Aop: 402


A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Thyroid peroxidase (TPO) inhibition leads to periventricular heterotopia formation in the developing rat brain

Short name
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TPO inhibition, thyroid, heterotopia, developmental neurotoxicity

Graphical Representation

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The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Katherine O’Shaughnessy1,

Mary Gilbert1,

1United States Environmental Protection Agency, Center for Public Health and Environmental Assessment, Public Health and Integrated Toxicology Division, Research Triangle Park, NC 27711

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Katherine (Katie) O'Shaughnessy   (email point of contact)


Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Katherine (Katie) O'Shaughnessy
  • Mary Gilbert


Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite
This AOP was last modified on August 03, 2021 10:40

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A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

This putative adverse outcome pathway (AOP) describes the relationship between inhibition of the enzyme thyroid peroxidase (TPO) and periventricular heterotopia formation in the developing rat brain. Periventricular heterotopia is characterized as ectopic neurons that collect near the lateral ventricles of the posterior forebrain, and is a neurodevelopmental defect that can be found in humans and other animals. Previous peer-reviewed work has shown that pregnant and lactating rats exposed to a thyroid peroxidase (TPO) inhibitor have reduced serum thyroid hormone concentrations, and their offspring later exhibit a permanent periventricular heterotopia. Additionally, functional studies have shown these affected offspring display an increased seizure incidence, and epilepsy is closely correlated to heterotopia in patients. This AOP describes how TPO inhibition during development leads to periventricular heterotopia and seizures in the rat. Data contributing to this AOP is mainly derived from experimental data, including dose response studies utilizing the pharmaceutical 6-propylthiouracil (PTU), a TPO inhibiting chemical.

AOP Development Strategy


Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help


Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

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Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Taxonomic Applicability

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Sex Applicability

The sex for which the AOP is known to be applicable. More help

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Currently, there are quantitative models and/or extrapolations for the early KERs from TPO inhibition to serum thyroid hormone concentrations during mammalian development (Hassan et al., 2017), but few for the later KERs (Hassan et al., 2017;  O'Shaughnessy et al. 2018a). Importantly, there are no studies that describe how serum thyroid hormone concentrations during the perinatal period in rats (postnatal day 0 (PN0) to PN6) relates to heterotopia formation. This is an important data gap as thyroid hormone reductions in rat pups during the perinatal period is both sufficient and necessary to induce this adverse outcome (O'Shaughnessy et al. 2019). For the rest of the KERs in this AOP, there is a varying amount of data from dose-response studies that demonstrate increasing impact with increasing chemical dose for all the KEs, and the direct and indirect KERs (O'Shaughnessy et al., 2018b). At present, the overall quantitative understanding of the AOP is insufficient to directly predict what degree of serum thyroxine (T4) reduction in rat pups would result in periventricular heterotopia formation without further study.

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help


List of the literature that was cited for this AOP. More help

Akhlaghi, A., Zamiri, M. J., Zare Shahneh, A., Jafari Ahangari, Y., Nejati Javaremi, A., Rahimi Mianji, G., Mollasalehi, M. R., Shojaie, H., Akhlaghi, A. A., Deldar, H., et al. (2012). Maternal hyperthyroidism is associated with a decreased incidence of cold-induced ascites in broiler chickens. Poultry science 91(5), 1165-72.

Andersen, S. L., Andersen, S., Liew, Z., Vestergaard, P., and Olsen, J. (2018). Maternal Thyroid Function in Early Pregnancy and Neuropsychological Performance of the Child at 5 Years of Age. The Journal of clinical endocrinology and metabolism 103(2), 660-670.

Berbel, P., Navarro, D., Auso, E., Varea, E., Rodriguez, A. E., Ballesta, J. J., Salinas, M., Flores, E., Faura, C. C., and de Escobar, G. M. (2010). Role of late maternal thyroid hormones in cerebral cortex development: an experimental model for human prematurity. Cerebral cortex 20(6), 1462-75.

Chang, K., and Shin, J. I. (2014). Association of gestational maternal hypothyroxinemia and increased autism risk: the role of brain-derived neurotrophic factor. Annals of neurology 75(6), 971.

