Inhibition, Deiodinase 3

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

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

14797-73-0

VLTRZXGMWDSKGL-UHFFFAOYSA-M

Perchlorate

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

DTXSID6024252

PR:000006482

PR type III iodothyronine deiodinase

CHEBI:18258

CHEBI 3,3',5-triiodo-L-thyronine

GO:0003824

GO catalytic activity

GO:0007552

GO metamorphosis

WIKI decreased

WIKI delayed

WIKI increased

Methimazole

2016-11-29T18:42:19

Stressor:48 Propylthiouracil

2020-08-28T17:00:54

Mercaptobenzothiazole

2016-11-29T18:42:17

Perchlorate

2016-11-29T18:42:26

WCS_8355

common ecological species African clawed frog

WikiUser_6

ApacheUser fish

8292

NCBI Amphibia

WikiUser_17

mammals

Inhibition, Deiodinase 3

Molecular

Taxonomic: According to the evaluation of the empirical taxonomic domain of applicability (tDOA) of an adverse outcome pathway network for thyroid hormone system disruption (THSD) by Haigis et al., 2023, the level of confidence for a linkage between DIO3 inhibition and altered thyroid hormone (TH) levels was considered high for fish and amphibians (Darras, 2021, Darras and Van Herck, 2012, Fini et al., 2007, Heijlen et al., 2014, Houbrechts et al., 2016, Mayasich et al., 2021, Mol et al., 1998, Noyes et al., 2011, Sanders et al., 1999, Thompson and Cline, 2016) and moderate for mammals (Darras, 2021, Darras and Van Herck, 2012, Hernandez et al., 2006, Ng et al., 2009, Olker et al., 2019). This was supported by structural protein conservation analysis by Lalone et al., 2018 and Haigis et al., 2023. Structural protein conservation of mammalian, fish, amphibian, reptilian and avian DIO3 was found compared to the human (Homo sapiens) protein target using the U.S. Environmental Protection Agency’s Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS v6.0; seqapass.epa.gov/seqapass/) tool, while acknowledging the potential existence of interspecies differences in conservation. No empirical evidence linking DIO3 inhibition to THSD was found for reptiles and birds. It should be mentioned that although the level of DIO3 conservation between chicken and the human reference was relatively high, SeqAPASS did not predict DIO3 conservation for birds in general.

