API

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Relationship: 2232

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Inhibition, Na+/I- symporter (NIS) leads to T4 in serum, Decreased

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Inhibition, Na+/I- symporter (NIS)
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
T4 in serum, Decreased

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Sodium Iodide Symporter (NIS) Inhibition leading to altered amphibian metamorphosis non-adjacent Moderate Moderate 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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
African clawed frog Xenopus laevis NCBI
mammals mammals High NCBI
fish fish Moderate NCBI
Amphibia Amphibia Moderate NCBI

Sex Applicability

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

Life Stage Applicability

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

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help
Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. 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 NIS inhibition and reduced thyroid hormone (TH) levels was considered high for mammals (Buckalew et al., 2020, Concilio et al., 2020, Dayem et al., 2008, Hallinger et al., 2017, Heltemes et al., 2003, Schmutzler et al., 2007, Selmi-Ruby et al., 2003, Wang et al., 2018) and moderate for fish and amphibians (Concilio et al., 2020, Hornung et al., 2010, Lindenthal et al., 2009, McMullen et al., 2017, Opitz et al., 2006; Opitz and Kloas, 2010, Thienpont et al., 2011). 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 NIS 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 NIS inhibition to THSD was found for reptiles and birds.

References

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

Buckalew, A. R., Wang, J., Murr, A. S., Deisenroth, C., Stewart, W. M., Stoker, T. E., and Laws, S. C. (2020). Evaluation of potential sodium-iodide symporter (NIS) inhibitors using a secondary Fischer rat thyroid follicular cell (FRTL-5) radioactive iodide uptake (RAIU) assay. Arch. Toxicol. 94, 873–885.

Concilio, S. C., Zhekova, H. R., Noskov, S. Y., and Russell, S. J. (2020). Inter-species variation in monovalent anion substrate selectivity and inhibitor sensitivity in the sodium iodide symporter (NIS). PLoS One 15, e0229085.

Dayem, M., Basquin, C., Navarro, V., Carrier, P., Marsault, R., Chang, P., Huc, S., Darrouzet, E., Lindenthal, S., and Pourcher, T. (2008). Comparison of expressed human and mouse sodium/iodide symporters reveals differences in transport properties and subcellular localization. J. Endocrinol. 197, 95–109.

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.

Hallinger, D. R., Murr, A. S., Buckalew, A. R., Simmons, S. O., Stoker, T. E., and Laws, S. C. (2017). Development of a screening approach to detect thyroid disrupting chemicals that inhibit the human sodium iodide symporter (NIS). Toxicol. In Vitro 40, 66–78.

Heltemes, L. M., Hagan, C. R., Mitrofanova, E. E., Panchal, R. G., Guo, J., and Link, C. J. (2003). The rat sodium iodide symporter gene permits more effective radioisotope concentration than the human sodium iodide symporter gene in human and rodent cancer cells. Cancer Gene Ther. 10, 14–22.

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. Toxicol. Sci. 118, 42–51.

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.

Lindenthal, S., Lecat-Guillet, N., Ondo-Mendez, A., Ambroise, Y., Rousseau, B., and Pourcher, T. (2009). Characterization of small-molecule inhibitors of the sodium iodide symporter. J. Endocrinol. 200, 357–365.

McMullen, J., Ghassabian, A., Kohn, B., and Trasande, L. (2017). Identifying subpopulations vulnerable to the thyroid-blocking effects of perchlorate and thiocyanate. J. Clin. Endocrinol. Metab. 102, 2637–2645.

Opitz, R., Trubiroha, A., Lorenz, C., Lutz, I., Hartmann, S., Blank, T., Braunbeck, T., and Kloas, W. (2006). Expression of sodium-iodide symporter mRNA in the thyroid gland of Xenopus laevis tadpoles: Developmental expression, effects of antithyroidal compounds, and regulation by TSH. J. Endocrinol. 190, 157–170.

Opitz, R., and Kloas, W. (2010). Developmental regulation of gene expression in the thyroid gland of Xenopus laevis tadpoles. Gen. Comp. Endocrinol. 168, 199–208.

Schmutzler, C., Gotthardt, I., Hofmann, P. J., Radovic, B., Kovacs, G., Stemmler, L., Nobis, I., Bacinski, A., Mentrup, B., Ambrugger, P., et al. (2007). Endocrine disruptors and the thyroid gland-a combined in vitro and in vivo analysis of potential new biomarkers. Environ. Health Perspect. 115, 77–83.

Selmi-Ruby, S., Watrin, C., Trouttet-Masson, S., Bernier-Valentin, F., Flachon, V., Munari-Silem, Y., and Rousset, B. (2003). The porcine sodium/iodide symporter gene exhibits an uncommon expression pattern related to the use of alternative splice sites not present in the human or murine species. Endocrinology 144, 1074–1085.

Thienpont, B., Tingaud-Sequeira, A., Prats, E., Barata, C., Babin, P. J., and Raldua, D. (2011). Zebrafish eleutheroembryos provide a suitable vertebrate model for screening chemicals that impair thyroid hormone synthesis. Environ. Sci. Technol. 45, 7525–7532.

Wang, J., Hallinger, D. R., Murr, A. S., Buckalew, A. R., Simmons, S. O., Laws, S. C., and Stoker, T. E. (2018). High-throughput screening and quantitative chemical ranking for sodium-iodide symporter inhibitors in ToxCast phase I chemical library. Environ. Sci. Technol. 52, 5417–5426.