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Relationship: 2373

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

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

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. 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

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
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 Allie Always (send email) Open for comment. Do not cite

Taxonomic Applicability

Select one or more structured terms 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. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help
Term Scientific Term Evidence Link
zebrafish Danio rerio High NCBI

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help
Sex Evidence
Unspecific Moderate

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help
Term Evidence
Embryo High
Larvae High

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. 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 functioning. Therefore, decreased triidothyronine (T3) levels in serum during eye development are likely to lead to structural and morphological alterations of the retina.

Evidence Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help
Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility 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 (see page 40 of the User Handbook for further information).   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. 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
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  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 layer 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. both treatments cause hypothyroidism. Supplementation of T3 reduced the rate of reinnervation.

Most knowledge comes from effects 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.

 

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help
Time-scale
This sub-section should be used to provide 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?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help
Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  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

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized 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.

References

List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). 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). https://doi.org/10.1038/s41467-020-17450-8

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. https://doi.org/10.1016/j.ygcen.2014.03.017

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. https://doi.org/10.1167/iovs.18-24461

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

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. https://doi.org/10.1002/dvdy.22392

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). https://doi.org/10.3390/ijms18010130

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 Materials, 414, 125408. https://doi.org/https://doi.org/10.1016/j.jhazmat.2021.125408

Zhu, B., Zhao, G., Yang, L., & Zhou, B. (2018). Tetrabromobisphenol A caused neurodevelopmental toxicity via disrupting thyroid hormones in zebrafish larvae. Chemosphere, 197, 353–361. https://doi.org/10.1016/j.chemosphere.2018.01.080