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T4 in serum, Decreased leads to Hippocampal gene expression, 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||TFHA/WNT Endorsed|
Life Stage Applicability
|During brain development||High|
Key Event Relationship Description
Many of the physiological effects of thyroid hormones (THs) are mediated through regulation of gene expression by zinc finger nuclear receptor proteins that are encoded by thyroid hormone genes alpha (Thra) and beta (Thrb). It is widely accepted that TH regulates gene transcription during brain development (Bernal, 2007; Anderson et al., 2003). The sole source of TH to the brain is from the circulating levels of the prohormone, thyroxine (T4). Once taken up from the serum to reach the brain, T4 is converted to triiodothyronine (T3) which binds to TH nuclear receptors (TRα and TRβ). On binding, and in the presence of regulatory cofactors, transcription of certain genes is either up- or down-regulated (Oppenheimer, 1983). However, only a small number of genes have been shown to be directly influenced by TH receptor binding, and of these, most are transcription factors (Quignodon et al., 2008; Thompson and Potter, 2000; Horn and Heuer, 2010). In this manner, THs do influence a wide variety of genes.
Evidence Supporting this KER
The weight of evidence for this indirect relationship is strong. It is well established that serum TH is the primary source of brain T4 from which neuronal T3, the active hormone, is locally generated and presented to the receptors in the nucleus of neurons to control gene transcription.
The biological plausibility of this KER is rated as strong. This is consistent with the known biology of the relationship between serum TH concentrations and brain TH concentrations, and the known action of TH to mediate gene transcription in brain and many other tissues.
Uncertainties and Inconsistencies
There are no inconsistencies in this KER, but there are some uncertainties. It is widely accepted that changes in serum THs will result in alterations in hippocampal gene expression. Several different animal models have been used to manipulate serum TH concentrations that also measure gene expression changes. Varying windows of exposure to TH disruption and developmental sample time and region examined have also varied across studies. However, dose-response data is lacking. Most investigations of hippocampal gene expression have employed treatments that induce severe hormone reductions induced by PTU or MMI, or by thyroidectomy. In addition, few reports have studied the genes in the hippocampus, the cortex being more accessible in young animals. Finally, when the hippocampus is the target, different genes at different ages are reported, making it difficult to compare findings.
There are no quantitative models that predict the degree of serum TH reduction that is required to alter hippocampal gene transcription. Most investigations for hippocampus have been conducted in the neonate after severe hormone reductions. Only four publications have reported dose-dependent effects on gene expression in at less than maximal hormone depletion (Bastian et al., 2012; 2014; O'Shaughnessy et al., 2018; Royland et al., 2008). O'Shaughnessy et al (2018) demostrates dose-response relationships between cortical T4 and T3 concentrations and changes in a variety of neocortical genes (e.g., Parv, Col11a2, Hr, Ngf) that were "statistically significant at doses that decreased brain t4 and/or T3". There was no quantitation of this relationship reported.
In addition, there is very little known about whether compensatory processes are available in the developing hippocampus that may modulate the impact of serum levels on hippocampal gene transcription. These available data suggest that a 40-50% decrement in serum T4 in the pup, is sufficient to observe changes in hippocampal gene expression. This is similar to finding for loss of hearing function in rats following postnatal chemical-induced hypothyroxinemia (Crofton, 2004).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Most of the data available has come from rodent models.
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