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Key Event: 1656

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Antagonism, Thyroid Receptor

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

TR Antagnoism

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Biological Context

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Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
TR Antagonism and DNT	MolecularInitiatingEvent	Kevin Crofton (send email)	Under development: Not open for comment. Do not cite	Under Development
TR antagonism leading to decreased cognition	MolecularInitiatingEvent	Eliska Kuchovska (send email)	Under development: Not open for comment. Do not cite
Oligodendrocyte differentiation and DNT	KeyEvent	Ellen Fritsche (send email)	Under development: Not open for comment. Do not cite
Decreased TH levels leading to developmental neurotoxicity	MolecularInitiatingEvent	Nathalie Dierichs (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
human	Homo sapiens		NCBI
mouse	Mus musculus		NCBI
mammals	mammals	High	NCBI
fish	fish	High	NCBI
Amphibia	Amphibia	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
During development and at adulthood	High

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Mixed	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Thyroid hormone receptors (TR) are a nuclear receptors that are activitated by binding of the thyroid hormones triiodothyronine (T3) and thyroxine (T4). The majority of TH bound to TR being T3 due to its 10-fold higher affinity. Bound receptors, homodimerized or heterodimerized with retinoic acid, bind to thyroid response elements and regulate gene expression by either increasing or decreasing tragent gene transcription activity. Important to note is ligand free TR can form complexes with corepressors to inhibit gene expression. There are two major thyroid hormone receptor subtypes, thyroid receptor alpha(TRα) and thyroid receptor beta (TRβ). There are two subtypes for each, TRb1, TRb2, TRa1, and TRa2. Notably, the carboxy-terminal structure of TRalpha2 prevents hormone binding and transscription (Sinha and Yen, 2018). There are a large number of genes regualated by TH. These include genes involved in

Both TRa and TRb are known to be expressed during neurodevelopment (ref).

The predominate TR form during brain develop is TRa1expression of the

Sinha R, Yen PM. Cellular Action of Thyroid Hormone. [Updated 2018 Jun 20]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK285568/

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

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 TR antagonism and reduced thyroid hormone (TH) levels was considered high for mammals, amphibians and fish (Bronchain et al., 2017, Deveau et al., 2020, Eldred et al., 2018, Kitamura et al., 2005a,b, Kollitz et al., 2018, Kudo et al., 2006, Kudo and Yamauchi, 2005, Lim et al., 2002, Lu et al., 2018, Marelli et al., 2016, Ng et al., 2001, O’Shea and Williams, 2002, Oka et al., 2013, Opitz et al., 2006, Paul-Friedman et al., 2019, Ren et al., 2020, Routti et al., 2021, Sanoh et al., 2020, Walter et al., 2021, Yamauchi et al., 2003, Yang and Chan, 2015). This was supported by structural protein conservation analysis by Lalone et al., 2018 and Haigis et al., 2023. Structural protein conservation of mammalian, amphibian, fish, reptilian and avian TRα/β 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. While there is some in vitro evidence of TR antagonism available in birds, evidence of a clear linkage with THSD is not available (Ishihara et al., 2003, Yamauchi et al., 2003). No empirical evidence linking TR antagonism to THSD was found for reptiles.

References

List of the literature that was cited for this KE description. More help

Bronchain, O. J., Chesneau, A., Monsoro-Burq, A. H., Jolivet, P., Paillard, E., Scanlan, T. S., Demeneix, B. A., Sachs, L. M., and Pollet, N. (2017). Implication of thyroid hormone signaling in neural crest cells migration: Evidence from thyroid hormone receptor beta knockdown and NH 3 antagonist studies. Mol. Cell. Endocrinol. 439, 233–246.

Deveau, C., Jiao, X., Suzuki, S. C., Krishnakumar, A., Yoshimatsu, T., Hejtmancik, J. F., and Nelson, R. F. (2020). Thyroid hormone receptor beta mutations alter photoreceptor development and function in Danio rerio (zebrafish). PLoS Genet. 16, e1008869.

Eldred, K. C., Hadyniak, S. E., Hussey, K. A., Brenerman, B., Zhang, P. W., Chamling, X., Sluch, V. M., Welsbie, D. S., Hattar, S., Taylor, J., et al. (2018). Thyroid hormone signaling specifies cone subtypes in human retinal organoids. Science 362.

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.

Ishihara, A., Nishiyama, N., Sugiyama, S. I., and Yamauchi, K. (2003). The effect of endocrine disrupting chemicals on thyroid hormone binding to Japanese quail transthyretin and thyroid hormone receptor. Gen. Comp. Endocrinol. 134, 36–43. (03)00197-7

Kitamura, S., Jinno, N., Suzuki, T., Sugihara, K., Ohta, S., Kuroki, H., and Fujimoto, N. (2005a). Thyroid hormone-like and estrogenic activity of hydroxylated PCBs in cell culture. Toxicology 208, 377–387.

Kitamura, S., Kato, T., Iida, M., Jinno, N., Suzuki, T., Ohta, S., Fujimoto, N., Hanada, H., Kashiwagi, K., and Kashiwagi, A. (2005b). Anti-thyroid hormonal activity of tetrabromobisphenol A, a flame retardant, and related compounds: Affinity to the mammalian thyroid hormone receptor, and effect on tadpole metamorphosis. Life Sci. 76, 1589–1601.

