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Event: 1153

Key Event Title

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

Inhibition, Deiodinase 3

Short name

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

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

Key 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

Process	Object	Action
catalytic activity	type III iodothyronine deiodinase	decreased

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
DIO3 inhib alters metamorphosis	MolecularInitiatingEvent	Jonathan Haselman (send email)	Under Development: Contributions and Comments Welcome

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
African clawed frog	Xenopus laevis		NCBI
fish	fish	High	NCBI
Amphibia	Amphibia	High	NCBI
mammals	mammals	Moderate	NCBI

Life Stages

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

Sex Applicability

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

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

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 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.

References

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

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.