Dainat, J., Saleh, L., Bressot, C., Marger, L., Bacou, F., and Vigneron, P. (1991). Effects of thyroid state alterations in ovo on the plasma levels of thyroid hormones and on the populations of fibers in the plantaris muscle of male and female chickens. Reprod Nutr Dev 31(6), 703-16.

Dobbing, J., and Sands, J. (1979). Comparative aspects of the brain growth spurt. Early human development 3(1), 79-83.

Gilbert, M. E., Goodman, J. H., Gomez, J., Johnstone, A. F., and Ramos, R. L. (2016a). Adult hippocampal neurogenesis is impaired by transient and moderate developmental thyroid hormone disruption. Neurotoxicology 59, 9-21.

Gilbert, M. E., Sanchez-Huerta, K., and Wood, C. (2016b). Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. Endocrinology 157(2), 774-87.

Gilbert, M. E., and Sui, L. (2006). Dose-dependent reductions in spatial learning and synaptic function in the dentate gyrus of adult rats following developmental thyroid hormone insufficiency. Brain research 1069(1), 10-22.

Hassan, I., El-Masri, H., Kosian, P. A., Ford, J., Degitz, S. J., and Gilbert, M. E. (2017). Neurodevelopment and Thyroid Hormone Synthesis Inhibition in the Rat: Quantitative Understanding Within the Adverse Outcome Pathway Framework. Toxicological sciences : an official journal of the Society of Toxicology 160(1), 57-73.

Hornung, M. W., Kosian, P. A., Haselman, J. T., Korte, J. J., Challis, K., Macherla, C., Nevalainen, E., and Degitz, S. J. (2015). In Vitro, Ex Vivo, and In Vivo Determination of Thyroid Hormone Modulating Activity of Benzothiazoles. Toxicological sciences : an official journal of the Society of Toxicology 146(2), 254-64.

Lavado-Autric, R., Auso, E., Garcia-Velasco, J. V., Arufe Mdel, C., Escobar del Rey, F., Berbel, P., and Morreale de Escobar, G. (2003). Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. The Journal of clinical investigation 111(7), 1073-82.

Martinez-Galan, J. R., Escobar del Rey, F., Morreale de Escobar, G., Santacana, M., and Ruiz-Marcos, A. (2004). Hypothyroidism alters the development of radial glial cells in the term fetal and postnatal neocortex of the rat. Brain research. Developmental brain research 153(1), 109-14.

Martinez-Galan, J. R., Pedraza, P., Santacana, M., Escobar del Ray, F., Morreale de Escobar, G., and Ruiz-Marcos, A. (1997). Early effects of iodine deficiency on radial glial cells of the hippocampus of the rat fetus. A model of neurological cretinism. The Journal of clinical investigation 99(11), 2701-9.

Matsumoto, N., Hoshiba, Y., Morita, K., Uda, N., Hirota, M., Minamikawa, M., Ebisu, H., Shinmyo, Y., and Kawasaki, H. (2017). Pathophysiological analyses of periventricular nodular heterotopia using gyrencephalic mammals. Human molecular genetics 26(6), 1173-1181.

Morreale de Escobar, G., and Escobar del Rey, F. (1999). Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. The New England journal of medicine 341(26), 2015-6; author reply 2017.

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., et al. (2016). Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part I: Fathead minnow. Aquat Toxicol 173, 192-203.

O'Shaughnessy, K. L., Kosian, P. A., Ford, J. L., Oshiro, W. M., Degitz, S. J., and Gilbert, M. E. (2018a). Developmental Thyroid Hormone Insufficiency Induces a Cortical Brain Malformation and Learning Impairments: A Cross-Fostering Study. Toxicological sciences : an official journal of the Society of Toxicology 163(1), 101-115.

O'Shaughnessy, K. L., Thomas, S. E., Spring, S. R., Ford, J. L., Ford, R. L., and Gilbert, M. E. (2019). A transient window of hypothyroidism alters neural progenitor cells and results in abnormal brain development. Sci Rep 9(1), 4662.

O'Shaughnessy, K. L., Wood, C., Ford, R. L., Kosian, P. A., Hotchkiss, M. G., Degitz, S. J., and Gilbert, M. E. (2018b). Thyroid hormone disruption in the fetal and neonatal rat: Predictive hormone measures and bioindicators of hormone action in the developing cortex. Toxicological sciences : an official journal of the Society of Toxicology doi: 10.1093/toxsci/kfy190.

