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Relationship: 2374

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

Altered, retinal layer structure leads to Altered, Visual function

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 High Low Lucia Vergauwen (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 Do not cite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
Adult Moderate
Juvenile Moderate
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

The structure of the vertebrate retina is well conserved and consists of the following layers: The retinal pigment epithelium (RPE), the photoreceptor layer (PRL), the outer plexiform layer (OPL), the inner nuclear layer (INL), the inner plexiform layer (IPL) and the ganglion cell layer (GCL). Each of these layers has a specific function for the physiology of the visual system. The RPE serves to protect and maintain the photoreceptors and absorbs excess light. The photoreceptors in the PRL consist of a light-receiving outer segment (OS) and the inner segment (IS), which contains the cell bodies. They send their signals to the bipolar cells in the INL, which transmit the signal to the ganglion cells. These form the optic nerve and are responsible for transmitting signals to the optic nerves. In both plexiform layers, the retinal neurons form their synaptic connections (Bibliowicz et al. 2011).

To study the eye, the zebrafish (Danio rerio) is at the forefront of many studies as a model organism. In zebrafish, eye development begins around 12 hpf (Houbrechts et al., 2016b) and by 72 hpf the layers of the retina are well developed (Malicki et al., 2016). Functional vision is established by 4-5 dpf (Brockerhoff, 2006; Chhetri et al., 2014).

 

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

It should be emphasised that all layers of the retina are interdependent. The RPE plays an essential role in the retinoid cycle for the photoreceptors (PRL), which perceive the light stimulus and transmit it via the bipolar cells to the ganglia (IPL), which form the optic nerve and transmit the signal to the optic nerve (Connaughton 2005). If these key sites of the phototransduction pathway are disrupted by, for example, endocrine disruptors, it stands to reason that there would be a significant impact on the optical sense and it is plausible that disorders of the eye structure can lead to visual disorders.  

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

Often, high variances occur in the results of behavioural studies because an organism has some compensatory mechanisms that allow it to survive. It is more difficult to compare data from different laboratories in such experiments. Similarly, extrapolating data from fish to mammalian data is particularly difficult for behavioural studies. 

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

Temporal evidence is supported by the studies of Houbrechts et al. (2016) and Van Camp et al. (2018) in genetic knockdown and knockout zebrafish respectively. Houbrechts et al. (2016) used a DIO 1 and 2 knockdown, which causes transient hypothyroidism. At 3 dpf they showed altered retinal layer structure and at 4 dpf they showed an altered response to light. By 7 dpf both the retinal layer structure and the response to light had returned to normal. Van Camp et al. (2018) used a DIO2 knockout model causing permanent hypothyroidism. They did shown both altered numbers of rods and cones in the retina and an altered response to light at 7 dpf.

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

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

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 zebrafish and humans, it is plausible to assume that a functioning eye structure is important for visual function across all vertebrates and invertebrates that have eyes.

Life stage applicability: The first visual responses based on retinal functionality appear around 70 hpf in zebrafish (Schmitt and Dowling 1999). It is plausible to assume that alterations of the eye structure would result in altered visual function across all life stages, but such alterations are most likely to occur during the development of the normal eye structure, which occurs in the embryo-eleutheroembryo phase.

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 visual function resulting from altered eye structure 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

Strauss O. The retinal pigment epithelium in visual function. Physiol Rev. 2005 Jul;85(3):845-81. doi: 10.1152/physrev.00021.2004. PMID: 15987797.

Avallone B, Crispino R, Cerciello R, Simoniello P, Panzuto R, Motta CM. Cadmium effects on the retina of adult Danio rerio. CR Biologies. 2015;338:40–7.

Baumann, L., Ros, A., Rehberger, K., Neuhauss, S. C. F., & 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. https://doi.org/10.1016/j.aquatox.2015.12.015

Bibliowicz, J., Tittle, R. K., & Gross, J. M. (2011). Toward a better understanding of human eye disease: Insights from the zebrafish, Danio rerio. In Progress in Molecular Biology and Translational Science(Vol. 100, Issue Table 1). https://doi.org/10.1016/B978-0-12-384878-9.00007-8

Brockerhoff, S. E. (2006). Measuring the optokinetic response of zebrafish larvae. Nature Protocols, 1(5), 2448–2451. https://doi.org/10.1038/nprot.2006.255

