sex.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430afc1430> AOPWiki 2019-05-22T05:15:39

2021-06-16T07:24:33

<upstream-id>a99ad392-6e7e-4f96-87d2-db5cd9d42ae3</upstream-id> <downstream-id>f4b52ee3-e3a1-4f4b-8020-a6bd6defe5c0</downstream-id> In animals, whatever the taxa, visual abilities are strongly linked to their lifestyle (feeding, avoidance of predators, movement, protection....). When these capacities are impaired, they lead to reduced fitness and are therefore strongly linked to a decrease in survival, particularly in the early stages of life.

Decreases in visual functions can have a strong impact on behavior, leading to changes in individual response and abilities in the environment, including, for example, perception of food or avoidance of predators. Variation in the visual system can also influence learning tasks when visual stimuli are used (Corral-López et al., 2017).  Sensory drive has been implicated in speciation in various taxa, largely based on phenotype-environment correlations and signatures of selection in sensory genes, including vision (Maan et al, 2017).  It is biologically plausible that an animal which has difficulties in finding food and avoiding predators will have lower survival chances in wildlife.

Only very few studies are available in which it was demonstrated that decreased visual capacities lead to reduced survival of the organism. In general, mortality is rarely assessed but survival-reducing factors (feeding, predation) are mainly investigated. Here we consider the work about different toxicants that disrupt complex fish behaviors, such as predator avoidance, reproductive, and social behaviors. Toxicant exposure often completely eliminates the performance of behaviors that are essential to fitness and survival in natural ecosystems, frequently after exposures of lesser magnitude than those causing significant mortality (Brown et al., 2004). <ul> <li>Fuiman et al. (2006) specifically investigated the importance of several putative survival skills for escaping a predator. They first analysed routine swimming, acoustic startle stimulus and visual startle stimulus of red drum larvae and subsequently performed a predation experiment using the same larvae in the presence of a live predator. The authors found that the effectiveness of escape responses was almost 100% and thus responsiveness determined survival under predation. Of the different putative survival skills, only visual responsiveness was significantly correlated to escape potential, while others such as acoustic responsiveness were not significantly contributing to escape potential. Further investigation showed that only visual responsiveness differed significantly between poorly responding larvae and better responders.</li> <li>Dehnert et al., 2019: In zebrafish, 2, 4-Dichlorophenoxyacetic acid exposure during eye development impaired visual behavior, i.e. reduced prey capture. Additionally, exposed fish showed reduced neural activity within the optic tectum following prey exposure.</li> <li>Besson et al., 2020 exposed metamorphosing convict surgeonfish to pharmacological treatments. They performed a 10−6 M NH3 treatment (a TH antagonist) to achieve TH signal disruption and they observed an adverse outcome on retinal layer level. Repressed retinal development at both day 2 and day 5 with a 10-25 % decrease of bipolar cell density was detected. They followed up with a behavior test at day 2 with blacktail snapper as a predator and got the following results: </li> </ul> 1. In the test using chemical cues of the predator the NH3-treated fish did not discriminate between water sources, while control fish clearly avoided predator cues. 2. In the visual cues test the NH3-treated fish showed no preference and spent 25 % more time in visual stimulus compared to controls. 3. In a survival predation test in an in situ arena they observed that day 2 NH3 treated fish exhibited 30% lower survival than d2 control fish. <ul> <li>Furthermore Besson et al., 2020 conducted a Chlorpyrifos (CPF) treatment 30 μg L−1 and observed a significant reduction (25%) in T4 levels at day 2 in CPF30 fish, as well as significantly reduced T3 levels in CPF30 fish (28%) compared with control fish. CPF30 fish also exhibited reduced densities of bipolar cell (10%) of retinal layer and CPF30 fish experienced lower survival.</li> <li>Flamarique et al. (2013) showed that thyroid hormone treatment impacted the development of the visual system in rainbow trout and reduced the distances and angles at which prey were located (variables that are known indicators of foraging performance). Using optical measurements and photon-catch calculations, the study showed that control rainbow trouts perceived prey (Daphnia) with greater contrast compared to thyroid-hormone-treated fish. Reduced foraging performance is likely to reduce survival in the wild.</li> <li>Heijlen et al. (2014) showed that knockdown of Type 3 Iodothyronine Deiodinase, known to disrupt eye development (Houbrechts et al. (2016), causes embryos to spend significantly less time moving, and perturbs the escape response after a tactile stimulus. An inability to escape predators likely reduces survival in the wild.</li> </ul>

It is obvious that impaired vision leads to higher mortality, as the sense of sight is important for survival, and if it is impaired, feeding or escape becomes more difficult. However, the number of studies investigating this connection is limited. It is often unclear to what extent this relationship is determined by altered visual function versus other pathways such as alterations in muscle development or other factors contributing to these types of behaviour. Also, the natural conditions, which depend on many variables, are difficult to reproduce in the laboratory or to compare between different laboratories.