Kollitz, E. M., De Carbonnel, L., Stapleton, H. M., and Ferguson, P. L. (2018). The affinity of brominated phenolic compounds for human and zebrafish thyroid receptor b: Influence of chemical structure. Toxicol. Sci. 163, 226–239.

Kudo, Y., and Yamauchi, K. (2005). In vitro and in vivo analysis of the thyroid disrupting activities of phenolic and phenol compounds in Xenopus laevis. Toxicol. Sci. 84, 29–37.

Kudo, Y., Yamauchi, K., Fukazawa, H., and Terao, Y. (2006). In vitro and in vivo analysis of the thyroid system-disrupting activities of brominated phenolic and phenol compounds in Xenopus laevis. Toxicol. Sci. 92, 87–95

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

Lim, W., Nguyen, N. H., Yang, H. Y., Scanlan, T. S., and David Furlow, J. (2002). A thyroid hormone antagonist that inhibits thyroid hormone action in vivo. J. Biol. Chem. 277, 35664–35670.

Lu, L., Zhan, T., Ma, M., Xu, C., Wang, J., Zhang, C., Liu, W., and Zhuang, S. (2018). Thyroid disruption by bisphenol S analogues via thyroid hormone receptor b: In vitro, in vivo, and molecular dynamics simulation study. Environ. Sci. Technol. 52, 6617–6625.

Marelli, F., Carra, S., Agostini, M., Cotelli, F., Peeters, R., Chatterjee, K., and Persani, L. (2016). Patterns of thyroid hormone receptor expression in zebrafish and generation of a novel model of resistance to thyroid hormone action. Mol. Cell. Endocrinol. 424, 102–117.

Ng, L., Hurley, J. B., Dierks, B., Srinivas, M., Saltó, C., Vennström, B., Reh, T. A., and Forrest, D. (2001). A thyroid hormone receptor that is required for the development of green cone photoreceptors. Nat. Genet. 27, 94–98.

Oka, T., Mitsui-Watanabe, N., Tatarazako, N., Onishi, Y., Katsu, Y., Miyagawa, S., Ogino, Y., Yatsu, R., Kohno, S., Takase, M., et al. (2013). Establishment of transactivation assay systems using fish, amphibian, reptilian and human thyroid hormone receptors. J. Appl. Toxicol. 33, 991–1000

O’Shea, P. J., and Williams, G. R. (2002). Insight into the physiological actions of thyroid hormone receptors from genetically modified mice. J. Endocrinol. 175, 553–570.

Opitz, R., Lutz, I., Nguyen, N. H., Scanlan, T. S., and Kloas, W. (2006). Analysis of thyroid hormone receptor ba mRNA expression in Xenopus laevis tadpoles as a means to detect agonism and antagonism of thyroid hormone action. Toxicol. Appl. Pharmacol. 212, 1–13.

Paul-Friedman, K., Martin, M., Crofton, K. M., Hsu, C. W., Sakamuru, S., Zhao, J., Xia, M., Huang, R., Stavreva, D. A., Soni, V., et al. (2019). Limited chemical structural diversity found to modulate thyroid hormone receptor in the Tox21 chemical library. Environ. Health Perspect. 127.

Ren, X. M., Yao, L., Xue, Q., Shi, J., Zhang, Q., Wang, P., Fu, J., Zhang, A., Qu, G., and Jiang, G. (2020). Binding and activity of tetrabromobisphenol a mono-ether structural analogs to thyroid hormone transport proteins and receptors. Environ. Health Perspect. 128, 1–14.

Routti, H., Harju, M., Lühmann, K., Aars, J., Ask, A., Goksøyr, A., Kovacs, K. M., and Lydersen, C. (2021). Concentrations and endocrine disruptive potential of phthalates in marine mammals from the Norwegian Arctic. Environ. Int. 152, 106458.

Sanoh, S., Hanada, H., Kashiwagi, K., Mori, T., Goto-Inoue, N., Suzuki, K., Ichi, T., Mori, J., Nakamura, N., Yamamoto, T., et al. (2020). Amiodarone bioconcentration and suppression of metamorphosis in Xenopus. Aquat. Toxicol. 228, 105623.

Walter, K. M., Singh, L., Singh, V., and Lein, P. J. (2021). Investigation of NH 3 as a selective thyroid hormone receptor modulator in larval zebrafish (Danio rerio). NeuroToxicology 84, 96–104.

Yamauchi, K., Ishihara, A., Fukazawa, H., and Terao, Y. (2003). Competitive interactions of chlorinated phenol compounds with 3,30,5-triiodothyronine binding to transthyretin: Detection of possible thyroid-disrupting chemicals in environmental waste water. Toxicol. Appl. Pharmacol. 187, 110–117.

Yang, J., and Chan, K. M. (2015). Evaluation of the toxic effects of brominated compounds (BDE-47, 99, 209, TBBPA) and bisphenol a (BPA) using a zebrafish liver cell line, ZFL. Aquat. Toxicol. 159, 138–147.