This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Inhibition of thyroid peroxidase leading to impaired fertility in fish
Point of Contact
- June-Woo Park
- Carlie LaLone
- Young Jun Kim
|Author status||OECD status||OECD project||SAAOP status|
|Open for comment. Do not cite||Under Development||1.59||Included in OECD Work Plan|
This AOP was last modified on June 04, 2021 15:12
|Thyroperoxidase, Inhibition||September 08, 2021 09:28|
|Thyroid hormone synthesis, Decreased||September 08, 2021 09:36|
|Reduction, Plasma 17beta-estradiol concentrations||September 26, 2017 11:30|
|Reduction, Plasma vitellogenin concentrations||September 16, 2017 10:14|
|Reduction, Cumulative fecundity and spawning||March 20, 2017 17:52|
|Reduction, Vitellogenin synthesis in liver||May 27, 2021 01:10|
|reduction in ovarian granulosa cells, Aromatase (Cyp19a1)||May 28, 2021 07:49|
|Thyroperoxidase, Inhibition leads to TH synthesis, Decreased||September 08, 2021 09:27|
|TH synthesis, Decreased leads to Reduction, Plasma 17beta-estradiol concentrations||September 18, 2018 20:54|
|Reduction, Plasma 17beta-estradiol concentrations leads to Reduction, Plasma vitellogenin concentrations||October 18, 2018 11:02|
|Reduction, Plasma vitellogenin concentrations leads to Reduction, Cumulative fecundity and spawning||September 18, 2018 20:55|
|Propylthiouracil||November 29, 2016 18:42|
|Methimazole||November 29, 2016 18:42|
|Ethylene thiourea||November 29, 2016 18:42|
This AOP links inhibition of thyroid peroxidase to reproductive toxicity in fish. This AOP describes one adverse outcome that may result from the inhibition of thyroid peroxidase (TPO). Thyroid peroxidase (TPO) is an enzyme for thyroid hormone (TH) synthesis. Chemical inhibition of TPO, the molecular-initiating event (MIE), results in decreased thyroid hormone (TH) synthesis. Reduction of TH induces the decline of E2 and VTG, which leads to decreased cumulative fecundity and spawning. Cumulative fertility is major endpoint for evaluation of reproductive toxicity caused by endocrine disruption. It is used as an endpoint for endocrine disruptor screening in OECD 229. Therefore, this AOP would be useful as a means to identify chemicals with known potential to adversely affect fish populations.
Acknowledgements: This research was supported by the National Research Council of Science & Technology(NST) grant by the Korea government (MSIP) (No. CAP-17-01-KIST Europe)
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Sequence||Type||Event ID||Title||Short name|
|1||MIE||279||Thyroperoxidase, Inhibition||Thyroperoxidase, Inhibition|
|2||KE||277||Thyroid hormone synthesis, Decreased||TH synthesis, Decreased|
|3||KE||408||reduction in ovarian granulosa cells, Aromatase (Cyp19a1)||reduction in ovarian granulosa cells, Aromatase (Cyp19a1)|
|4||KE||219||Reduction, Plasma 17beta-estradiol concentrations||Reduction, Plasma 17beta-estradiol concentrations|
|5||KE||285||Reduction, Vitellogenin synthesis in liver||Reduction, Vitellogenin synthesis in liver|
|6||KE||221||Reduction, Plasma vitellogenin concentrations||Reduction, Plasma vitellogenin concentrations|
|7||AO||78||Reduction, Cumulative fecundity and spawning||Reduction, Cumulative fecundity and spawning|
Relationships Between Two Key Events (Including MIEs and AOs)
Life Stage Applicability
|Adult, reproductively mature||High|
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
- MIE: Thyroperoxidase, Inhibition: The present MIE, an inhibition peroxidase (TPO) function led to a perturbation in the expression of key genes in thyroid hormone synthesis and release pathways. Specifically as the TPO inhibited by MMI and PTU was reflected in the several thyroid hormone synthesis and release pathway genes (Alison et al., 2012).
- KE 1: Thyroid hormone synthesis, Decrease: A lot of studies have a correlation between TPO activition leading to decrease of thyroid hormone. Many studies was exposed that TPO inhibition lead to a decreased or inactivate of thyroid hormones levels (Shaoying et al., 2011; Antonio et al., 2006; Tonacchera et al., 2004; De Groef et al., 2006; Waltz wt al., 2010).
Considerations for Potential Applications of the AOP (optional)
Alison E.M. Vickers, Jason Heale, John R. Sinclair, Stephen Morris, Josh M. Rowe, Robyn L. Fisher. 2012. Thyroid organotypic rat and human cultures used to investigate drug effects on thyroid function, hormone synthesis and release pathways. Toxicology and Applied Pharmacology, volume 260, Issue 1, PP. 81-88.
