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Relationship: 2374
Title
Altered, retinal layer structure leads to Altered, Visual function
Upstream event
Downstream event
Key Event Relationship Overview
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 | Allie Always (send email) | Open for citation & comment | Under Review |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
zebrafish | Danio rerio | High | NCBI |
Sex Applicability
Sex | Evidence |
---|---|
Unspecific | Moderate |
Life Stage Applicability
Term | Evidence |
---|---|
Embryo | High |
Adult | Moderate |
Juvenile | Moderate |
Larvae | High |
Key Event Relationship Description
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
Evidence Supporting this KER
Biological Plausibility
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
- 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
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
Quantitative Understanding of the Linkage
Quantitative understanding of this linkage is currently limited.
Response-response Relationship
Time-scale
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
Domain of Applicability
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
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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
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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
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