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Relationship: 2373


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

Decreased, Triiodothyronine (T3) leads to Altered, retinal layer structure

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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
Thyroperoxidase inhibition leading to altered visual function via altered retinal layer structure adjacent Moderate Low Lucia Vergauwen (send email) Open for citation & comment EAGMST Under Review

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
zebrafish Danio rerio High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Embryo High
Larvae High

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

Although the exact mechanisms need further investigation, studies show that thyroid hormones (THs) are required for healthy eye development in vertebrates (Wester et al. 1990, Suliman & Novales Flamarique 2013, Deveau et al., 2019) and it has been described that retinal development, photoreceptor differentiation and colour vision are directly regulated by THs. Not only in zebrafish (Bertrand et al. 2007), but also in mice (Ng et al. 2010) and chickens (Trimarchi et al. 2008), THs are directly linked to the transcription of essential visual opsins and the differentiation of retinal cells, as well as the overall structure of the retina, which is essential for proper visual functioning. Therefore, decreased triidothyronine (T3) levels during eye development are likely to lead to structural and morphological alterations of the retina. The site of decreased T3 in this case is the retinal layers.

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

THs, TH receptors, and deiodinase (DIO) enzymes are important for eye and retinal development in vertebrates. Dio enzymes activate and inactivate THs, consequently playing a central role in regulating TH levels in target tissues. In zebrafish, TH receptors and dio enzymes have been localized in the retina from 24 hpf onwards, probably regulating the differentiation of retinal structures and photoreceptors (Gan et al. (2010), Duval, M. G., & Allison, W. T. (2018)). It is known from amphibians that when TH levels start to rise at the beginning of metamorphosis, the morphology of the eyes starts changing (Fini et al. 2012). In chicken, the developing eye shows a dynamic expression pattern of Deiodinase 2 (DIO2) and Deiodinase 3 (DIO3), probably regulating photoreceptor differentiation and cornea development (reviewed by Darras 2015).


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

Several studies have shown molecular responses to hypothyroidism that are related to eye development (Bagci et al., 2015; Houbrechts et al., 2016; Baumann et al., 2019) but the exact molecular processes linking lower TH level to disturbances of the layers in the retina is not yet fully understood. 

Both decreased as well as increased TH action has been shown to impact retinal development.

  • For example, Ng et al. (2010) showed altered cone appearance in the retina following both DIO3 knockout (leading to hyperthyroidism) and THRb2 knockout (corresponding to hypothyroidism).
  • Besson et al. (2020) used pharmacological treatments (T3 + iopanoic acid (IOP), NH3) to not only disrupt but also activate the TH signaling pathway. They used 10−6M T3 + (iopanoic acid) (T3 treatment) to achieve TH signal activation. Here, IOP was used as an inhibitor of deiodinase enzymes, following comparable work in mammals and amphibians, and as routinely used in fish to prevent the immediate degradation of injected T3. The combined treatment thus causes elevated T3 levels. Detected effects on retinal layers were elevated densities of bipolar cells at day 2 in surgeonfish.
  • Suppressing TH signaling in retina dystrophy mouse models (a mouse model of retinal degeneration) seems to protect cone viability (Ma et al., 2014; 2016). The authors suggested that the impact of TH on cone survival is independent of its impact on cone opsin expression. The mechanism underlying the effect on cone viability has not been elucidated. 
  • Bhumika et al. (2014) showed accelerated reinnervation of the optic tectum after optic nerve crush in zebrafish that had been treated with IOP or a TR antagonist. B     oth treatments cause hypothyroidism. Supplementation of T3 reduced the rate of reinnervation.

Another uncertainty lies in the systemic versus local changes in T3 levels. Although the assumed site of T3 decrease is assumed to be in the retinal layers itself, most fish early life stage studies only quantify whole body T3 levels which does not allow for making the distinction between systemic and local T3 levels.

Most knowledge comes from effects observed in developing organisms. There are some gaps in our knowledge about how TH levels affect the eyes of already fully developed organisms and/or whether they have similarly serious effects on the retinal layers. It can be assumed that the effects, if any, are weaker. Studies (Reider et al. 2014) found that layer thickness varied across ages suggesting that these retinal layers are differentially sensitive to for example MMI and/or that there are different critical periods of sensitivity of the retinal tissue.



