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AOP: 402

Title

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
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
TPO inhibition, thyroid, heterotopia, developmental neurotoxicity
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.0

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

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Katherine O’Shaughnessy1, oshaughnessy.katie@epa.gov

Mary Gilbert1, gilbert.mary@epa.gov

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)

Contributors

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  • Katherine (Katie) O'Shaughnessy
  • Mary Gilbert

Coaches

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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on April 29, 2023 16:03

Revision dates for related pages

Page Revision Date/Time
Thyroperoxidase, Inhibition November 04, 2022 09:24
Thyroid hormone synthesis, Decreased November 04, 2022 09:25
Decrease, Serum thyroid hormone (T4/T3) September 16, 2017 10:16
Brain thyroid hormone (T4/T3) decreased January 19, 2023 20:08
Altered, Thyroid hormone-dependent gene expression December 09, 2020 14:22
Abnormal, neuroblast migration January 19, 2023 20:10
Periventricular heterotopia formation January 19, 2023 20:13
Increase, seizure April 14, 2017 14:59

Abstract

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

Context

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Strategy

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Summary of the AOP

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Events:

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
Type Event ID Title Short name
MIE 279 Thyroperoxidase, Inhibition Thyroperoxidase, Inhibition
KE 277 Thyroid hormone synthesis, Decreased TH synthesis, Decreased
KE 771 Decrease, Serum thyroid hormone (T4/T3) Decrease, Serum thyroid hormone (T4/T3)
KE 2093 Brain thyroid hormone (T4/T3) decreased Decreased brain T4/T3
KE 1829 Altered, Thyroid hormone-dependent gene expression Altered, TH-dependent gene expression
KE 2094 Abnormal, neuroblast migration Abnormal cell migration in brain
AO 2095 Periventricular heterotopia formation Heterotopia formation
AO 1348 Increase, seizure Increase, seizure

Relationships Between Two Key Events (Including MIEs and AOs)

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Network View

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Prototypical Stressors

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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

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Sex Evidence
Mixed High

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

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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

References

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.