Chawla, B., Swain, W., Williams, A. L., & Bohnsack, B. L. (2018). Retinoic acid maintains function of neural crest–derived ocular and craniofacial structures in adult zebrafish. Investigative Ophthalmology and Visual Science, 59(5), 1924–1935. https://doi.org/10.1167/iovs.17-22845

Chhetri, J., Jacobson, G., & Gueven, N. (2014). Zebrafish-on the move towards ophthalmological research. Eye (Basingstoke), 28(4), 367–380. https://doi.org/10.1038/eye.2014.19

Crowley-Perry, M., Barberio, A. J., Zeino, J., Winston, E. R., & Connaughton, V. P. (2021). Zebrafish optomotor response and morphology are altered by transient, developmental exposure to bisphenol-a. Journal of Developmental Biology,9(2). https://doi.org/10.3390/jdb9020014

Connaughton, V. P., Graham, D., & Nelson, R. (2004). Identification and morphological classification of horizontal, bipolar, and amacrine cells within the zebrafish retina. Journal of Comparative Neurology, 477(4), 371–385. https://doi.org/10.1002/cne.20261

Flamarique, I. N. (2013). Opsin switch reveals function of the ultraviolet cone in fish foraging. Proceedings of the Royal Society B: Biological Sciences, 280(1752). https://doi.org/10.1098/rspb.2012.2490

Frau, S., Novales Flamarique, I., Keeley, P. W., Reese, B. E., & Muñoz-Cueto, J. A. (2020). Straying from the flatfish retinal plan: Cone photoreceptor patterning in the common sole (Solea solea) and the Senegalese sole (Solea senegalensis). Journal of Comparative Neurology, 528(14), 2283–2307. https://doi.org/10.1002/cne.24893

Heijlen, M., Houbrechts, A. M., Bagci, E., Van Herck, S. L. J., Kersseboom, S., Esguerra, C. V., Blust, R., Visser, T. J., Knapen, D., & Darras, V. M. (2014). Knockdown of type 3 iodothyronine deiodinase severely perturbs both embryonic and early larval developme

Houbrechts, A. M., Vergauwen, L., Bagci, E., Van houcke, J., Heijlen, M., Kulemeka, B., Hyde, D. R., Knapen, D., & Darras, V. M. (2016). Deiodinase knockdown affects zebrafish eye development at the level of gene expression, morphology and function. Molecular and Cellular Endocrinology, 424, 81–93. https://doi.org/10.1016/j.mce.2016.01.018

Malicki, J., Pooranachandran, N., Nikolaev, A., Fang, X., & Avanesov, A. (2016). Analysis of the retina in the zebrafish model. In Methods in Cell Biology(Vol. 134). Elsevier Ltd. https://doi.org/10.1016/bs.mcb.2016.04.017

Masuda, T., Shimazawa, M., Hara, H., 2017. Retinal diseases associated with oxidative stress and the effects of a free radical scavenger (edaravone). Oxid. Med. Cell. Longev. 2017, 9208489.

Moreno-Marmol T, Cavodeassi F, Bovolenta P. 2018. Setting Eyes on the Retinal Pigment Epithelium. Frontiers in Cell and Developmental Biology 6.

Morris AC, Fadool JM. 2005. Studying rod photoreceptor development in zebrafish. Physiology & Behavior 86(3):306-313.

Naujokas, M.F., Anderson, B., Ahsan, H., et al., 2013. The broad scope of health effects from chronic arsenic exposure: update on a worldwide public health problem. Environ. Health Perspect. 121 (3), 295e302.

Raymond PA, Barthel LK, Curran GA. 1995. DEVELOPMENTAL PATTERNING OF ROD AND CONE PHOTORECEPTORS IN EMBRYONIC ZEBRAFISH. Journal of Comparative Neurology 359(4):537-550.

Schmitt EA, Dowling JE. 1999. Early retinal development in the zebrafish, Danio rerio: Light and electron microscopic analyses. Journal of Comparative Neurology 404(4):515-536.

Vancamp P, Houbrechts AM, Darras VM. Insights from zebrafish deficiency models to understand the impact of local thyroid hormone regulator action on early development. Gen Comp Endocrinol. 2019 Aug 1;279:45-52. doi: 10.1016/j.ygcen.2018.09.011. Epub 2018 Sep 19. PMID: 30244055.

Walter, K. M., Miller, G. W., Chen, X., Harvey, D. J., Puschner, B., & Lein, P. J. (2019). Changes in thyroid hormone activity disrupt photomotor behavior of larval zebrafish. Neurotoxicology, 74, 47–57. https://doi.org/10.1016/j.neuro.2019.05.008