This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Thyroperoxidase inhibition leading to altered visual function via altered retinal layer structure
Point of Contact
- Lucia Vergauwen
- Lisa Gölz
|Author status||OECD status||OECD project||SAAOP status|
|Open for citation & comment||EAGMST Under Review||1.35||Included in OECD Work Plan|
This AOP was last modified on August 06, 2022 04:37
Revision dates for related pages
|Thyroperoxidase, Inhibition||November 04, 2022 09:24|
|Thyroid hormone synthesis, Decreased||November 04, 2022 09:25|
|Thyroxine (T4) in serum, Decreased||October 10, 2022 08:52|
|Decreased, Triiodothyronine (T3)||October 07, 2022 08:26|
|Increased Mortality||July 08, 2022 07:32|
|Decrease, Population growth rate||January 03, 2023 09:09|
|Altered, retinal layer structure||July 08, 2022 07:26|
|Altered, Visual function||July 08, 2022 07:30|
|Thyroperoxidase, Inhibition leads to TH synthesis, Decreased||November 04, 2022 09:27|
|Thyroperoxidase, Inhibition leads to T4 in serum, Decreased||July 08, 2022 08:33|
|TH synthesis, Decreased leads to T4 in serum, Decreased||October 10, 2022 08:56|
|T4 in serum, Decreased leads to Decreased, Triiodothyronine (T3)||October 10, 2022 09:02|
|Decreased, Triiodothyronine (T3) leads to Altered, retinal layer structure||July 08, 2022 08:18|
|Altered, retinal layer structure leads to Altered, Visual function||July 08, 2022 08:23|
|Altered, Visual function leads to Increased Mortality||July 08, 2022 08:26|
|Increased Mortality leads to Decrease, Population growth rate||July 08, 2022 08:29|
|Propylthiouracil||November 29, 2016 18:42|
|Methimazole||November 29, 2016 18:42|
Visual function is particularly important for survival, especially of developing life stages. Some chemicals, including thyroid hormone system disrupting chemicals (THSDCs), can impair eye development. The chain of events, from the molecular interaction of thyroid hormone system disruption (THSD) to the consequences at the level of vision, is not yet fully understood. The development of this AOP aims to contribute to filling these gaps and investigates how inhibition of the enzyme thyroperoxidase and resulting changes in thyroid hormone(TH) levels can lead to effects on the retinal layers and subsequently at the population level.
The focus of this AOP is on fish, as the largest amount of data is available for this taxonomic group. Data obtained with a variety of different techniques to induce or mimick TH synthesis disruption have been included (addressing KE 227: "Decreased thyroid hormone synthesis"), for example, exposure to THSDCs, generation of transgenic or mutant fish, microinjection, morpholino knockdown, thyroid ablation, etc. The resulting changes in hormone levels have been studied (KE 281: "Decreased thyroxine (T4) in serum" , KE 1003: "Decreased triiodothyronine (T3)"), as well as changes in the retinal layers (KE 1877: "Altered retinal layer structure"). These include e.g. cell size, cell layer structure, organisation and number of photoreceptors, pigmentation and information on morphological changes (e.g. cell shapes). At a higher level of biological organization, physiological and behavioural changes were investigated (AO 1643: "Altered visual function"), including e.g. optokinetic response, optomotor response, light response, etc. The present AOP is closely linked to AOPs 155-159 on THSD leading to impaired swim bladder inflation in fish, as well as AOP 297 on retinoic acid effects on eye development.
AOP Development Strategy
This AOP is based on data derived from several extensive literature searches. First, data was collected on different biological levels: Results at the molecular level, data on hormone levels, data on the tissue level and on the behavioural/physiological level. In a next step, KEs and KERs were identified and defined and a more detailed search was initiated. While initially an AOP network including several different effects on eye development was considered, in a next step AOP 363 was selected and further refined, and again an intensive and very detailed final literature search was conducted. The search for bibliographic data was conducted online in "pubmed", "sciencedirect/Scopus" and "Web of Science". The initial search terms were: "(zebra-)fish", "eye development", "retina", "thyroid/hormone disorders", "visual behavio(u)r", "photoreceptors" and combinations of these terms. A very detailed manual search followed for the various KEs and KERs. Not only articles on chemical exposure of different animals were considered, but also more basic studies using other THSD induction techniques such as transgenic or mutant fish, microinjection, morpholino oligonucleotides, thyroidectomy, etc. The range of data that was assessed is wide, from gene expression and hormone levels to physiological and behavioural changes in different animals. In total, around 120 articles from this structured search were analysed in terms of experimental design and information on different biological levels. The majority of literature used fish, especially zebrafish (85%), which is why this AOP focuses on fish, but it can probably be applied to other vertebrate species as well.
