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Decreased, Triiodothyronine (T3) in serum leads to Altered, retinal layer structure
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 increased mortality via altered retinal layer structure||adjacent||Lucia Vergauwen (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
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. 2001) 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 T3 levels in serum during eye development are likely to lead to structural and morphological alterations of the eyes.
Evidence Supporting this KER
THs, TH receptors, and deiodinase (Dio) enzymes are important for eye and retinal development in vertebrates. Dio either inactivate T3 or convert T4 (thyroxine) to T3, 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.
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 (D2) and Deiodinase 3 (D3), probably regulating photoreceptor differentiation and cornea development (reviewed by Darras 2015).
Uncertainties and Inconsistencies
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. Also, the molecular process of how a lower TH level leads to disturbances of the layers in the eye is not yet fully understood. There is little mammalian data on this KER.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
- 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
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 zebrafish and humans, 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.
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.
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
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
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