Not Specified High High Moderate

Darras, V. M. (2021). Deiodinases: How nonmammalian research helped shape our present view. Endocrinology 162. Darras, V. M., and Van Herck, S. L. J. (2012). Iodothyronine deiodinase structure and function: From ascidians to humans. J. Endocrinol. 215, 189–206. Fini, J. B., Le Mevel, S., Turque, N., Palmier, K., Zalko, D., Cravedi, J. P., and Demeneix, B. A. (2007). An in vivo multiwell-based fluorescent screen for monitoring vertebrate thyroid hormone disruption. Environ. Sci. Technol. 41, 5908–5914. Haigis A-C., Vergauwen L., LaLone C.A., Villeneuve D.L., O'Brien J.M., Knapen D. (2023). Cross-species applicability of an adverse outcome pathway network for thyroid hormone system disruption. Toxicol Sci. 195, 1-27. Heijlen, M., Houbrechts, A. M., Bagci, E., Van Herck, S. L. J., Kersseboom, S., Esguerra, C. V., Blust, R., Visser, T. J., Knapen, D., and Darras, V. M. (2014). Knockdown of type 3 iodothyronine deiodinase severely perturbs both embryonic and early larval development in zebrafish. Endocrinology 155, 1547–1559. Hernandez, A., Martinez, M. E., Fiering, S., Galton, V. A., and St. Germain, D. (2006). Type 3 deiodinase is critical for the maturation and function of the thyroid axis. J. Clin. Invest. 116, 476–484. Houbrechts, A. M., Vergauwen, L., Bagci, E., Van houcke, J., Heijlen, M., Kulemeka, B., Hyde, D. R., Knapen, D., and Darras, V. M. (2016). Deiodinase knockdown affects zebrafish eye development at the level of gene expression, morphology and function. Mol. Cell. Endocrinol. 424, 81–93. Lalone, C. A., Villeneuve, D. L., Doering, J. A., Blackwell, B. R., Transue, T. R., Simmons, C. W., Swintek, J., Degitz, S. J., Williams, A. J., and Ankley, G. T. (2018). Evidence for cross species extrapolation of mammalian-based high-throughput screening assay results. Environ. Sci. Technol. 52, 13960–13971. Mayasich, S. A., Korte, J. J., Denny, J. S., Hartig, P. C., Olker, J. H., DeGoey, P., O’Flanagan, J., Degitz, S. J., and Hornung, M. W. (2021). Xenopus laevis and human type 3 iodothyronine deiodinase enzyme cross-species sensitivity to inhibition by ToxCast chemicals. Toxicol. In Vitro 73, 105141. Mol, K. A., Van Der Geyten, S., Burel, C., Kühn, E. R., Boujard, T., and Darras, V. M. (1998). Comparative study of iodothyronine outer ring and inner ring deiodinase activities in five teleostean fishes. Fish Physiol. Biochem. 18, 253–266. Ng, L., Hernandez, A., He, W., Ren, T., Srinivas, M., Michelle, M., Galton, V. A., St Germain, D. L., and Forrest, D. (2009). A protective role for type 3 deiodinase, a thyroid hormone-inactivating enzyme, in cochlear development and auditory function. Endocrinology 150, 1952–1960. Noyes, P. D., Hinton, D. E., and Stapleton, H. M. (2011). Accumulation and debromination of decabromodiphenyl ether (BDE-209) in juvenile fathead minnows (Pimephales promelas) induces thyroid disruption and liver alterations. Toxicol. Sci. 122, 265–274. Olker, J. H., Korte, J. J., Denny, J. S., Hartig, P. C., Cardon, M. C., Knutsen, C. N., Kent, P. M., Christensen, J. P., Degitz, S. J., and Hornung, M. W. (2019). Screening the ToxCast phase 1, phase 2, and e1k chemical libraries for inhibitors of iodothyronine deiodinases. Toxicol. Sci. 168, 430–442. Sanders, J. P., Van der Geyten, S., Kaptein, E., Darras, V. M., Kühn, E. R., Leonard, J. L., and Visser, T. J. (1999). Cloning and characterization of type III iodothyronine deiodinase from the fish Oreochromis niloticus. Endocrinology 140, 3666–3673. Thompson, C. K., and Cline, H. T. (2016). Thyroid hormone acts locally to increase neurogenesis, neuronal differentiation, and dendritic arbor elaboration in the tadpole visual system. J. Neurosci. 36, 10356–10375. AOPWiki 2016-11-29T18:41:30