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Type||Event ID||Title||Short name|
|MIE||279||Thyroperoxidase, Inhibition||Thyroperoxidase, Inhibition|
|KE||277||Thyroid hormone synthesis, Decreased||TH synthesis, Decreased|
|KE||281||Thyroxine (T4) in serum, Decreased||T4 in serum, Decreased|
|KE||1003||Decreased, Triiodothyronine (T3)||Decreased, Triiodothyronine (T3)|
|KE||1877||Altered, retinal layer structure||Altered, retinal layer structure|
|KE||1643||Altered, Visual function||Altered, Visual function|
|AO||351||Increased Mortality||Increased Mortality|
|AO||360||Decrease, Population growth rate||Decrease, Population growth rate|
Relationships Between Two Key Events (Including MIEs and AOs)
|Thyroperoxidase, Inhibition leads to TH synthesis, Decreased||adjacent||High||Moderate|
|TH synthesis, Decreased leads to T4 in serum, Decreased||adjacent||Moderate||Moderate|
|T4 in serum, Decreased leads to Decreased, Triiodothyronine (T3)||adjacent||Moderate||Moderate|
|Decreased, Triiodothyronine (T3) leads to Altered, retinal layer structure||adjacent||Moderate||Low|
|Altered, retinal layer structure leads to Altered, Visual function||adjacent||High||Low|
|Altered, Visual function leads to Increased Mortality||adjacent||Moderate||Low|
|Increased Mortality leads to Decrease, Population growth rate||adjacent||Moderate||Moderate|
|Thyroperoxidase, Inhibition leads to T4 in serum, Decreased||non-adjacent||High||Moderate|
Life Stage Applicability
Overall Assessment of the AOP
Domain of Applicability
The weight of evidence supporting the first linkage of this AOP between the MIE, TPO inhibition, and the KE of decreased TH synthesis, is strong and supported by more than three decades of research in animals including humans. Several papers have measured alterations in TPO and subsequent effects on TH synthesis (Cooper et al., 1982; Cooper et al.,1983; Divi and Doerge, 1994).
Also for the next KER, it is widely accepted that TPO inhibition leads to declines in serum T4 levels in adult mammals. Strong qualitative and quantitative relationships exist between reduced TH synthesis and reduced serum T4 (Ekerot et al., 2013; Degon et al., 2008; Cooper et al., 1982; 1983; Leonard et al., 2016; Zoeller and Tan, 2007). Nevertheless, while a majority of the empirical evidence comes from work with laboratory rodents, there is a large amount of supporting data from humans (with anti-hyperthyroidism drugs including propylthiouracil and methimazole), some amphibian species (e.g., frog), fish species (e.g., zebrafish and fathead minnow), and some avian species (e.g, chicken) (Cooper et al. (1982; 1983); Hornung et al. (2010); Van Herck et al. (2013); Paul et al. (2013); Nelson et al. (2016); Alexander et al. (2017); Stinckens et al. (2020)).
Although the following KER (T4 in serum decreased leads to Triiodothyronine (T3) decreased) is also plausibly applicable across vertebrates, variation can be expected due to feedback/compensatory mechanisms that can also differ across species. In zebrafish and fathead minnow, several studies reported the evidence for a relationship between whole body T4 and T3 levels (Nelson et al., 2016; Stinckens et al., 2020, Wang et al., 2020).
The linkage between the MIE, decreased T3, and the KE of altered retinal layer structure, is evident in the different vertebrate classes. There is ample evidence that THs have an influence on the development of the retinal layer structure. Although there are some differences in eye structure between species, it is known that the retina follows the typical organisation of vertebrates. Within vertebrates, it consists of several layers such as the retinal pigment epithelium (RPE), photoreceptors, neurons and choroid. It is plausible to assume that TH levels are important for healthy eye development in all vertebrates.
TH receptors have a general function in different cell types of the vertebrate retina, they mediate specific events in retinal and photoreceptor development. The decrease of TH levels can lead to disturbances of the retinal layers, as shown by studies in various vertebrates such as fish species, rats, mice and humans (Baumann (2016), Komoike et al. (2013), Besson et al. (2020), Gamborino (2000), Houbrechts (2016), (Li et al. 2012)). In humans, hypothyroidism is also linked to impaired color vision (Racheva et al., 2020).
