Upstream eventT4 in serum, Decreased
Decreased, Thyroxine (T4) in tissues
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Thyroperoxidase inhibition leading to altered amphibian metamorphosis||adjacent||Moderate||Low|
|Xenopus laevis||Xenopus laevis||Moderate||NCBI|
Life Stage Applicability
Key Event Relationship Description
Thyroxine (T4) uptake from serum into tissues plays a substantial role in thyroid hormone action, as it can then be available for enzymatic conversion to the active hormone, triiodothyronine (T3). Uptake of T4 into cells/tissues is mediated by active transport proteins that exhibit unique expression profiles depending on tissue type and timing of development (Hennemann et al., 2001; Visser et al., 2011, 2007; Connors et al., 2010; Friesema et al., 2005). Specific regulation of transporter profiles plays a role in timing of thyroid hormone uptake into specific tissues for proper sequencing of development and protection against metabolism and clearance of thyroid hormone during critical developmental periods. Although several different classes of proteins have been identified as capable of transporting T4 (and T3) across plasma membranes, three proteins in particular have been shown to have high affinity and specificity toward thyroid hormone; namely, MCT8, MCT10 and OATP1c1 (Friesema et al., 2003, 2008; Pizzagalli et al., 2002; Jansen et al., 2007; Mayer et al., 2014). These transport proteins have primarily been studied in relation to mammalian brain development, so the details of their role in other species and tissues during vertebrate development are not well-understood.
Evidence Supporting this KER
The evidence supporting this KER is strong but is primarily weighted toward biochemical associations and thyroid endocrinology dogma. Specifically, much of the weight of evidence is centered around what is known about active and selective membrane transport of T4, ontogeny of deiodinase enzymes responsible for the localized metabolic activation/deactivation of T4 and tissue/organ pathologies and gene expression responses associated with hyper and hypothyroid conditions.
Thyroid hormone uptake from plasma into tissues is mediated by a number of active transport proteins exhibiting unique profiles depending on tissue type and timing of development (Hennemann et al., 2001; Visser et al., 2011; Connors et al., 2010). The scientific literature suggests that specific regulation of transporter profiles plays a role in timing of thyroid hormone uptake into specific tissues. However, when thyroid hormone levels in the plasma are deficient, it is highly plausible that tissue levels of thyroid hormone will also be deficient. Studies have shown a strong relationship between plasma and tissue thyroid hormone concentrations, but emphasize the complexity of the relationship due to presumptive local regulation of both active transport and subsequent biochemical modification of thyroid hormone within cells by deiodinase enzymes.
Decreases in tissue T4 could plausibly occur in several ways individually or in combination, (1) circulating levels of T4 decrease to critical levels that even compensatory increases in active transport cannot overcome, (2) TH-specific transporters are non-functional either due to mutation, inhibited by a xenobiotic or their transcriptional expression is repressed, (3) enhanced T4 catabolism by type III deiodinase in peripheral tissues or by phase II metabolic enzymes in the liver.
Thyroid hormone signaling has been studied for decades and is described in great detail in textbooks and review articles...