Pathak, A., Sinha, R. A., Mohan, V., Mitra, K., and Godbole, M. M. (2011). Maternal thyroid hormone before the onset of fetal thyroid function regulates reelin and downstream signaling cascade affecting neocortical neuronal migration. Cerebral cortex 21(1), 11-21.

Paul, K. B., Hedge, J. M., Rotroff, D. M., Hornung, M. W., Crofton, K. M., and Simmons, S. O. (2014). Development of a thyroperoxidase inhibition assay for high-throughput screening. Chemical research in toxicology 27(3), 387-99.

Phoenix, T. N., and Temple, S. (2010). Spred1, a negative regulator of Ras-MAPK-ERK, is enriched in CNS germinal zones, dampens NSC proliferation, and maintains ventricular zone structure. Genes & development 24(1), 45-56.

Rami, A., and Rabie, A. (1988). Effect of thyroid deficiency on the development of glia in the hippocampal formation of the rat: an immunocytochemical study. Glia 1(5), 337-45.

Salas-Lucia, F., Pacheco-Torres, J., Gonzalez-Granero, S., Garcia-Verdugo, J. M., and Berbel, P. (2020). Transient Hypothyroidism During Lactation Alters the Development of the Corpus Callosum in Rats. An in vivo Magnetic Resonance Image and Electron Microscopy Study. Front Neuroanat 14, 33.

Samadi, A., Skocic, J., and Rovet, J. F. (2015). Children born to women treated for hypothyroidism during pregnancy show abnormal corpus callosum development. Thyroid : official journal of the American Thyroid Association 25(5), 494-502.

Santi, M. R., and Golden, J. A. (2001). Periventricular heterotopia may result from radial glial fiber disruption. Journal of neuropathology and experimental neurology 60(9), 856-62.

Schmid, M. T., Weinandy, F., Wilsch-Brauninger, M., Huttner, W. B., Cappello, S., and Gotz, M. (2014). The role of alpha-E-catenin in cerebral cortex development: radial glia specific effect on neuronal migration. Frontiers in cellular neuroscience 8, 215.

Spann, M. N., Cheslack-Postava, K., and Brown, A. S. (2019). The association of serologically documented maternal thyroid conditions during pregnancy with bipolar disorder in offspring. Bipolar disorders doi: 10.1111/bdi.12879.

Stinckens, E., Vergauwen, L., Schroeder, A. L., Maho, W., Blackwell, B. R., Witters, H., Blust, R., Ankley, G. T., Covaci, A., Villeneuve, D. L., et al. (2016). Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part II: Zebrafish. Aquat Toxicol 173, 204-217.

Thienpont, B., Barata, C., and Raldua, D. (2013). Modeling mixtures of thyroid gland function disruptors in a vertebrate alternative model, the zebrafish eleutheroembryo. Toxicology and applied pharmacology 269(2), 169-75.

Tietge, J. E., Butterworth, B. C., Haselman, J. T., Holcombe, G. W., Hornung, M. W., Korte, J. J., Kosian, P. A., Wolfe, M., and Degitz, S. J. (2010). Early temporal effects of three thyroid hormone synthesis inhibitors in Xenopus laevis. Aquat Toxicol 98(1), 44-50.

West, J. R. (1987). Fetal alcohol-induced brain damage and the problem of determining temporal vulnerability: a review. Alcohol Drug Res 7(5-6), 423-41.

Williams, F., Watson, J., Ogston, S., Hume, R., Willatts, P., Visser, T., and Scottish Preterm Thyroid, G. (2012). Mild maternal thyroid dysfunction at delivery of infants born </=34 weeks and neurodevelopmental outcome at 5.5 years. The Journal of clinical endocrinology and metabolism 97(6), 1977-85.

Yamamoto, H., Mandai, K., Konno, D., Maruo, T., Matsuzaki, F., and Takai, Y. (2015). Impairment of radial glial scaffold-dependent neuronal migration and formation of double cortex by genetic ablation of afadin. Brain research 1620, 139-52.