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Event: 1155

Key Event Title

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

Inhibition, Pendrin

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

Inhibition, Pendrin

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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
signaling	pendrin	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
Pendrin 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

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, while there is some in vitro and in vivo evidence of pendrin inhibition available in mammals, evidence of a clear linkage with THSD is not available (Bernardinelli et al., 2016, Bizhanova and Kopp, 2009, Carvalho and Dupuy, 2017, Cil et al., 2016; Haggie et al., 2016, Reimold et al., 2011, Scott and Karniski, 2000, Wangemann et al., 2009). Structural protein conservation of mammalian, fish, amphibian, reptilian and avian pendrin 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 (Haigis et al., 2023). No empirical evidence for pendrin inhibition nor for a linkage with THSD was found for fish, amphibians, reptiles and birds.

References

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

Bernardinelli, E., Costa, R., Nofziger, C., Paulmichl, M., and Dossena, S. (2016). Effect of known inhibitors of ion transport on pendrin (SLC26A4) activity in a human kidney cell line. Cell. Physiol. Biochem. 38, 1984–1998.

Bizhanova, A., and Kopp, P. (2009). Minireview: The sodium-iodide symporter NIS and pendrin in iodide homeostasis of the thyroid. Endocrinology 150, 1084–1090.

Carvalho, D. P., and Dupuy, C. (2017). Thyroid hormone biosynthesis and release. Mol. Cell. Endocrinol. 458, 6–15.

Cil, O., Haggie, P. M., Phuan, P. W., Tan, J. A., and Verkman, A. S. (2016). Small-molecule inhibitors of pendrin potentiate the diuretic action of furosemide. J. Am. Soc. Nephrol. 27, 3706–3714.

Haggie, P. M., Phuan, P. W., Tan, J. A., Zlock, L., Finkbeiner, W. E., and Verkman, A. S. (2016). Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis. FASEB J. 30, 2187–2197.

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.

Reimold, F. R., Heneghan, J. F., Stewart, A. K., Zelikovic, I., Vandorpe, D. H., Shmukler, B. E., and Alper, S. L. (2011). Pendrin function and regulation in Xenopus oocytes. Cell. Physiol. Biochem. 28, 435–450. www.karger.com/cpb.

Scott, D. A., and Karniski, L. P. (2000). Human pendrin expressed in xenopus laevis oocytes mediates chloride/formate exchange. Am. J. Physiol. Cell Physiol. 278, C207–C211.

Wangemann, P., Kim, H.-M., Billings, S., Nakaya, K., Li, X., Singh, R., Sharlin, D. S., Forrest, D., Marcus, D. C., and Fong, P. (2009). Developmental delays consistent with cochlear hypothyroidism contribute to failure to develop hearing in mice lacking Slc26a4/ pendrin expression. Am J Physiol Renal Physiol 297, F1435–F1447.