Aop: 271

AOP Title


Inhibition of thyroid peroxidase leading to impaired fertility in fish

Short name:


TPO inhibition and impaired fertility

Graphical Representation


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  • June-Woo Park, Korea Institute of Toxicology JRC-APT (Joint Research Center for Alternative and Predictive Toxicology)
  • Carlie LaLone, US EPA
  • Young Jun Kim, Environmental Safety Group, KIST Europe, JRC-APT 

Point of Contact


June-Woo Park   (email 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 Do not cite

This AOP was last modified on July 14, 2020 03:20


Revision dates for related pages

Page Revision Date/Time
Thyroperoxidase, Inhibition August 07, 2018 15:09
Thyroid hormone synthesis, Decreased August 11, 2018 13:21
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
Thyroperoxidase, Inhibition leads to TH synthesis, Decreased August 11, 2018 19:01
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.

Background (optional)


Disruption of the thyroid hormones (THs), thyroxine (T4) and triiodothyronine (T3) as play important roles in the regulation of many biological processes, such as development, growth, reproduction and metabolism in all vertebrates that can lead to adverse outcomes development (Hadley 1984; Schreiber and Richardson 1997). Commonly, the thyroid hormone is mainly controlled by the hypothalamic-pituitary-thyroid (HPT) axis, which regulates TH synthesis, secretion, transport and metabolism to maintain TH homeostasis (Dietrich et al. 2012). T4 is secreted by thyroid follicles under the stimulation of the thyroid-stimulating hormone (TSH) released by the pituitary. T3, the biologically active form of THs, is generated from T4 conversion by de-iodination.

Many studies have reported thyroid hormone disruptions and most studies assessing the deleterious effects of thyroid hormone disruption have focused on development, growth, metabolism, immune and reproduction (Quesada-Garcia et al. 2014; Sharma et al. 2016; van der Ven et al. 2006). In fish, other different effects during early development resulting from to disruption of the thyroid hormone endocrine system have been reported (e.g., pigmentation index, swim bladder inflation, hatching time, body and eye size, somite formation, heartbeat, tail and pericardial oedema, escape response and photoreceptor development) (Bagci et al., 2015, Heijlen et al., 2014, Jomaa et al., 2014). Previous studies have shown that thyroid disease is the second common endocrine disorder in women of childbearing age, and THs are vital for normal reproductive function (Medenica et al. 2015; Ramprasad et al. 2012). Also, THs hormones play a factors critical role in the ovarian function (Jiang et al. 2000). It is known the THs, T3 and T4 are involved in various biological processes, energy metabolism, including growth, cellular differentiation, maturation and embryonic development (Kress et al. 2009; Mullur et al. 2014; Simonides and van Hardeveld 2008; Thompson and Potter 2000).

As an increasing number of studies has shown that THs exert an important role in reproduction of vertebrates, there exists studies that they influence the reproduction system of fish. Fish with thyroid hormone disruption showed alteration of fertility and sex-related gene expression, delay in sex differentiation and imbalance sex ratio (specific gender-biased population) (Sharma and Patino 2013; Sharma et al. 2016; van der Ven et al. 2006). Although there is many study on thyroid hormone disruption influence on reproduction in fish, little information is available on the mechanisms by which this happens.


Summary of the AOP


Events: 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 219 Reduction, Plasma 17beta-estradiol concentrations Reduction, Plasma 17beta-estradiol concentrations
KE 221 Reduction, Plasma vitellogenin concentrations Reduction, Plasma vitellogenin concentrations
AO 78 Reduction, Cumulative fecundity and spawning Reduction, Cumulative fecundity and spawning

Relationships Between Two Key Events
(Including MIEs and AOs)


Title Adjacency Evidence Quantitative Understanding
Thyroperoxidase, Inhibition leads to TH synthesis, Decreased adjacent
TH synthesis, Decreased leads to Reduction, Plasma 17beta-estradiol concentrations adjacent
Reduction, Plasma 17beta-estradiol concentrations leads to Reduction, Plasma vitellogenin concentrations adjacent
Reduction, Plasma vitellogenin concentrations leads to Reduction, Cumulative fecundity and spawning adjacent

Network View





Life Stage Applicability


Life stage Evidence
Adult, reproductively mature High

Taxonomic Applicability


Term Scientific Term Evidence Link
fish fish High NCBI

Sex Applicability


Sex Evidence
Female High

Overall Assessment of the AOP


Domain of Applicability


Essentiality of the Key Events


Evidence Assessment


Quantitative Understanding


Considerations for Potential Applications of the AOP (optional)




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.

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.

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.