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Aop: 402

Title

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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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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

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Allie Always   (email point of contact)

Contributors

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  • Katherine (Katie) O'Shaughnessy
  • Mary Gilbert
  • Allie Always

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite
This AOP was last modified on July 16, 2022 18:37

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Abstract

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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)
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Key Events (KE)
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Adverse Outcomes (AO)
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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

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Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Known Modulating Factors

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Quantitative Understanding

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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)

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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.

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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.

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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.