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
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
  • One feedback loop mechanism could be triggered by iodine deficiency or inhibition of iodine uptake. It appears probably that the inhibition increases the secretion of Thyroid stimulating hormone, which could stimulate the expression of the NIS-transporter. This increase in TSH could shift the ratio in favour of T3.

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

Life-stage applicability: Most studies on TH-regulated retinal structure are performed during vertebrate development. There is evidence of the impact of reduced T3 (caused by inhibition of thyroperoxidase) on retinal layer structure at 48, 66, 72, 96 and 120 hpf during zebrafish embryo-eleutheroembryo development (Baumann and others 2016; Komoike and others 2013; Reider and Connaughton 2014).

Taxonomic applicability: The visual system of the zebrafish follows the typical organisation of vertebrates and is often used as a model to study human eye diseases. Although there are some differences in eye structure between fish and mammals, it is plausible to assume that TH levels are important for healthy eye development across all vertebrates.

Sex applicability: Zebrafish are undifferentiated gonochorists since both sexes initially develop an immature ovary (Maack and Segner, 2003). Immature ovary development progresses until approximately the onset of the third week. Later, in female fish immature ovaries continue to develop further, while male fish undergo transformation of ovaries into testes. Final transformation into testes varies among male individuals, however finishes usually around 6 weeks post fertilization. Effects on retinal layers resulting from TH level changes during early development are therefore expected to be independent of sex.


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

Baumann L, Ros A, Rehberger K, Neuhauss SCF, Segner H. 2016. Thyroid disruption in zebrafish (Danio rerio) larvae: Different molecular response patterns lead to impaired eye development and visual functions. Aquatic Toxicology 172:44-55.

Bagci E, Heijlen M, Vergauwen L, Hagenaars A, Houbrechts AM, Esguerra CV, Blust R, Darras VM, Knapen D. 2015. Deiodinase knockdown during early zebrafish development affects growth, development, energy metabolism, motility and phototransduction. PLOS One 10:e0123285.

Baumann L, Segner H, Ros A, Knapen D, Vergauwen L. 2019. Thyroid Hormone Disruptors Interfere with Molecular Pathways of Eye Development and Function in Zebrafish. International Journal of Molecular Sciences 20(7).

Besson, M., Feeney, W. E., Moniz, I., François, L., Brooker, R. M., Holzer, G., Metian, M., Roux, N., Laudet, V., & Lecchini, D. (2020). Anthropogenic stressors impact fish sensory development and survival via thyroid disruption. Nature Communications, 11(1).

Bhumika, S., & Darras, V. M. (2014). Role of thyroid hormones in different aspects of nervous system regeneration in vertebrates. General and Comparative Endocrinology, 203, 86–94.

Duval, M. G., & Allison, W. T. (2018). Photoreceptor progenitors depend upon coordination of gdf6a, thrβ, and tbx2b to generate precise populations of cone photoreceptor subtypes. Investigative Ophthalmology and Visual Science, 59(15), 6089–6101.

Darras VM, Houbrechts AM, Van Herck SLJ. Intracellular thyroid hormone metabolism as a local regulator of nuclear thyroid hormone receptor-mediated impact on vertebrate development. Biochim Biophys Acta - Gene Regul Mech. 2015;1849(2):130-141. doi:10.1016/j.bbagrm.2014.05.004

Fini, J. B., le Mével, S., Palmier, K., Darras, V. M., Punzon, I., Richardson, S. J., Clerget-Froidevaux, M. S., & Demeneix, B. A. (2012). Thyroid hormone signaling in the Xenopus laevis embryo is functional and susceptible to endocrine disruption. Endocrinology, 153(10), 5068–5081.

Gan, K. J., & Flamarique, I. N. (2010). Thyroid hormone accelerates opsin expression during early photoreceptor differentiation and induces opsin switching in differentiated TRα-expressing cones of the salmonid retina. Developmental Dynamics, 239(10), 2700–2713.

