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Thyroid peroxidase (TPO) inhibition leads to periventricular heterotopia formation in the developing rat brain
Point of Contact
- Katherine (Katie) O'Shaughnessy
- Mary Gilbert
|Handbook Version||OECD status||OECD project|
This AOP was last modified on April 29, 2023 16:03
Revision dates for related pages
|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|
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
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|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)
Life Stage Applicability
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Known Modulating Factors
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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