Life stage applicability:
This AOP considers effects of TPO inhibitors on the development of the retina during the embryo and larval life stage. In order to more specifically evaluate the life stage applicability of the impact of TPO inhibition on retinal layer structure and visual function leading to increased mortality, the timing of the ontogeny of the target organ needs to be matched to the timing of the ontogeny of the HPT-axis. Fish, amphibians and birds develop externally and rely on maternally transferred THs and TH machinery during the earliest stages of embryonic development. The first thyroid follicles in zebrafish appear around 55 hpf and endogenous T4 production has been observed at 72 hpf (Walter and others 2019). Since TPO is principally located in the thyroid follicles and responsible for the synthesis of TH which are released to circulation, important impacts on thyroidal TH synthesis due to TPO inhibition are not expected before 72 hpf. This hypothesis is in line with the observation that inflation of the posterior chamber of the swim bladder appears to be unaffected by TPO inhibition in zebrafish and fathead minnow (Nelson and others 2016; Stinckens and others 2016). We therefore hypothesize that effects on the retina are caused between activation of embryonic TH synthesis (around 72 hpf) and 5 dpf. In zebrafish, chemically-induced adverse effects on retinal layer structure are typically observed at 96 or 120 hpf. By 60 hpf, the different layers of the retina can be distinguished (Morris and Fadool 2005; Schmitt and Dowling 1999) but differentiation and maturation required for a functional retina continues until well beyond 84 hpf (Raymond and others 1995). For example, the first proper optokinetic response occurs around 4 dpf (Cohen et al., 2022). Based on these arguments, we identify early (< 72 hpf) processes that may not be (highly) sensitive to TPO inhibition and late (> 72 hpf) embryonic processes that are sensitive to TPO inhibition. Early processes can however be sensitive to other mechanisms of TH system disruption that impact on maternal THs, including deiodinase inhibition, since deiodinases are required to activate maternal T4 (Stinckens et al., 2016). While manu of the studies listed as evidence in this AOP are in line with this hypothesis, some studies raise uncertainties. For example, Reider and Connaughton (2014) observed reduction of ganglion cell layer thickness after exposing zebrafish embryos to MMI until 66 hpf and raising them afterwards in clean water until 72 hpf. It should be noted that there is still uncertainty about the exact timing of the activation of TH synthesis. The time window between 48 and 72 hpf has not been studied yet. Maternally transferred mRNA coding for TPO and NIS, as well as embryonic expression of thyroglobulin (Vergauwen et al., 2018) and the presence of the first thyroid follicle could allow for the start of TH synthesis between 55 and 72 hpf and therefore a corresponding sensitivity of developmental processes to TPO inhibition in this period.
There are potential, alternative pathways that may lead to altered retinal layer structure and that are not the subject of this AOP. For example, TPO expression has been observed locally in the eyes of mice (Li and others 2012), suggesting a potential role of local TH synthesis in eye development before the thyroid follicles become active. This process could be sensitive to TPO inhibition. There is currently insufficient information to evaluate this hypothesis. Among others, it is not clear whether TH synthesis can take place in the absence of a follicular epithelium. Additionally, TH-independent pathways may contribute to the impact on the retinal layer structure. For example, Komoike et al. (2013) suggested TH-independent apoptosis and Li et al. (2012) hypothesized that the inhibition of peroxidase activity in general could disrupt the formation of the extracellular matrix. Finally, TH system disruptors often act on multiple targets simultaneously, potentially affecting retinal layer structure through different TH dependent pathways (e.g., TPO and deiodinase inhibition by propylthiouracil).
Mammals on the other hand continuously receive maternal THs via the placenta during embryonic development. Therefore, exposure to inhibitors of TH synthesis is expected to have an effect on the earliest phases of embryonic development by inhibiting maternal TH synthesis (Klein and Mitchell, 1999; Klein et al., 2001, Elred et al. 2018).
Taken together, there is strong support for applicability of the current AOP to embryo-larval/embryo-foetal stages of vertebrates. Since the term 'eleutheroembryo' (stage starting at hatching and ending with free-feeding fish) is not applicable to all vertebrates, the terms 'embryo' and 'larvae' were selected to reflect this.
Fish species have different patterns of gonadal differentiation. Many species are undifferentiated gonochorists (e.g., zebrafish, fathead minnows), in which an indifferent gonad first develops into an ovary-like gonad which then further differentiates into either a mature ovary or a testis (Maack and Segner, 2003). Other fish species such as medaka are differentiated gonochorists where the indifferent gonad develops directly into an ovary or a testis. In both cases, in the early life stages in which the eyes develop, the gonads have not yet started to differentiate. For example, in zebrafish the eyes develop in the first 5 days of development and the gonads differentiate in the period around 20-50 dpf. In species such as zebrafish, even sex determination has not occurred by the time the eyes develop, since it is dependent on environmental factors. This means that in the life stages of interest for this AOP (embryo-larval), sex has not been established yet nor has gonad differentiation started. Therefore, sex is not assumed to be an important factor in determining the effect of TPO inhibitors on retinal structure development.