2025-11-19T05:33:59

Increased, Triiodothyronine (T3) in tissues

Tissue

Not Specified

AOPWiki 2016-11-29T18:41:30

2016-12-03T16:37:53

Altered, Amphibian metamorphosis

Organ

Vertebrate metamorphosis is a biological transformation process that transitions an organism from one life stage to another; it is defined by growth of new tissues, programmed death of other tissues and physiological transformation of yet other tissues (Laudet, 2011; Brown and Cai, 2007). In the case of most amphibians, metamorphosis mediates the transition from aquatic to terrestrial life, while in bony and jawless fish, metamorphosis mediates transitions between life stages that offer various advantages for survival and reproduction. In vertebrates, metamorphosis is orchestrated by the hypothalamus-pituitary-thyroid (HPT) axis involving complex timing of gene expression/repression within various tissues, whereas in some cases across taxonomic classes, metamorphosis has been shown to be controlled very differently by the HPT axis. Thyroid hormone-mediated amphibian metamorphosis can be characterized by three phases during larval development: (1) pre-metamorphosis, (2) pro-metamorphosis and (3) metamorphic climax. All three of these phases coincide with activity states of the HPT axis. Pre-metamorphosis is characterized by a fully aquatic organism with low-level function of the thyroid gland and very low circulating levels of thyroid hormone. Pro-metamorphosis is characterized by the onset of full thyroid axis function and the initiation of rising levels of thyroid hormone in the plasma, with consequential changes in anatomy and physiology defining the transition from aquatic to terrestrial life. Metamorphic climax occurs when circulating thyroid hormone levels peak, which subsequently decrease to levels maintained homeostatically as adults. This climax period also represents the time at which all anatomical and physiological changes induced by thyroid hormone have either been initiated or are already completed. Detailed descriptions of these processes are reviewed by Brown and Cai (2007). Altered metamorphosis occurs when these thyroid hormone-mediated processes are perturbed, primarily during pro-metamorphosis and metamorphic climax. These perturbations can lead to either, delayed/arrested development, accelerated development or asynchronous development depending on the xenobiotic mode of action or MIE. Genetic defects or xenobiotic exposure that reduce thyroid hormone synthesis can delay metamorphosis, and in extreme cases, can completely arrest development. The most profound impacts on TH-mediated metamorphosis have be demonstrated through inhibition of key proteins in the TH synthesis pathway including the sodium-iodide symporter (Tietge et al., 2005, 2010; Hornung et al., 2010) and thyroperoxidase (Degitz et al., 2005; Tietge et al., 2010, 2013; Hornung et al., 2010, 2015). Alternatively, agonism of the thyroid axis through inhibition of negative feedback at the level of the hypothalamus-pituitary, or premature activation of thyroid receptor-mediated transcription can accelerate metamorphosis (Degitz et al., 2005), which can lead to asynchronous development due to errors in gene expression timing across the various metamorphic tissues. Asynchronous development can also occur due to inhibition of deiodinase (DIO) enzymes in peripheral tissues. DIO enzymes are responsible for activation and catabolism of TH; when dio gene expression profiles are altered, or the enzymes themselves undergo chemical inhibition, the imbalance of prohormone (T4), active hormone (T3) and inactive hormone (rT3, T2) can cause aberrant tissue development.

Rates of metamorphosis in model amphibian species, Xenopus laevis, are measured multiple ways, both of which rely on a developmental staging atlas developed by Nieuwkoop and Faber (NF)(1994). The method utilized within the 21 d Amphibian Metamorphosis Assay regulatory test guideline (OECD, 2009; US EPA 2009) relate the distribution of developmental stage of control larvae to the distributions of developmental stages of treated/exposed larvae. These data are typically analyzed for differences from control using non-parametric statistical approaches such as the Kruskal-Wallis test followed by Dunn's test for pairwise comparisons. The method utilized within the Larval Amphibian Growth and Development Assay regulatory test guideline (OECD, 2015; US EPA 2015) relate the number of days to reach metamorphic climax (NF stage 62) in control larvae to the number of days to NF stage 62 in treated/exposed larvae. These data are typically analyzed for differences from control using a Cox mixed-effects proportional hazard model. Asynchronous development is identified as disruption of the relative timing of morphogenic milestones and/or somatic development within a single larvae undergoing metamorphosis. The inability to identify an organism's developmental stage based on accepted criteria, such as outlined in Nieuwkoop and Faber (1994) for Xenopus sp. or Gosner (1960) for anurans, constitutes evidence of asynchronous development and would be counted as an incidence. Evaluations of severity are possible but the accuracy and resolution of the results would depend on the experience of the observer. One possible statistical approach for analyzing these data collected from a regulatory test guideline (OECD, 2009, 2015) would be a Rao-Scott-Cochran-Armitage by slices test (Green et al., 2014), as is often used for analysis of histopathology incidence and severity data.

