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|
|Under development: Not open for comment. Do not cite|
This AOP was last modified on October 11, 2021 12:07
|Thyroperoxidase, Inhibition||September 08, 2021 09:28|
|Thyroid hormone synthesis, Decreased||September 08, 2021 09:36|
|Thyroxine (T4) in serum, Decreased||September 08, 2021 09:34|
|Decreased, Triiodothyronine (T3) in serum||September 08, 2021 09:42|
|Increased Mortality||September 08, 2021 07:07|
|Decrease, Population trajectory||September 03, 2021 11:24|
|Altered, retinal layer structure||September 16, 2021 05:54|
|Altered, Visual function||September 16, 2021 06:19|
|Thyroperoxidase, Inhibition leads to TH synthesis, Decreased||September 08, 2021 09:27|
|Thyroperoxidase, Inhibition leads to T4 in serum, Decreased||September 08, 2021 09:52|
|TH synthesis, Decreased leads to T4 in serum, Decreased||October 14, 2021 08:38|
|T4 in serum, Decreased leads to Decreased, Triiodothyronine (T3) in serum||September 08, 2021 07:09|
|Decreased, Triiodothyronine (T3) in serum leads to Altered, retinal layer structure||October 17, 2021 16:09|
|Altered, retinal layer structure leads to Altered, Visual function||October 17, 2021 16:18|
|Altered, Visual function leads to Increased Mortality||September 28, 2021 12:09|
|Increased Mortality leads to Decrease, Population trajectory||September 03, 2021 12:08|
|Propylthiouracil||November 29, 2016 18:42|
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Sequence||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) in serum||Decreased, Triiodothyronine (T3) in serum|
|KE||1877||Altered, retinal layer structure||Altered, retinal layer structure|
Relationships Between Two Key Events (Including MIEs and AOs)
|Thyroperoxidase, Inhibition leads to TH synthesis, Decreased||adjacent||High||Low|
|TH synthesis, Decreased leads to T4 in serum, Decreased||adjacent||Moderate||Low|
|T4 in serum, Decreased leads to Decreased, Triiodothyronine (T3) in serum||adjacent||Moderate||Moderate|
|Decreased, Triiodothyronine (T3) in serum leads to Altered, retinal layer structure||adjacent|
|Altered, retinal layer structure leads to Altered, Visual function||adjacent|
|Altered, Visual function leads to Increased Mortality||adjacent|
|Increased Mortality leads to Decrease, Population trajectory||adjacent||High||Moderate|
|Thyroperoxidase, Inhibition leads to T4 in serum, Decreased||non-adjacent||High||Low|
Life Stage Applicability
Overall Assessment of the AOP
Domain of Applicability
Life stage applicability: This AOP currently considers the impact of reduced TH synthesis on the development of the retina which starts during embryonic development across vertebrates and continues during later life stages, e.g., until after birth in mammals and into the larval stage in fish. The focus is mainly on embryolarval/embryofoetal development. At this point, this AOP does not consider potential effects of thyroid hormone system disruption on the already developed retina during later life stages.
In order to more specifically evaluate the life stage applicability of the impact on thyroperoxidase 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.
In zebrafish, 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 continues until well beyond 84 hpf (Raymond and others 1995). The first thyroid follicle appears around 55 hpf and endogenous T4 production has been observed at 72 hpf (Walter and others 2019). Since thyroperoxidase 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 thyroperoxidase 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 thyroperoxidase inhibition in zebrafish and fathead minnow (Nelson and others 2016; Stinckens and others 2016). Thyroperoxidase expression has however additionally been observed locally in the eyes of mice and zebrafish (Li and others 2012), suggesting a potential role of local TH synthesis in eye development before the thyroid follicles become active.
In summary, in zebrafish the formation of the retinal layers occurs before the activation of thyroidal TH synthesis but further differentiation and maturation continues until well after the onset of thyroidal TH synthesis. There is ample evidence of the impact of thyroperoxidase inhibition on retinal layer structure at the age of 5 dpf, and there is some evidence showing early effects at 48, 66 and 72 hpf (Komoike and others 2013; Reider and Connaughton 2014) suggesting the importance of local TH synthesis in the eyes. Currently there is insufficient evidence to clearly evaluate the importance of inhibition of local TPO in the eyes versus thyroidal TPO for the development of proper retinal layer structure.
Mammals on the other hand continuously receive maternal THs via the placenta. 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 (REF).
Taken together, there is strong support for applicability of the current AOP to embryolarval/embryofoetal stages of vertebrates.
Essentiality of the Key Events
Considerations for Potential Applications of the AOP (optional)
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.
Li Z, Ptak D, Zhang L, Walls EK, Zhong W, Leung YF. 2012. Phenylthiourea Specifically Reduces Zebrafish Eye Size. Plos One 7(6).
Morris AC, Fadool JM. 2005. Studying rod photoreceptor development in zebrafish. Physiology & Behavior 86(3):306-313.
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.
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.
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.
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.
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.
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.