This does however not preclude the occurrence of sex dependent changes in eye structure during later life after gonadal differentiation. For example, Chen et al. (2018) exposed marine medaka to perfluorobutane sulfonate (PFBS) for an entire life cycle and this resulted in sex-dependent changes in eye water content and neurotransmitter levels in the eyes.
Essentiality of the Key Events
Essentiality means that a stressor can activate an AOP and its various KEs, and that cessation of this stressor can prevent this activation or lead to a recovery of the adverse effects. Certain studies, such as gene knockdown, recovery or knockout experiments, have been reviewed to evaluate this. Evidence for essentiality in this AOP can be classified as high. Direct evidence from specifically designed experimental studies illustrating essentiality is available for several KEs in the AOP. Especially the evidence of essentiality of decreased T3 levels for effects on the eyes is very important and strongly supports this AOP.
- Biological plausibility:
Most of the KERs (309, 305, 366, 2374, 2375, 2013) were found to be highly biologically plausible. For example, TPO is known to be a key enzyme of the TH system and plays an important role in controlling important functions such as neuronal development, including eye development. Similarly, the thyroid hormone T4 is known to be activated to T3 by DIOs in the liver and other organs. Both T3 and T4 are present during retinal development (Roberts and others 2006), and key components such as DIOs (Heijlen and others 2013; summarized by Viets and others 2016), TH receptors (Gan and Flamarique 2010), and TPO (Li and others 2012) are also expressed in the vertebrate retina during retinal development. However, there are compensatory mechanisms that limit the impact on T3 levels, possibly through increased deiodinase activity or other feedback or compensatory mechanisms, as well as some gaps in knowledge. Therefore, the biological plausibility of KER 2038 and 2373 was determined to be moderate.
- Empirical support is moderate for most KERs in the AOP and low for the most upstream KERs.
- Overall WoE ranges from moderate to high. As prescribed by the User's handbook, biological plausibility was given slightly more weight in this decision compared to empirical evidence.
Known Modulating Factors
The difficulties in generating quantitative data for this AOP may be due to the fact that both decreased and increased T3 levels affect the development of retinal structure, confirming that this process is under strict control of balanced TH levels, but also making it difficult to describe the quantitative relationship between T3 levels and altered retinal structure (Stinckens et al., 2020).
However, the combinations of some studies show some correlations: For example, the study by Rehberger et al. (2018) shows a decrease in T3 and T4 with increasing PTU concentration in zebrafish embryos, Baumann et al. (2016) found both retinal malformations and behavioural abnormalities due to impaired visual performance in larvae at these concentrations (and at much higher concentrations). Baumann et al. (2016) also showed a correlation between increased TPO gene expression (measured as a fold change) and decreased RPE diameter with increasing PTU exposure in 5 dpf zebrafish.
There is quantitative data on KER1 (TPO, inhibition (KE 279) results in TH synthesis, reduced (KE 277), also. For example, Hassan et al (2017) quantified TH synthesis blocked by PTU and MMI in an in vitro TPO inhibition study to predict TH concentrations in rat serum. Similarly, Fisher et al. (2013) modelled the effect of TPO inhibition on serum TH concentrations during early development in rats. Haselman et al. (2020), in Xenopus laevis, demonstrated the temporal profiles of thyroid iodotyrosines (MIT/DIT) and iodothyronines (T4/T3), the products of TPO activity, after exposure to three different model TPO inhibitors (MMI, PTU, MBT) at different concentrations.
Considerations for Potential Applications of the AOP (optional)
THSDCs are increasingly recognized as a serious environmental problem for aquatic species, as well as for humans. Especially the THSD effects on (neuro-)developmental processes pose a risk to different vertebrate species. The current framework for assessment of THSD effects is separated between human and environmental health, and in the latter, it is restricted to amphibians. The implementation of thyroid-related endpoints into test guidelines using fish is urgently needed and is currently being addressed in different EU-funded research projects (Holbech et al., 2020) and in project 2.64 of the OECD TG work plan, “Inclusion of thyroid endpoints in OECD fish Test Guidelines”. Moreover, this testing gap has been recognized by OECD VMG-Eco in 2016 at two EU workshops, “Setting Priorities for Further Development and Validation of Test Methods and Testing Approaches'' and “Supporting the Organization of a Workshop on Thyroid Disruption” in 2017.