B. Jomaa, S.A.B. Hermsen, M.Y. Kessels, J.H.J. Van Den Berg, A.A.C.M. Peijnenburg, J.M.M.J.G. Aarts, A.H. Piersma, I.M.C.M. Rietjens. 2014. Developmental toxicity of thyroid-active compounds in a zebrafish embryotoxicity test. ALTEX 31, pp. 303-317.
De Groeg B, Decallonne BR, Van der Geyten S, Darras VM, Bouillon R. 2006. Perchlorate versus other environmental sodium/iodide symporter inhibitors: potential thyroid-related health effects. Europ J Endocr. 155:17-25.
Dietrich, J.W., Landgrafe, G. and Fotiadou, E.H. 2012. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis. J Thyroid Res 2012, 351864.
E. Bagci, M. Heijlen, L. Vergauwen, A. Hagenaars, A.M. Houbrechts, C.V. Esguerra, R. Blust, V.M. Darras, D. Knapen. 2015. Deiodinase knockdown during early zebrafish development affects growth, development, energy metabolism, motility and phototransduction. PLoS One, p. e0123285.
Hadley, M.J.N.J. 1984. Endocrinology Prentice-Hall.
Jiang, J.Y., Umezu, M. and Sato, E. 2000. Improvement of follicular development rather than gonadotrophin secretion by thyroxine treatment in infertile immature hypothyroid rdw rats.
J Reprod Fertil 119, 193-199.
Kress, E., Samarut, J. and Plateroti, M. 2009. Thyroid hormones and the control of cell proliferation or cell differentiation: paradox or duality? Mol Cell Endocrinol 313, 36-49.
Medenica, S., Nedeljkovic, O., Radojevic, N., Stojkovic, M., Trbojevic, B. and Pajovic, B. 2015. Thyroid dysfunction and thyroid autoimmunity in euthyroid women in achieving fertility.
Eur Rev Med Pharmacol Sci 19, 977-987.
M. Heijlen, A.M. Houbrechts, E. Bagci, S.L.J. Van Herck, S. Kersseboom, C.V. Esguerra, R. Blust, T.J. Visser, D. Knapen, V.M. Darras. 2014. Knockdown of type 3 iodothyronine deiodinase severely perturbs both embryonic and early larval development in zebrafish. Endocrinology 155, pp. 1547-1559.
Mullur, R., Liu, Y.Y. and Brent, G.A. 2014. Thyroid hormone regulation of metabolism. Physiol Rev 94, 355-382.
Quesada-Garcia, A., Valdehita, A., Kropf, C., Casanova-Nakayama, A., Segner, H. and Navas, J.M. 2014. Thyroid signaling in immune organs and cells of the teleost fish rainbow trout (Oncorhynchus mykiss). Fish Shellfish Immunol 38, 166-174.
Ramprasad, M., Bhattacharyya, S.S. and Bhattacharyya, A. 2012. Thyroid disorders in pregnancy. Indian J Endocrinol Metab 16, S167-170.
Schreiber, G. and Richardson, S.J. 1997. The evolution of gene expression, structure and function of transthyretin. Comp Biochem Physiol B Biochem Mol Biol 116, 137-160.
Sharma, P. and Patino, R. 2013. Regulation of gonadal sex ratios and pubertal development by the thyroid endocrine system in zebrafish (Danio rerio). Gen Comp Endocrinol 184, 111-119.
Sharma, P., Tang, S., Mayer, G.D. and Patino, R. 2016. Effects of thyroid endocrine manipulation onsex-related gene expression and population sex ratios in Zebrafish. Gen Comp Endocrinol 235, 38-47.
Simonides, W.S. and van Hardeveld, C. 2008. Thyroid hormone as a determinant of metabolic and contractile phenotype of skeletal muscle. Thyroid 18, 205-216.
Thompson, C.C. and Potter, G.B. 2000. Thyroid hormone action in neural development. Cereb Cortex 10, 939-945.
Tonacchera M, Pinchera A, Dimida A, Ferrarini E, Agretti P, Vitti P, Santini F, Crump K, Gibbs J. 2004. Relative potencies and additivity or perchlorate, thiocyanate, nitrate, and iodide on the inhibition of radioative iodide uptake by the human sodium iodide symporter. Thyroid. 14: 1012-1019.
van der Ven, L.T., van den Brandhof, E.J., Vos, J.H., Power, D.M. and Wester, P.W. 2006. Effects of the antithyroid agent propylthiouracil in a partial life cycle assay with zebrafish. Environ Sci Technol 40, 74-81.
Waltz F, Pillette L, Ambroise Y. 2010. A nonradioactive iodide uptake assay for sodium iodide symporter function. Anal Biochem. 396:91-95.