Anurans Xenopus laevis

High Unspecific

High

Development

High

Brown, D.D. and Cai, L., 2007. Amphibian metamorphosis. Developmental biology, 306(1), pp.20-33. Degitz, S.J., Holcombe, G.W., Flynn, K.M., Kosian, P.A., Korte, J.J. and Tietge, J.E., 2005. Progress towards development of an amphibian-based thyroid screening assay using Xenopus laevis. Organismal and thyroidal responses to the model compounds 6-propylthiouracil, methimazole, and thyroxine. Toxicological sciences, 87(2), pp.353-364. Gosner, K.L., 1960. A simplified table for staging anuran embryos and larvae with notes on identification. Herpetologica, 16(3), pp.183-190. Green, J.W., Springer, T.A., Saulnier, A.N. and Swintek, J., 2014. Statistical analysis of histopathological endpoints. Environmental toxicology and chemistry, 33(5), pp.1108-1116. Hornung, M.W., Degitz, S.J., Korte, L.M., Olson, J.M., Kosian, P.A., Linnum, A.L. and Tietge, J.E., 2010. Inhibition of thyroid hormone release from cultured amphibian thyroid glands by methimazole, 6-propylthiouracil, and perchlorate. Toxicological Sciences, 118(1), pp.42-51. Laudet, V., 2011. The origins and evolution of vertebrate metamorphosis. Current Biology, 21(18), pp.R726-R737. Nieuwkoop, P.D. and Faber, J., 1994. Normal Table of Xenopus laevis (Daudin) Garland Publishing. New York, 252. OECD. (2009). Test No. 231: Amphibian Metamorphosis Assay, OECD Guidelines for the Testing of Chemicals, Section 2. OECD Publishing, Paris. OECD. (2015). Test No. 241: The Larval Amphibian Growth and Development Assay (LAGDA), OECD Guidelines for the Testing of Chemicals, Section 2. OECD Publishing, Paris. Tietge, J.E., Butterworth, B.C., Haselman, J.T., Holcombe, G.W., Hornung, M.W., Korte, J.J., Kosian, P.A., Wolfe, M. and Degitz, S.J., 2010. Early temporal effects of three thyroid hormone synthesis inhibitors in Xenopus laevis. Aquatic Toxicology, 98(1), pp.44-50. Tietge, J.E., Holcombe, G.W., Flynn, K.M., Kosian, P.A., Korte, J.J., Anderson, L.E., Wolf, D.C. and Degitz, S.J., 2005. Metamorphic inhibition of Xenopus laevis by sodium perchlorate: effects on development and thyroid histology. Environmental Toxicology and Chemistry, 24(4), pp.926-933. Tietge, J.E., Degitz, S.J., Haselman, J.T., Butterworth, B.C., Korte, J.J., Kosian, P.A., Lindberg-Livingston, A.J., Burgess, E.M., Blackshear, P.E. and Hornung, M.W., 2013. Inhibition of the thyroid hormone pathway in Xenopus laevis by 2-mercaptobenzothiazole. Aquatic toxicology, 126, pp.128-136. U.S. EPA. (2009). OCSPP 890.1100: Amphibian Metamorphosis Assay (AMA), Endocrine Disruptor Screening Program Test Guidelines, 890 Series. Available at: www.regulations.gov, ID: EPA-HQ-OPPT-2009-0576-0002. Accessed March 20, 2020. U.S. EPA. (2015). OCSPP 890.2300: Larval Amphibian Growth and Development Assay (LAGDA), Endocrine Disruptor Screening Program Test Guidelines, 890 Series. Available at: www.regulations.gov, ID: EPA-HQ-OPPT-2014-0766-0020. Accessed March 20, 2020. AOPWiki 2016-11-29T18:41:29