The present AOP provides strong evidence that eye development represents a very promising endpoint that could be implemented into existing OECD test guidelines that cover developmental phases of fish, such as the Fish Embryo Acute Toxicity (FET) test (OECD TG 236), the Fish Early Life Stage Toxicity (FELS) Test (OECD TG 210) and the Fish Sexual Development Test (FSDT, OECD TG 234). Especially the FET seems to be well suited for implementation of histopathological analyses of retinal structures for the detection of cellular changes that will ultimately result in decreased visual capacities and fitness impairment of exposed larvae. Combined with mechanistic analyses, such as gene expression or TH level measurements, a modified FET for detection of THSD in fish seems very promising for future THSD testing with fish. A major advantage is that a large part of the proposed endpoints in zebrafish can be assessed in embryonic life stages, which are considered “non-protected” alternatives to animal testing.
Consequently, based on AOP 363, together with other AOPs linking THSD to visual function that are under development (AOP 364, 365), we provide evidence that fish eye development, with focus on morphological and structural alterations, can be included as apical endpoint into fish endocrine disruption test guidelines for THSD. However, the TH-specificity of eye-related endpoints should be examined, since other signaling pathways, such as the estrogenic, retinoid, IGF-1 and aryl hydrocarbon receptor, can also affect eye development (Molla et al., 2019; Chen et al., 2020). Consequently, measurement of TH levels or performance of thyroid histopathology are required to support the causal link between the THSD mechanism and the observed effects in the eyes.
Antonica, F., Kasprzyk, D. F., Opitz, R., Iacovino, M., Liao, X. H., Dumitrescu, A. M., Refetoff, S., Peremans, K., Manto, M., Kyba, M., & Costagliola, S. (2012). Generation of functional thyroid from embryonic stem cells. Nature, 491(7422), 66–71.https://doi.org/10.1038/nature11525
Axelstad, M., Hansen, P. R., Christiansen, S., Kiersgaard, M. K., Nellemann, C., & Hass, U. (2008). Effects of developmental exposure to UV-filter octyl-methoxycinnamate (OMC) on rat offspring. Reproductive Toxicology, 26(1), 57. https://doi.org/10.1016/j.reprotox.2008.05.004
Bagci, E., Heijlen, M., Vergauwen, L., Hagenaars, A., Houbrechts, A. M., Esguerra, C. V., Blust, R., Darras, V. M., & Knapen, D. (2015). Deiodinase knockdown during early zebrafish development affects growth, development, energy metabolism, motility and phototransduction. PLoS ONE, 10(4), 1–22. https://doi.org/10.1371/journal.pone.0123285
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.
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), 1543. https://doi.org/10.3390/ijms20071543
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
Chen, X., Walter, K. M., Miller, G. W., Lein, P. J., & Puschner, B. (2018). Simultaneous quantification of T4, T3, rT3, 3,5-T2 and 3,3′-T2 in larval zebrafish (Danio rerio) as a model to study exposure to polychlorinated biphenyls. Biomedical Chromatography, 32(6), 1–10. https://doi.org/10.1002/bmc.4185
Chen, Z., Cai, A., Zheng, H., Huang, H., Sun, R., Cui, X., Ye, W., Yao, Q., Chen, R., & Kou, L. (2020). Carbidopa suppresses prostate cancer via aryl hydrocarbon receptor-mediated ubiquitination and degradation of androgen receptor. Oncogenesis, 9(5). https://doi.org/10.1038/s41389-020-0236-x
Cohen, A., Popowitz, J., Delbridge-Perry, M., Rowe, C. J., & Connaughton, V. P. (2022). The Role of Estrogen and Thyroid Hormones in Zebrafish Visual System Function. Frontiers in Pharmacology, 13. https://doi.org/10.3389/fphar.2022.837687
Cooke, P. S. (1996). Thyroid hormone and the regulation of testicular development. Animal Reproduction Science, 42(1–4), 333–341. https://doi.org/10.1016/0378-4320(96)01489-3
COOPER, D. S., KIEFFER, D., HALPERN, R., SAXE, V., MOVER, H., MALOOF, F., & RIDGWAY, E. C. (1983). Propylthiouracil (PTU) Pharmacology in the Rat,II. Effects of PTU on Thyroid Function*. Endocrinology, 113(3), 921–928. https://doi.org/10.1210/endo-113-3-921
COOPER, D. S., KIEFFER, J. D., SAXE, V., MOVER, H., MALOOF, F., & RIDGWAY, E. C. (1984). Methimazole Pharmacology in the Rat: Studies Using a Newly Developed Radioimmunoassay for Methimazole*. Endocrinology, 114(3), 786–793. https://doi.org/10.1210/endo-114-3-786
Crofton, K. M., Kodavanti, P. R. S., Derr-Yellin, E. C., Casey, A. C., & Kehn, L. S. (2000). PCBs, thyroid hormones, and ototoxicity in rats: Cross-fostering experiments demonstrate the impact of postnatal lactation exposure. Toxicological Sciences, 57(1), 131–140. https://doi.org/10.1093/toxsci/57.1.131
