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Hippocampal gene expression, Altered leads to Hippocampal anatomy, Altered
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals||adjacent||Moderate||Low||Kevin Crofton (send email)||Open for citation & comment||WPHA/WNT Endorsed|
|Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals||adjacent||Moderate||Low||Mary Gilbert (send email)||Under Development: Contributions and Comments Welcome|
|Thyroid Receptor Antagonism and Subsequent Adverse Neurodevelopmental Outcomes in Mammals||adjacent||Moderate||Low||Kevin Crofton (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Upregulation of Thyroid Hormone Catabolism via Activation of Hepatic Nuclear Receptors, and Subsequent Adverse Neurodevelopmental Outcomes in Mammals||adjacent||Katie Paul Friedman (send email)||Not under active development||Under Development|
Life Stage Applicability
|During brain development||Moderate|
Key Event Relationship Description
The basic biological processes that link gene regulation in the structural formation and function of all organs of the body are similar throughout the developing organism. In the developing brain, genes encode proteins critical for developmental events intrinsic to structural development (e.g., neurogenesis, neuronal migration, synaptogenesis, myelination). The development of the hippocampus is no exception to this general rule of biology.
Evidence Supporting this KER
The overall weight of evidence is moderate for a direct linkage between perturbation of the expression of genes in brain (and in hippocampus specifically) and neuroanatomical abnormalities. It is widely acknowledged that the development of the structure of the hippocampus is under the control of hippocampal gene expression. However, while an extensive body of literature exists linking some genes to hippocampal structure, there is no complete compendium on the total number of genes involved, nor direct causative links between the myriad of genes and the intricate development (both timing and location) of the majority of hippocampal structure.
The biological plausibility of this KER is rated as strong. It is well established that gene regulation controls brain development. This also applies to the development of the hippocampus, where nuclear thyroid receptors that regulate gene transcription, directly or indirectly via transcription factor regulation, to control translation.
Uncertainties and Inconsistencies
There are no inconsistencies in this KER, but there are some uncertainties. Few studies exist that report both gene expression changes and structural changes in the hippocampus in same study to provide direct causative evidence for this KER. Lacking also is the specific suite of genes that are altered in the hippocampus at particular developmental times that are causal to the structural defects reported. For future research, it is critical to generate data in which the upstream KE is modulated in a ‘dose-response’ manner to better support the causative relationship. Significant data gaps also exist for basic fetal hippocampal development.
There are no data on the quantitative linkages between gene expression changes and altered hippocampal anatomy.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The majority of data in support of this KER is from rodent models. The evolutionary conservation of thyroid receptors (Holzer et al., 2017) coupled with their role in TR regulated gene transcription in neurodevelopment, suggests that this KER may also be applicable to other species.
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