Houbrechts AM, Delarue J, Gabriëls IJ, Sourbron J, Darras VM. Permanent deiodinase type 2 Deficiency strongly perturbs zebrafish development, growth, and fertility. Endocrinology. 2016;157(9):3668-3681. doi:10.1210/en.2016-1077

Komoike Y, Matsuoka M, Kosaki K. 2013. Potential Teratogenicity of Methimazole: Exposure of Zebrafish Embryos to Methimazole Causes Similar Developmental Anomalies to Human Methimazole Embryopathy. Birth Defects Research Part B-Developmental and Reproductive Toxicology 98(3):222-229.

Gamborino MJ, Sevilla-Romero E, Muñoz A, Hernández-Yago J, Renau-Piqueras J, Pinazo-Durán MD. Role of thyroid hormone in craniofacial and eye development using a rat model. Ophthalmic Res. 2001;33(5):283-291. doi:10.1159/000055682

Ma HW, Ding XQ. 2016. Thyroid hormone signaling and cone photoreceptor viability. Retinal Degenerative Diseases: Mechanisms and Experimental Therapy. 854:613-618.

Ma HW, Thapa A, Morris L, Redmond TM, Baehr W, Ding XQ. 2014. Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration. Proceedings of the National Academy of Sciences of the United States of America. 111(9):3602-3607.

Ng L, Lyubarsky A, Nikonov SS, Ma M, Srinivas M, Kefas B, St Germain DL, Hernandez A, Pugh EN, Jr., Forrest D. 2010. Type 3 deiodinase, a thyroid-hormone-inactivating enzyme, controls survival and maturation of cone photoreceptors. J Neurosci. 30(9):3347-3357.

Reider M, Connaughton VP. 2014. Effects of Low-Dose Embryonic Thyroid Disruption and Rearing Temperature on the Development of the Eye and Retina in Zebrafish. Birth Defects Research Part B-Developmental and Reproductive Toxicology 101(5):347-354.

Quesada-García A, Encinas P, Valdehita A, et al. Thyroid active agents T3 and PTU differentially affect immune gene transcripts in the head kidney of rainbow trout (Oncorynchus mykiss). Aquat Toxicol. 2016;174:159-168. doi:10.1016/j.aquatox.2016.02.016

Schmidt F and Braunbeck T. Alterations along the Hypothalamic-Pituitary-Thyroid Axis of the Zebrafish (Danio rerio ) after Exposure to Propylthiouracil. 2011. Journal of Thyroid Research. Volume 2011, Article ID 376243, 17 pages. doi:10.4061/2011/376243

Stinckens E, Vergauwen L, Blackwell BR, Anldey GT, Villeneuve DL, Knapen D. 2020. Effect of thyroperoxidase and deiodinase inhibition on anterior swim bladder inflation in the zebrafish. Environmental Science & Technology. 54(10):6213-6223.

Wang, W. Der, Hsu, H. J., Li, Y. F., & Wu, C. Y. (2017). Retinoic acid protects and rescues the development of zebrafish embryonic retinal photoreceptor cells from exposure to paclobutrazol. International Journal of Molecular Sciences, 18(1).

Walter KM, Miller GW, Chen XP, Yaghoobi B, Puschner B, Lein PJ. 2019. Effects of thyroid hormone disruption on the ontogenetic expression of thyroid hormone signaling genes in developing zebrafish (danio rerio). General and Comparative Endocrinology. 272:20-32.

Yu, Y., Hou, Y., Dang, Y., Zhu, X., Li, Z., Chen, H., Xiang, M., Li, Z., & Hu, G. (2021). Exposure of adult zebrafish (Danio rerio) to Tetrabromobisphenol A causes neurotoxicity in larval offspring, an adverse transgenerational effect. Journal of Hazardous Materials414, 125408.

Zhu, B., Zhao, G., Yang, L., & Zhou, B. (2018). Tetrabromobisphenol A caused neurodevelopmental toxicity via disrupting thyroid hormones in zebrafish larvae. Chemosphere197, 353–361.