Degon, M., Chipkin, S. R., Hollot, C. V., Zoeller, R. T., & Chait, Y. (2008). A computational model of the human thyroid. Mathematical Biosciences, 212(1), 22–53. https://doi.org/10.1016/j.mbs.2007.10.009
Divi, R. L., & Doerge, D. R. (1994). Mechanism-Based Inactivation of Lactoperoxidase and Thyroid Peroxidase by Resorcinol Derivatives. Biochemistry, 33(32), 9668–9674. https://doi.org/10.1021/bi00198a036
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
Ekerot, P., Ferguson, D., Glämsta, E.-L., Nilsson, L. B., Andersson, H., Rosqvist, S., & Visser, S. A. G. (2013). Systems Pharmacology Modeling of Drug-Induced Modulation of Thyroid Hormones in Dogs and Translation to Human. Pharmaceutical Research, 30(6), 1513–1524. https://doi.org/10.1007/s11095-013-0989-4
Eldred, K. C., Hadyniak, S. E., Hussey, K. A., Brenerman, B., Zhang, P.-W., Chamling, X., Sluch, V. M., Welsbie, D. S., Hattar, S., Taylor, J., Wahlin, K., Zack, D. J., & Johnston, R. J. (2018). Thyroid hormone signaling specifies cone subtypes in human retinal organoids. Science, 362(6411). https://doi.org/10.1126/science.aau6348
Fisher, J. W., Li, S., Crofton, K., Zoeller, R. T., McLanahan, E. D., Lumen, A., & Gilbert, M.E. (2013). Evaluation of iodide deficiency in the lactating rat and pup using a biologically based dose-response model. Toxicological Sciences, 132(1), 75–86. https://doi.org/10.1093/toxsci/kfs336
Gamborino, M. J., Sevilla-Romero, E., Muñoz, A., Hernández-Yago, J., Renau-Piqueras, J., & Pinazo-Durán, M. D. (2001). Role of thyroid hormone in craniofacial and eye development using a rat model. Ophthalmic Research,33(5), 283–291. https://doi.org/10.1159/000055682
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
Goldey, E. S., Kehn, L. S., Rehnberg, G. L., & Crofton, K. M. (1995). Effects of Developmental Hypothyroidism on Auditory and Motor Function in the Rat. Toxicology and Applied Pharmacology, 135(1), 67–76. https://doi.org/10.1006/taap.1995.1209
Haselman, J. T., Olker, J. H., Kosian, P. A., Korte, J. J., Swintek, J. A., Denny, J. S., Nichols, J. W., Tietge, J. E., Hornung, M. W., & Degitz, S. J. (2020). Targeted Pathway-based In Vivo Testing Using Thyroperoxidase Inhibition to Evaluate Plasma Thyroxine as a Surrogate Metric of Metamorphic Success in Model Amphibian Xenopus laevis. Toxicological Sciences, 175(2), 236–250. https://doi.org/10.1093/toxsci/kfaa036
Hassan, I., El-Masri, H., Kosian, P. A., Ford, J., Degitz, S. J., & Gilbert, M. E. (2017). Neurodevelopment and Thyroid Hormone Synthesis Inhibition in the Rat: Quantitative Understanding Within the Adverse Outcome Pathway Framework. Toxicological Sciences, 160(1), 57–73. https://doi.org/10.1093/toxsci/kfx163
Heijlen, M., Houbrechts, A. M., & Darras, V. M. (2013). Zebrafish as a model to study peripheral thyroid hormone metabolism in vertebrate development. General and Comparative Endocrinology, 188(1), 289–296. https://doi.org/10.1016/j.ygcen.2013.04.004
Hill, R. N., Crisp, T. M., Hurley, P. M., Rosenthal, S. L., & Singh, D. v. (1998). Risk assessment of thyroid follicular cell tumors. Environmental Health Perspectives, 106(8), 447–457. https://doi.org/10.1289/ehp.98106447
Holbech, H., Matthiessen, P., Hansen, M., Schüürmann, G., Knapen, D., Reuver, M., Flamant, F., Sachs, L., Kloas, W., Hilscherova, K., Leonard, M., Arning, J., Strauss, V., Iguchi, T., & Baumann, L. (2020). ERGO: Breaking down the wall between human health and environmental testing of endocrine disrupters. International Journal of Molecular Sciences, 21(8). https://doi.org/10.3390/ijms21082954
Houbrechts, A. M., Delarue, J., Gabriëls, I. J., Sourbron, J., & Darras, V. M. (2016). 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
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
Hornung, M. W., Degitz, S. J., Korte, L. M., Olson, J. M., Kosian, P. A., Linnum, A. L., & Tietge, J. E. (2010). Inhibition of Thyroid Hormone Release from Cultured Amphibian Thyroid Glands by Methimazole, 6-Propylthiouracil, and Perchlorate. Toxicological Sciences, 118(1), 42–51. https://doi.org/10.1093/toxsci/kfq166
Klein, R. Z., & Mitchell, M. L. (1999). Maternal Hypothyroidism and Child Development. Hormone Research in Paediatrics, 52(2), 55–59. https://doi.org/10.1159/000023435
Klein, R. Z., Sargent, J. D., Larsen, P. R., Waisbren, S. E., Haddow, J. E., & Mitchell, M. L. (2001). Relation of severity of maternal hypothyroidism to cognitive development of offspring. Journal of Medical Screening, 8(1), 18–20. https://doi.org/10.1136/jms.8.1.18
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.