2020-09-02T11:19:05

Altered, Thyroid hormone-dependent gene expression

Altered, TH-dependent gene expression

Molecular

Not Specified AOPWiki 2020-12-09T14:22:38

2020-12-09T14:22:38

<upstream-id>3dfae6f9-ae28-4e7a-b801-170a154b7fe7</upstream-id> <downstream-id>6af3bb25-dd94-4061-99b0-a0868eaed35f</downstream-id>

Not Specified High High Moderate

Taxonomic: According to the evaluation of the empirical taxonomic domain of applicability (tDOA) of an adverse outcome pathway network for thyroid hormone system disruption (THSD) by Haigis et al., 2023, the level of confidence for a linkage between DIO3 inhibition and altered thyroid hormone (TH) levels was considered high for fish and amphibians (Darras, 2021, Darras and Van Herck, 2012, Fini et al., 2007, Heijlen et al., 2014, Houbrechts et al., 2016, Mayasich et al., 2021, Mol et al., 1998, Noyes et al., 2011, Sanders et al., 1999, Thompson and Cline, 2016) and moderate for mammals (Darras, 2021, Darras and Van Herck, 2012, Hernandez et al., 2006, Ng et al., 2009, Olker et al., 2019). This was supported by structural protein conservation analysis by Lalone et al., 2018 and Haigis et al., 2023. Structural protein conservation of mammalian, fish, amphibian, reptilian and avian DIO3 was found compared to the human (Homo sapiens) protein target using the U.S. Environmental Protection Agency’s Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS v6.0; seqapass.epa.gov/seqapass/) tool, while acknowledging the potential existence of interspecies differences in conservation. No empirical evidence linking DIO3 inhibition to THSD was found for reptiles and birds. It should be mentioned that although the level of DIO3 conservation between chicken and the human reference was relatively high, SeqAPASS did not predict DIO3 conservation for birds in general.