Increase according to global health of the population (e.g on trout (Post and Parkinson, 2001)

Moderate Unspecific

Moderate

All life stages

High

Taxonomic applicability: The visual system of the fish (e.g., zebrafish) follows the typical organisation of vertebrates and is often used as a model to study human eye diseases. Although there are some differences, it is plausible to assume that visual function is important for survival across all vertebrates and invertebrates that have eyes. Sex applicability: Zebrafish are undifferentiated gonochorists since both sexes initially develop an immature ovary (Maack and Segner, 2003). Immature ovary development progresses until approximately the onset of the third week. Later, in female fish immature ovaries continue to develop further, while male fish undergo transformation of ovaries into testes. Final transformation into testes varies among male individuals, however finishes usually around 6 weeks post fertilization. Effects on mortality resulting from altered visual function are therefore expected to be independent of sex. Life stage applicability: It is plausible to assume that altered visual function of the eye would result in a higher mortality across all life stages. This could be especially true for the embryonic stages, the most sensitive stage of life. Vision plays a crucial role (in the early life stages) of most species, as eye development and establishment of functional vision is essential for perception of food or avoidance of predators for example (Carvalho et al., 2002).

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430aff5500> AOPWiki 2021-05-11T05:27:51

2022-07-08T08:26:57

<upstream-id>f4b52ee3-e3a1-4f4b-8020-a6bd6defe5c0</upstream-id> <downstream-id>c4a44b16-78e5-4173-9ac7-88055f8e5355</downstream-id> Increased mortality in the reproductive population may lead to a declining population. This depends on the excess mortality due to the applied stressor and the environmental parameters such as food availability and predation rate. Most fish species are r-strategist, meaning they produce a lot of offspring instead of investing in parental care. This results in natural high larval mortality causing only a small percentage of the larvae to survive to maturity. If the excess larval mortality due to a stressor is small, the population dynamics might result in constant population size. Should the larval excess be more significant, or last on the long-term, this will affect the population. To calculate the long-term persistence of the population, population dynamic models should be used.

Survival rate is an obvious determinant of population size and is therefore included in population modeling (e.g., Miller et al., 2020).

<ul> <li>Survival to reproductive maturity is a parameter of demographic significance. Assuming resource availability (i.e., food, habitat, etc.) is not limiting to the extant population, sufficient mortality in the reproductive population may ultimately lead to declining population trajectories.</li> <li>Under some conditions, reduced larval survival may be compensated by reduced predation and increased food availability, and therefore not result in population decline (Stige et al., 2019).</li> </ul>

<ul> <li>According to empirical data, combined with population dynamic models, feeding larvae are the crucial life stage in zebrafish (and other r-strategists) for the regulation of the population. (Schäfers et al., 1993)</li> <li>In fathead minnow, natural survival of early life stages has been found to be highly variable and influential on population growth (Miller and Ankley, 2004)</li> <li>Rearick et al. (2018) used data from behavioural assays linked to survival trials and applied a modelling approach to quantify changes in antipredator escape performance of larval fathead minnows in order to predict changes in population abundance. This work was done in the context of exposure to an environmental oestrogen. Exposed fish had delayed response times and slower escape speeds, and were more susceptible to predation. Population modelling showed that this can result in population decline.</li> <li>In the context of fishing and fisheries, ample evidence of a link between increased mortality and a decrease of population size has been given. Important insights can result from the investigation of optimum modes of fishing that allow for maintaining a population (Alekseeva and Rudenko, 2018). Jacobsen and Essington (2018) showed the impact of varying predation mortality on forage fish populations.</li> <li>Boreman (1997) reviewed methods for comparing the population-level effects of mortality in fish populations induced by pollution or fishing.</li> </ul>

<ul> <li>The extent to which larval mortality affects population size could depend on the fraction of surplus mortality compared to a natural situation.</li> <li>There are scenarios in which individual mortality may not lead to declining population size. These include instances where populations are limited by the availability of habitat and food resources, which can be replenished through immigration. Effects of mortality in the larvae can be compensated by reduced competition for resources (Stige et al., 2019).</li> <li>The direct impact of pesticides on migration behavior can be difficult to track in the field, and documentation of mortality during migration is likely underestimated (Eng 2017).</li> </ul>

<ul> <li>Assuming other relevant demographic parameters are available, the effect of increased mortality rates on population status can be quantitatively predicted using standard population modeling approaches.</li> <li>Stage population matrix models (Caswell, 2000) simulate population growth rates based on age-specific parameters and can be adapted to a range of species (Pinceel et al., 2016). For zebrafish, individually based models (IBM) have been developed to link responses at the individual level to the population level (Beaudouin et al., 2015). However, authors agree that survival is one of the most uncertain parameters in the model and more research on the topic is needed.</li> </ul>

Moderate Unspecific

High

All life stages

High High

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430b034a70> AOPWiki 2019-12-20T16:07:12

2022-07-08T08:29:35

Thyroperoxidase inhibition leading to altered visual function via altered photoreceptor patterning

TPOi photoreceptor patterning

Cataia Ives

Under Development

1.35

2.0

There is a wealth of information on the inhibition of TPO by drugs such as MMI and PTU, as well as environmental xenobiotics. In the landmark paper on TH system disruption by environmental chemicals, Brucker-Davis (1998) identified environmental chemicals that depressed TH synthesis by inhibiting TPO. Hurley (1998) listed TPO as a major target for thyroid tumor inducing pesticides. More recent work has tested over 1000 chemicals using a high-throughput screening assay (Paul-Friedman et al., 2016).

Increased mortality is one of the most common regulatory assessment endpoints, along with reduced growth and reduced reproduction.

Maintenance of sustainable fish and wildlife populations (i.e., adequate to ensure long-term delivery of valued ecosystem services) is a widely accepted regulatory goal upon which risk assessments and risk management decisions are based.

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AOPWiki 2020-12-09T07:47:23

2023-09-25T16:27:04