Lasley, S. M., & Gilbert, M. E. (2011). Developmental thyroid hormone insufficiency reduces expression of brain-derived neurotrophic factor (BDNF) in adults but not in neonates. Neurotoxicology and Teratology, 33(4), 464–472. https://doi.org/10.1016/j.ntt.2011.04.001
Leonard, J. A., Tan, Y.-M., Gilbert, M., Isaacs, K., & El-Masri, H. (2016). Estimating Margin of Exposure to Thyroid Peroxidase Inhibitors Using High-Throughput in vitro Data, High-Throughput Exposure Modeling, and Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling. Toxicological Sciences, 151(1), 57–70. https://doi.org/10.1093/toxsci/kfw022
Li Z, Ptak D, Zhang L, Walls EK, Zhong W, Leung YF. 2012. Phenylthiourea Specifically Reduces Zebrafish Eye Size. Plos One 7(6).
Maack G, Segner H. 2003. Morphological development of the gonads in zebrafish. Journal of Fish Biology 62(4):895-906.
Marelli, F., Carra, S., Agostini, M., Cotelli, F., Peeters, R., Chatterjee, K., & Persani, L. (2016). Patterns of thyroid hormone receptor expression in zebrafish and generation of a novel model of resistance to thyroid hormone action. Molecular and Cellular Endocrinology, 424, 102–117. https://doi.org/10.1016/j.mce.2016.01.020
Molla, M. H. R., Hasan, M. T., Jang, W. J., Soria Diaz, C. D., Appenteng, P., Marufchoni, H., Jahan, B., & Brown, C. L. (2019). Thyroid hormone-induced swim bladder and eye maturation are transduced by IGF-1 in zebrafish embryos. Aquaculture Research, 50(11), 3462–3470. https://doi.org/10.1111/are.14305
Morris AC, Fadool JM. 2005. Studying rod photoreceptor development in zebrafish. Physiology & Behavior 86(3):306-313.
Nelson, K. R., Schroeder, A. L., Ankley, G. T., Blackwell, B. R., Blanksma, C., Degitz, S. J.,Flynn, K. M., Jensen, K. M., Johnson, R. D., Kahl, M. D., Knapen, D., Kosian, P. A., Milsk, R. Y., Randolph, E. C., Saari, T., Stinckens, E., Vergauwen, L., & Villeneuve, D. L. (2016). Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part I: Fathead minnow. Aquatic Toxicology, 173, 192–203. https://doi.org/10.1016/j.aquatox.2015.12.024
Opitz, R., Antonica, F., & Costagliola, S. (2013). New Model Systems to Illuminate Thyroid Organogenesis. Part I: An Update on the Zebrafish Toolbox. European Thyroid Journal, 2(4), 229–242. https://doi.org/10.1159/000357079
Paul, K. B., Hedge, J. M., Macherla, C., Filer, D. L., Burgess, E., Simmons, S. O., Crofton, K. M., & Hornung, M. W. (2013). Cross-species analysis of thyroperoxidase inhibition by xenobiotics demonstrates conservation of response between pig and rat. Toxicology, 312(1), 97–107. https://doi.org/10.1016/j.tox.2013.08.006
Taurog, A. (1999). Molecular evolution of thyroid peroxidase. Biochimie, 81(5), 557–562. https://doi.org/10.1016/S0300-9084(99)80110-2
van Herck, S. L. J., Geysens, S., Delbaere, J., & Darras, V. M. (2013). Regulators of thyroid hormone availability and action in embryonic chicken brain development. General and Comparative Endocrinology, 190, 96–104. https://doi.org/10.1016/j.ygcen.2013.05.003
Vergauwen, L., Cavallin, J. E., Ankley, G. T., Bars, C., Gabriëls, I. J., Michiels, E. D. G., Fitzpatrick, K. R., Periz-Stanacev, J., Randolph, E. C., Robinson, S. L., Saari, T. W., Schroeder, A. L., Stinckens, E., Swintek, J., van Cruchten, S. J., Verbueken, E., Villeneuve, D. L., & Knapen, D. (2018). Gene transcription ontogeny of hypothalamic-pituitary-thyroid axis development in early-life stage fathead minnow and zebrafish. General and Comparative Endocrinology, 266, 87–100. https://doi.org/10.1016/j.ygcen.2018.05.001