Darras, V. M. (2021). Deiodinases: How nonmammalian research helped shape our present view. Endocrinology 162. Darras, V. M., and Van Herck, S. L. J. (2012). Iodothyronine deiodinase structure and function: From ascidians to humans. J. Endocrinol. 215, 189–206. Fini, J. B., Le Mevel, S., Turque, N., Palmier, K., Zalko, D., Cravedi, J. P., and Demeneix, B. A. (2007). An in vivo multiwell-based fluorescent screen for monitoring vertebrate thyroid hormone disruption. Environ. Sci. Technol. 41, 5908–5914. Haigis A-C., Vergauwen L., LaLone C.A., Villeneuve D.L., O'Brien J.M., Knapen D. (2023). Cross-species applicability of an adverse outcome pathway network for thyroid hormone system disruption. Toxicol Sci. 195, 1-27. Heijlen, M., Houbrechts, A. M., Bagci, E., Van Herck, S. L. J., Kersseboom, S., Esguerra, C. V., Blust, R., Visser, T. J., Knapen, D., and Darras, V. M. (2014). Knockdown of type 3 iodothyronine deiodinase severely perturbs both embryonic and early larval development in zebrafish. Endocrinology 155, 1547–1559. Hernandez, A., Martinez, M. E., Fiering, S., Galton, V. A., and St. Germain, D. (2006). Type 3 deiodinase is critical for the maturation and function of the thyroid axis. J. Clin. Invest. 116, 476–484. Houbrechts, A. M., Vergauwen, L., Bagci, E., Van houcke, J., Heijlen, M., Kulemeka, B., Hyde, D. R., Knapen, D., and Darras, V. M. (2016). Deiodinase knockdown affects zebrafish eye development at the level of gene expression, morphology and function. Mol. Cell. Endocrinol. 424, 81–93. Lalone, C. A., Villeneuve, D. L., Doering, J. A., Blackwell, B. R., Transue, T. R., Simmons, C. W., Swintek, J., Degitz, S. J., Williams, A. J., and Ankley, G. T. (2018). Evidence for cross species extrapolation of mammalian-based high-throughput screening assay results. Environ. Sci. Technol. 52, 13960–13971. Mayasich, S. A., Korte, J. J., Denny, J. S., Hartig, P. C., Olker, J. H., DeGoey, P., O’Flanagan, J., Degitz, S. J., and Hornung, M. W. (2021). Xenopus laevis and human type 3 iodothyronine deiodinase enzyme cross-species sensitivity to inhibition by ToxCast chemicals. Toxicol. In Vitro 73, 105141. Mol, K. A., Van Der Geyten, S., Burel, C., Kühn, E. R., Boujard, T., and Darras, V. M. (1998). Comparative study of iodothyronine outer ring and inner ring deiodinase activities in five teleostean fishes. Fish Physiol. Biochem. 18, 253–266. Ng, L., Hernandez, A., He, W., Ren, T., Srinivas, M., Michelle, M., Galton, V. A., St Germain, D. L., and Forrest, D. (2009). A protective role for type 3 deiodinase, a thyroid hormone-inactivating enzyme, in cochlear development and auditory function. Endocrinology 150, 1952–1960. Noyes, P. D., Hinton, D. E., and Stapleton, H. M. (2011). Accumulation and debromination of decabromodiphenyl ether (BDE-209) in juvenile fathead minnows (Pimephales promelas) induces thyroid disruption and liver alterations. Toxicol. Sci. 122, 265–274. Olker, J. H., Korte, J. J., Denny, J. S., Hartig, P. C., Cardon, M. C., Knutsen, C. N., Kent, P. M., Christensen, J. P., Degitz, S. J., and Hornung, M. W. (2019). Screening the ToxCast phase 1, phase 2, and e1k chemical libraries for inhibitors of iodothyronine deiodinases. Toxicol. Sci. 168, 430–442. Sanders, J. P., Van der Geyten, S., Kaptein, E., Darras, V. M., Kühn, E. R., Leonard, J. L., and Visser, T. J. (1999). Cloning and characterization of type III iodothyronine deiodinase from the fish Oreochromis niloticus. Endocrinology 140, 3666–3673. Thompson, C. K., and Cline, H. T. (2016). Thyroid hormone acts locally to increase neurogenesis, neuronal differentiation, and dendritic arbor elaboration in the tadpole visual system. J. Neurosci. 36, 10356–10375. AOPWiki 2016-11-29T18:41:37

2025-11-19T05:35:08

<upstream-id>6af3bb25-dd94-4061-99b0-a0868eaed35f</upstream-id> <downstream-id>c0658c0d-bd63-4456-89b8-0ab09a4017c3</downstream-id>

Not Specified

AOPWiki 2020-12-09T14:36:51

2020-12-09T14:36:51

<upstream-id>c0658c0d-bd63-4456-89b8-0ab09a4017c3</upstream-id> <downstream-id>ef60129b-a04b-4bf3-a9cd-8eb7856cfc08</downstream-id>

Not Specified

AOPWiki 2020-12-09T14:38:09

2020-12-09T14:38:09

Type III iodotyrosine deiodinase (DIO3) inhibition leading to altered amphibian metamorphosis

DIO3 inhib alters metamorphosis

Jonathan Haselman

Jonathan T. Haselman, Center for Computational Toxicology and Exposure, US EPA, Duluth, MN, USA <haselman.jon@epa.gov> Sigmund J. Degitz, Center for Computational Toxicology and Exposure, US EPA, Duluth, MN, USA <degitz.sigmund@epa.gov> Michael W. Hornung, Center for Computational Toxicology and Exposure, US EPA, Duluth, MN, USA <hornung.michael@epa.gov> Sally A. Mayasich, Center for Computational Toxicology and Exposure, US EPA, Duluth, MN, USA <mayasich.sally@epa.gov>

