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Thyroperoxidase, Inhibition leads to T4 in serum, Decreased
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||Moderate||Kevin Crofton (send email)||Open for citation & comment||TFHA/WNT Endorsed|
|Thyroperoxidase inhibition leading to increased mortality via reduced anterior swim bladder inflation||non-adjacent||High||Low||Dries Knapen (send email)||Open for adoption||EAGMST Under Review|
|Thyroperoxidase inhibition leading to altered amphibian metamorphosis||non-adjacent||High||High||Jonathan Haselman (send email)||Under Development: Contributions and Comments Welcome|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Thyroperoxidase (TPO) is the enzyme that catalyzes iodine organification of thyroglobulin to produce thyroglobulin (Tg)-bound T3 and T4 in the lumen of thyroid follicles. Tg-bound THs are endocytosed across the apical lumen-follicular cell membrane, undergo thyroglobulin proteolysis, followed by hormone section into the blood stream (see Taurog, 2005 for review). This indirect KER describes the relationship of TPO inhibition to reduced circulating levels of thyroid hormone (TH) in the serum.
Evidence Supporting this KER
The weight of evidence linking thyroperoxidase inhibition to reductions in circulating serum TH is strong. Many studies support this basic linkage. There is no inconsistent data.
It is a well-accepted fact that inhibition of the only enzyme capable of synthesizing THs, TPO, results in subsequent decrease in serum TH concentrations. A large amount of evidence from clinical and animal studies clearly support the commonly accepted dogma that inhibition of TPO leads to decreased serum THs.
Uncertainties and Inconsistencies
There are no inconsistencies in this KER, but there are some uncertainties. The predominant uncertainty regarding the indirect key event relationship between inhibition of TPO activity and decreased serum T4 is the quantitative nature of this relationship, i.e., to what degree must TPO be inhibited in order to decrease serum T4 by a certain magnitude. Many animal (rat) studies typically employ relatively high exposures of TPO-inhibiting chemicals that result in hypothyroidism (severe decrements in T4 and T3). Thus, a dose-response relationship between TPO inhibition and decreased serum T4 is not typically defined. However, there are numerous publications demonstrating clear dose- and duration- dependent relationships between TPO inhibitors dose and reduced serum T3 and T4 in rodent models (see for example: Cooper et al., 1983; Hood et al., 1999; Goldey et al., 2005; Gilbert, 2011). The relationship between maternal and fetal levels of hormone following chemically-induced TPO inhibiton has not been well characterized and may differ based on kinetics. Reductions in serum TH in the fetus, in rat and human is derived a chemical’s effect on the maternal thyroid gland as well as the fetal thyroid gland.
The indirect linkage between exposure to known TPO inhibitors and decreased serum TH has not been defined quantitatively. The two key event relationships that mediate this relationship (TPO inhibition leading to decreased TH synthesis, and decreased TH synthesis leading to decreased serum TH) have been incorporated into some quantitative models. A quantitative biologically-based dose-response model for iodine deficiency in the rat includes relationships between thyroidal T4 synthesis and serum T4 concentrations in developing rats Fisher et al. (2013). Ekerot et al. (2012) modeled TPO, T3, T4 and TSH in dogs and humans based on exposure to myeloperoxidase inhibitors that also inhibit TPO and was has recently adapted for rat (Leonard et al., 2016). While the original model predicted serum TH and TSH levels as a function of oral dose, it was not used to explicitly predict the relationship between serum hormones and TPO inhibition, or thyroidal hormone synthesis. Leonard et al. (2016) recently incorporated TPO inhibition into the model. Degon et al (2008) developed a human thyroid model that includes TPO but does not make quantitative prediction of organification changes due to inhibition of the TPO enzyme.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Use of TPO inhibitors as anti-hyperthyroidism drugs in humans and pets (Emiliano et al., 2010; Trepanier, 2006) and effects of these drugs on serum TH concentrations in rats (US EPA, 2005), amphibian, fish and avian species (Coady et al., 2010; Grommen et al., 2011; Nelson et al., 2016; Rosebrough et al., 2006; Stinckens et al.; 2020; Tietge et al., 2012), strongly supports a causative linkage between inhibition of TPO and decreased serum T4 across species.
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