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T4 in serum, Decreased 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||non-adjacent||High||Low||Kevin Crofton (send email)||Open for citation & comment||WPHA/WNT Endorsed|
Life Stage Applicability
|During brain development||High|
Key Event Relationship Description
The vast majority of brain thyroxine (T4) is from the serum. Once taken up from the serum, T4 is converted to triiodothyronine (T3) which binds to the nuclear receptors (TRα and TRβ) to control thyroid-mediated gene expression (Oppenheimer, 1983). It is well established that TH regulates genes critical for brain development (Bernal, 2007; Anderson et al., 2003). As such, the structural development of the hippocampus is modulated by TR-mediated gene transcription, and alterations in serum TH can adversely impact hippocampal neuroanatomy.
Evidence Supporting this KER
The weight of evidence for this indirect relationship is strong. There is a vast amount of literature that supports this KER in multiple species.
The biological plausibility of this KER is rated as strong. The relationship is consistent with the known biology of the regulation of serum TH concentrations, brain TH concentrations, and the known action of TH to modulate genes critical for developmental processes that control structural development of the brain in general, including the hippocampus.
Uncertainties and Inconsistencies
This has been repeatedly demonstrated. However, with some studies noted above, most investigations have been conducted in the neonate after severe hormone reductions induced by PTU, MMI or thyroidectomy. These severe changes alter a wide variety of general growth and developmental processes. In one of the few dose-response studies assessing hippocampal anatomy, alterations in simple guidenline metrics of linear morphometry and volume of hippocampal subfields following developmental exposure to the PTU were largely restricted to the high dose group, despite alterations in downstream KEs of hippocampal physiology and cognitive function. This may result from inadequacy of the assessment tools or the timing of the observations. Similarly, in chemically induced serum hormone reductions of comparable magnitude as those induced by PTU or MMI, observations of hippocampal morphology are not always seen (PTU vs ETU or mancozeb, European Commission, 2017). Consideration of the sensitivity of neuroanatomical and neurobehavioral method used, as well as chemical kinetics that drive the reduction of maternal, fetal, or neonatal TH reduction, may be key to understanding these discrepancies. More data is needed that link more limited decrements in serum TH to specific hippocampal anatomical changes. The role of direct fetal TPO inhibition contribution to fetal TH and subsequent changes to hippocampal structure and subsequent downstream KEs in humans is a knowledge gap.
Most investigations for hippocampal anatomy have been conducted in the neonate after severe hormone reductions. There is currently insufficient data for quantitative analysis of serum T4 and hippocampal neuroanatomy.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Most of the available data has come from rodent models. Human clinincal studies have documented changes in hippocampal volume in children with congenital hypothyroidism (Wheeler et al., 2011).
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