BY-SA

1.0

This putative AOP describes the potential for an adverse outcome resulting from the inhibition of Type III iodothyronine deiodinase (DIO3) during amphibian metamorphosis. Initial development of this AOP is based on literature in which amphibian deiodinases are genetically disrupted and prediction from tissue expression patterns. Chemical inhibition of DIO3, the molecular-initiating event (MIE), results in decreased transformation of thyroxine (T4) to the inactive form, 3,3’,5’-triiodothyronine (reverse T3, or rT3) and also decreased transformation of T3 to inactive form T2 in peripheral tissues. Thyroid hormones (THs), including appropriate levels of the inactive rT3 form, are essential for normal sequential development of amphibian tissues and organs, and activities of the three deiodinases found in amphibians, as in mammals, function in a highly regulated balance. Therefore, chemicals that interfere with the DIO3 catalyzing reaction of T4 inner-ring deiodination (IRD) to rT3 have the potential to cause overabundance of T4 as well as the active T3 form, potentially resulting in altered metamorphic development. Adverse consequences of rT3 insufficiency may vary based on timing of exposure and produce different effects at different developmental stages. In the African clawed frog, Xenopus laevis, DIO3 seems to be predominant during the early pre-metamorphosis development phase, protecting tissues from the actions of TH. Inhibition of DIO3 could alter T4/T3/rT3 feedback balance causing events that normally occur during pro-metamorphosis and post-metamorphic climax to occur too early and result in alterations in limb development, intestinal remodeling, gill resorption and/or tail resorption.

Altered metamorphosis is a critical apical endpoint evaluated as part of regulatory test guideline studies (OECD, 2009, 2015; US EPA 2009, 2015). Measurable effects on metamorphic rates can be an indication of endocrine disruption, and more specifically thyroid disruption, due to the requirement of thyroid hormone for amphibians to undergo metamorphosis. Although this outcome is evaluated at the level of the individual organism, delayed or arrested metamorphosis can have implications toward population-level effects; however, significant effects on metamorphic rates are typically considered in a weight-of-evidence evaluation to determine a chemical's potential to cause thyroid disruption.

adjacent

Low

Low adjacent

Low

Moderate adjacent

Low

Moderate

High Unspecific

High

Development

High

Becker, K.B., Stephens, K.C., Davey, J.C., Schneider, M.J., Galton, V.A. (1997). “The Type 2 and Type 3 iodothyronine deiodinases play important roles in coordinating development in Rana catesbeiana tadpoles.” Endocrinology 138(7): 2989-2997. Galton VA, de Waard E, Parlow AF, St Germain DL, Hernndez, A. (2014) “Life without deiodinases.” Endocrinology. 155(10): 4081–4087. Galton, V.A., Schneider, M.J., Clark, A.S., St. Germain, D.L. (2009). “Life without thyroxine to 3,5,3’-triiodothyronine conversion: studies in mice devoid of the 5’-deiodinases.” Endocrinology 150(6): 2957–2963. Hernandez, A., Martinez ME, Fiering S, Galton VA, St Germain D (2006). Type 3 deiodinase is critical for the maturation and function of the thyroid axis. J Clin Invest 116:476–484. Morvan-Dubois, G., Demeneix, B.A., Sachs, L.M. (2008). “Xenopus laevis as a model for studying thyroid hormone signaling: From development to metamorphosis.” Mol Cell Endocrinol. 293: 71-79. Morvan-Dubois, G., Sebillot, A., Kuiper, G.G.J.M., Verhoelst, C.H.J., Darras, V.M., Visser, T.J., Demeneix, B.A. (2006). “Deiodinase activity is present in Xenopus laevis during early embryogenesis.” Endocrinolgy 147(10): 4941-4949. Huang, H., Marsh-Armstrong, N., Brown, D.D. (1999). Metamorphosis is inhibited in transgenic Xenopus laevis tadpoles that overexpress type III deiodinase. Proc. Nat. Acad. Sci. USA 96: 962-967. AOPWiki 2016-11-29T18:41:17

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