Viets, K., Eldred, K. C., & Johnston, R. J. (2016). Mechanisms of Photoreceptor Patterning in Vertebrates and Invertebrates. Trends in Genetics, 32(10), 638–659. https://doi.org/10.1016/j.tig.2016.07.004
Vickers, A. E. M., Heale, J., Sinclair, J. R., Morris, S., Rowe, J. M., & Fisher, R. L. (2012). Thyroid organotypic rat and human cultures used to investigate drug effects on thyroid function, hormone synthesis and release pathways. Toxicology and Applied Pharmacology, 260(1), 81–88. https://doi.org/10.1016/j.taap.2012.01.029
Nelson K, Schroeder A, Ankley G, Blackwell B, Blanksma C, Degitz S, Flynn K, Jensen K, Johnson R, Kahl M et al. . 2016. Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part I: Fathead minnow. Aquatic Toxicology 173:192-203.
Racheva K, Totev T, Natchev E, Bocheva N, Beirne R, Zlatkova M. 2020. Color discrimination assessment in patients with hypothyroidism using the farnsworth-munsell 100 hue test. Journal of the Optical Society of America a-Optics Image Science and Vision. 37(4):A18-A25.
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.
Rehberger, K., Baumann, L., Hecker, M., & Braunbeck, T. (2018). Intrafollicular thyroid hormone staining in whole-mount zebrafish (Danio rerio) embryos for the detection of thyroid hormone synthesis disruption. Fish Physiology and Biochemistry, 44(3), 997–1010. https://doi.org/10.1007/s10695-018-0488-yReider 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.
Roberts, M. R., Srinivas, M., Forrest, D., De Escobar, G. M., & Reh, T. A. (2006). Making the gradient: Thyroid hormone regulates cone opsin expression in the develoninn mouse retina. Proceedings of the National Academy of Sciences of the United States of America, 103(16), 6218–6223. https://doi.org/10.1073/pnas.0509981103
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.
Shibutani, M., Woo, G.-H., Fujimoto, H., Saegusa, Y., Takahashi, M., Inoue, K., Hirose, M., & Nishikawa, A. (2009). Assessment of developmental effects of hypothyroidism in rats from in utero and lactation exposure to anti-thyroid agents. Reproductive Toxicology, 28(3), 297–307. https://doi.org/10.1016/j.reprotox.2009.04.011
Stinckens E, Vergauwen L, Schroeder A, Maho W, Blackwell B, Witters H, Blust R, Ankley G, Covaci A, Villeneuve D et al. . 2016. Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part II: Zebrafish. Aquatic Toxicology 173:204-217.
Stinckens, E., Vergauwen, L., Blackwell, B. R., Ankley, G. T., Villeneuve, D. L., & Knapen, D. (2020). Effect of Thyroperoxidase and Deiodinase Inhibition on Anterior Swim Bladder Inflation in the Zebrafish. Environmental Science and Technology, 54(10), 6213–6223. https://doi.org/10.1021/acs.est.9b07204
Suzuki, S. C., Bleckert, A., Williams, P. R., Takechi, M., Kawamura, S., & Wong, R. O. L. (2013). Cone photoreceptor types in zebrafish are generated by symmetric terminal divisions of dedicated precursors. Proceedings of the National Academy of Sciences of the United States of America, 110(37), 15109–15114. https://doi.org/10.1073/pnas.1303551110
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.
Wang, J.X., Shi, G.H., Yao, J.Z., Sheng, N., Cui, R.N., Su, Z.B., Guo, Y., Dai, J.Y., 2020. Perfluoropolyether carboxylic acids (novel alternatives to PFOA) impair zebrafish posterior swim bladder development via thyroid hormone disruption. Environment International 134.
Zoeller, R. T., Tan, S. W., & Tyl, R. W. (2007). General Background on the Hypothalamic-Pituitary-Thyroid (HPT) Axis. Critical Reviews in Toxicology, 37(1–2), 11–53. https://doi.org/10.1080/10408440601123446