To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:2373
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 altered visual function via altered retinal layer structure||adjacent||Moderate||Low||Allie Always (send email)||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 Do not cite|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. 2010) 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 triidothyronine (T3) levels in serum during eye development are likely to lead to structural and morphological alterations of the retina.
Evidence Supporting this KER
THs, TH receptors, and deiodinase (DIO) enzymes are important for eye and retinal development in vertebrates. Dio enzymes activate and inactivate THs, 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 (Gan et al. (2010),Duval, M. G., & Allison, W. T. (2018)). 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 (DIO2) and Deiodinase 3 (DIO3), probably regulating photoreceptor differentiation and cornea development (reviewed by Darras 2015).
Uncertainties and Inconsistencies
Several studies have shown molecular responses to hypothyroidism that are related to eye development (Bagci et al., 2015; Houbrechts et al., 2016; Baumann et al., 2019) but the exact molecular processes linking lower TH level to disturbances of the layers in the retina is not yet fully understood.
Both decreased as well as increased TH action has been shown to impact retinal development.
- For example, Ng et al. (2010) showed altered cone appearance in the retina following both DIO3 knockout (leading to hyperthyroidism) and THRb2 knockout (corresponding to hypothyroidism).
- Besson et al. (2020) used pharmacological treatments (T3 + iopanoic acid (IOP), NH3) to not only disrupt but also activate the TH signaling pathway. They used 10−6M T3 + (iopanoic acid) (T3 treatment) to achieve TH signal activation. Here, IOP was used as an inhibitor of deiodinase enzymes, following comparable work in mammals and amphibians, and as routinely used in fish to prevent the immediate degradation of injected T3. The combined treatment thus causes elevated T3 levels. Detected effects on retinal layer were elevated densities of bipolar cells at day 2 in surgeonfish.
- Suppressing TH signaling in retina dystrophy mouse models (a mouse model of retinal degeneration) seems to protect cone viability (Ma et al., 2014; 2016). The authors suggested that the impact of TH on cone survival is independent of its impact on cone opsin expression. The mechanism underlying the effect on cone viability has not been elucidated.
- Bhumika et al. (2014) showed accelerated reinnervation of the optic tectum after optic nerve crush in zebrafish that had been treated with IOP or a TR antagonist. both treatments cause hypothyroidism. Supplementation of T3 reduced the rate of reinnervation.
Most knowledge comes from effects in developing organisms. 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. Studies (Reider et al. 2014) found that layer thickness varied across ages suggesting that these retinal layers are differentially sensitive to for example MMI and/or that there are different critical periods of sensitivity of the retinal tissue.
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 fish and mammals, 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.
Bagci E, Heijlen M, Vergauwen L, Hagenaars A, Houbrechts AM, Esguerra CV, Blust R, Darras VM, Knapen D. 2015. Deiodinase knockdown during early zebrafish development affects growth, development, energy metabolism, motility and phototransduction. PLOS One 10:e0123285.
Baumann L, Segner H, Ros A, Knapen D, Vergauwen L. 2019. Thyroid Hormone Disruptors Interfere with Molecular Pathways of Eye Development and Function in Zebrafish. International Journal of Molecular Sciences 20(7).
Besson, M., Feeney, W. E., Moniz, I., François, L., Brooker, R. M., Holzer, G., Metian, M., Roux, N., Laudet, V., & Lecchini, D. (2020). Anthropogenic stressors impact fish sensory development and survival via thyroid disruption. Nature Communications, 11(1). https://doi.org/10.1038/s41467-020-17450-8
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
Ma HW, Ding XQ. 2016. Thyroid hormone signaling and cone photoreceptor viability. Retinal Degenerative Diseases: Mechanisms and Experimental Therapy. 854:613-618.
Ma HW, Thapa A, Morris L, Redmond TM, Baehr W, Ding XQ. 2014. Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration. Proceedings of the National Academy of Sciences of the United States of America. 111(9):3602-3607.
Ng L, Lyubarsky A, Nikonov SS, Ma M, Srinivas M, Kefas B, St Germain DL, Hernandez A, Pugh EN, Jr., Forrest D. 2010. Type 3 deiodinase, a thyroid-hormone-inactivating enzyme, controls survival and maturation of cone photoreceptors. J Neurosci. 30(9):3347-3357.
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
Schmidt F and Braunbeck T. Alterations along the Hypothalamic-Pituitary-Thyroid Axis of the Zebrafish (Danio rerio ) after Exposure to Propylthiouracil. 2011. Journal of Thyroid Research. Volume 2011, Article ID 376243, 17 pages. doi:10.4061/2011/376243
Stinckens E, Vergauwen L, Blackwell BR, Anldey GT, Villeneuve DL, Knapen D. 2020. Effect of thyroperoxidase and deiodinase inhibition on anterior swim bladder inflation in the zebrafish. Environmental Science & Technology. 54(10):6213-6223.
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
Walter KM, Miller GW, Chen XP, Yaghoobi B, Puschner B, Lein PJ. 2019. Effects of thyroid hormone disruption on the ontogenetic expression of thyroid hormone signaling genes in developing zebrafish (danio rerio). General and Comparative Endocrinology. 272:20-32.
Yu, Y., Hou, Y., Dang, Y., Zhu, X., Li, Z., Chen, H., Xiang, M., Li, Z., & Hu, G. (2021). Exposure of adult zebrafish (Danio rerio) to Tetrabromobisphenol A causes neurotoxicity in larval offspring, an adverse transgenerational effect. Journal of Hazardous Materials, 414, 125408. https://doi.org/https://doi.org/10.1016/j.jhazmat.2021.125408
Zhu, B., Zhao, G., Yang, L., & Zhou, B. (2018). Tetrabromobisphenol A caused neurodevelopmental toxicity via disrupting thyroid hormones in zebrafish larvae. Chemosphere, 197, 353–361. https://doi.org/10.1016/j.chemosphere.2018.01.080