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Key Event Title
Altered, retinal layer structure
|Level of Biological Organization|
Key Event Components
|retina layer formation||retina||morphological change|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|TPOi retinal layer structure||KeyEvent||Lucia Vergauwen (send email)||Open for citation & comment||EAGMST Under Review|
Key Event Description
The anatomy and histology of the eye are highly conserved among vertebrates. The cornea and lens refract and focus light onto the posterior chamber of the eye, the vitreous cavity, which is covered by the retina. The retina consists of three specialised layers of cells, the outermost of which is formed by photoreceptors that absorb light and transmit the subsequent neural signal to the innermost layers, which consist of neurons specialised in processing and transmitting this neural signal (Wässle and Riemann, 1978; Cameron and Carney, 2000 ; Rockhill et al, 2000; Fadool, 2003). The neurons of the innermost layer converge to form the optic nerve, which transmits visual information to the brain (Gestri et al., 2012). The retina has different types of photoreceptors, the cones, which are responsible for colour vision, and the rods, which enable vision in the dark or in very low light conditions. In adults, cones are distributed in the retina in a precise and very regular arrangement, forming a photoreceptor mosaic. The precise spatiotemporal pattern of maturation of cones may affect the organization of this mosaic, and THs appear to play a role in the coordination of this maturation process (Suzuki et al., 2013). In the fish retina, this arrangement is most evident in the outer nuclear layer where the position of each cone subtype is precisely arranged relative to the others (Fadool, 2003; Robinson et al., 1993) resulting in a highly ordered crystalline-like mosaic.
The retinal pigment epithelium (RPE) is important to maintain a healthy and functional retina (Strauss 2005). The strong connection between the RPE cells with the tight junction, creates a blood-retinal barrier to mediate the directional transport of ions, water and nutrients while removing waste products. Another key function of the RPE is to absorb excess light energy to protect the neural retina from phototoxicity (Plafker 2012). Phagocytosis of spilled photoreceptor outer segments (Lister 2002) is another function of the RPE to maintain balanced photoreceptor growth, which is important for their physiological function.
Studies that detect and measure altered retinal layer structure after exposure to THs or endocrine disruptors show, for example, altered cone cell number (Allison et al., 2006; Houbrechts et al., 2016; Vancamp et al., 2019), altered retinal cell number (Dong et al., 2014), or a general alteration of retinal morphology (Gamborino et al., 2001; Houbrechts et al., 2016; Komoike et al., 2013; Li et al., 2012; Reider & Connaughton, 2014), alteration of the RPE (Baumann et al., 2016), abnormal cone differentiation (Duval & Allison, 2018; Suzuki et al., 2013; Viets et al., 2016) or prevention of the opsin switch (Gan & Flamarique, 2010; Raine & Hawryshyn, 2009). Especially the TH receptor TRβ seems to be a key regulator by determining the expression of photoreceptor development in the retina (Ng et al., 2010; Suzuki et al., 2013; Deveau et al., 2019, 2020).
How It Is Measured or Detected
For assessment of eye structure and layers, mostly simple morphometric analyses based on histological sections are sufficient. This can either be electron microscopy for subcellular changes, or normal light microscopy for cellular changes. Specific antibody staining might help to identify the different retinal layers and photoreceptor types, but usually, they are easily distinguishable by normal histological staining (e.g. HE staining).
Measurement of cell layer diameter is the most popular and simple method to assess changes in eye structure and layers. Moreover, measurement of the pigmentation grade of the retinal pigment epithelium can be used to assess structural changes. Moreover, semi-quantitative assessment of severity grades of morphological changes can be assessed.
(reviewed in Chen 2020)
Domain of Applicability
Taxonomic applicability: In general, the eye structure is very conserved among vertebrates, but some differences exist with regard to shape and expression of the different retinal layers. Fig. 1 (from Richardson 2012) demonstrates the histology of the human vs the zebrafish eye. As in humans, the mature zebrafish retina consists of three nuclear layers separated by two plexiform layers. The photoreceptor rod and cone nuclei are located in the outer nuclear layer; the amacrine, horizontal, and Müller glial cell bodies are found in the inner nuclear layer and the ganglion cell bodies are placed in the ganglion cell layer. The plexiform layers connect these layers. In contrast to zebrafish, the human retina lacks UV-sensitive cones.
Other structural differences between species are mostly related to their lifestyle (e.g. nocturnal vs diurnal) (Bibliowicz 2011) and cannot be generalized for specific vertebrate classes.
Life-stage applicability: Eye structure differs between life stages, as the different retinal layers do not develop at the same time and the eye itself grows with the organism. Eye development in zebrafish closely resembles the one in humans and other vertebrates. The eye develops from three different embryological tissues that form the specific structures of the eye, starting with the optic vesicle at 16 hpf, which further develops into the two-layered optic cup composed of the retinal neuroepithelium and pigmented epithelium until 20 hpf. Lens development begins as a lens placode that forms a solid lens mass by 22 hpf. Afterwards, the neuroectodermal layers of the optic vesicle invaginate ventrally by 24 hpf. By 48 hpf, zebrafish eye morphogenesis is almost complete with only retinal neurogenesis continuing. Retinal pigment epithelium flattening and final differentiation occurs around 27 hpf (Moreno-Marmol and others 2018). By 60 hpf, the different layers of the retina can be distinguished (Morris and Fadool 2005; Schmitt and Dowling 1999). Thereafter, further differentiation and maturation of the layers and cell types continues (Raymond and others 1995). For example, rods continue to mature until around 20 dpf (Morris and Fadool 2005). Impacts on retinal layer structure have been reported 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). Since the term 'eleutheroembryo' (stage starting at hatching and ending with free-feeding) is not available, the terms 'embryo' and 'larvae' were selected to reflect this.
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 during early development are therefore expected to be independent of sex.
At later life stages, however, sex dependency cannot be excluded. Sexual dimorphism of eye sclera surface exposure has been recently discovered (Danel et al. 2018; Danel et al., 2020). Danel et al. (2020) also found that women have rounder eye fissures and brighter irises compared to men. Maekawa et al. (2010) observed eye abnormalities such as microphthalmia and cataract in female mice but not in male mice when the fatty acid composition of the diet was changed during gestation. The authors hypothesized that this was due to differences in lipid metabolism. This suggests that effects of other factors on eye structure could also be sex- dependent in vertebrates.
Evidence for perturbation by stressor: Multiple studies demonstrate that eye development and its resulting structure can be disrupted by different stressors (reviewed for example by Chen 2020).
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