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Relationship: 2374

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

Altered, retinal layer structure leads to Altered, Visual function

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Altered, retinal layer structure

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Altered, Visual function

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	High	Low	Lucia Vergauwen (send email)	Open for citation & comment	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
Adult	Moderate
Juvenile	Moderate
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

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 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

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.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Baumann et al., 2016 used propylthiouracil (PTU) and tetrabromobisphenol A (TBBPA) to disrupt the thyroid hormone system in zebrafish larvae. This exposure induced different molecular response patterns leading to impaired eye development (reduction of RPE cell diameter, pigmentation and eye size). Behavioural analyses showed that these larvae were also disrupted in their visual capacities, such as decrease in optokinetic response and increase in light preference of PTU-treated larvae.
Avallone et al. (2015) studied the effects of cadmium exposure on the vision of adult zebrafish. The morpho-cytological changes of the retina (Nerve fiber layer clearly thickened and vacuolated, presence of compact pycnotic nuclei, empty area, change in the thickness of pigmented retinal epithelium and at the level of cones inner segments, extended folds of treated retinas, presence of cell debris and/of blood cells in vitreal chamber) were investigated by light and electron microscopy, while the functionality of the cadmium-exposed retinas was assessed by re-illumination behavioural tests with white or coloured light. Cadmium toxicity was shown to cause significant cell degeneration and loss of organisation at both macroscopic and microscopic levels. These changes were directly related to functional responses, particularly by increasing light sensitivity of exposed fish. Avoidance of bright light had increased in exposed fish.
Houbrechts et al. (2016) used a knockdown of deiodinase 1 and 2 genes in zebrafish embryos to induce transient hypothyroidism and observed a wider and less dense ganglion cell layer at 3 dpf together with a reduced response (increase of swimming activity) to light at 4 dpf. By 7 dpf both the change in the ganglion cell layer as well as the altered response to light had recovered and resembled those of the untreated larvae.
Flamarique et al. (2013) used thyroid hormone treatment to transform the UV cones of young rainbow trout into blue cones and showed that this reduced the distances and angles at which prey were located (variables that are known indicators of foraging performance). Using optical measurements and photon-catch calculations, the study showed that control rainbow trouts perceived prey (Daphnia) with greater contrast compared to thyroid-hormone-treated fish, demonstrating that the presence of UV cones enhances foraging performance of young rainbow trout.
Walter et al. (2019) found out that developmental exposure to either T4 or T3 in zebrafish embryos altered photomotor behavior. The response to a sudden transition from light to dark differed from that in untreated fish.
Heijlen et al. (2014) showed that knockdown of Type 3 Iodothyronine Deiodinase, known to disrupt retinal layer structure (Houbrechts et al. (2016), caused embryos to spend significantly less time moving, and perturbed the escape response after a tactile stimulus. It is unclear to what extent this relationship is determined by alterations in muscle development or other factors contributing to these types of behaviour.
Houbrechts et al. (2016b) showed that permanent deiodinase 2 deficiency in zebrafish resulted in a reduction of the number of R/G cones and rods that persisted through 7 dpf together with a reduced response to light (observed at 6 dpf).
Chawla et al. (2018) investigated the role of Retinoic Acid (RA) in embryonic development of craniofacial structures in zebrafish. An increase in RA caused morphological changes of the eyes: a decrease of both cellular density of the corneal epithelium and cellularity of the inner segment. Inhibition of RA synthesis with 4-diethylamino- benzaldehyde (DEAB) resulted in structural changes of the retina, including the obliteration of photoreceptors and ganglion cell layer, and decreased cellularity of the outer and inner nuclear layers. Treated fish showed strong impairment of the optokinetic reflex.

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

Often, high variances occur in the results of behavioural studies that may be due to a variety of factors including genetic differences, variation in feeding status, etc. It is also difficult to compare data from different laboratories in such experiments. Similarly, extrapolating data from fish to mammalian data is particularly difficult for behavioural studies.

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Quantitative understanding of this linkage is currently limited.

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

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 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 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. More help

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

Houbrechts, A. M., Delarue, J., Gabriëls, I. J., Sourbron, J., & Darras, V. M. (2016b). Permanent deiodinase type 2 Deficiency strongly perturbs zebrafish development, growth, and fertility. Endocrinology, 157(9), 3668–3681. https://doi.org/10.1210/en.2016-1077

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.

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.

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