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Relationship: 366

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Thyroperoxidase, Inhibition leads to T4 in serum, Decreased

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Thyroperoxidase, Inhibition

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

T4 in serum, Decreased

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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	Evgeniia Kazymova (send email)	Open for citation & comment	WPHA/WNT Endorsed
Thyroperoxidase inhibition leading to increased mortality via reduced anterior swim bladder inflation	non-adjacent	High	Low	Evgeniia Kazymova (send email)	Under Development: Contributions and Comments Welcome	WPHA/WNT Endorsed
Thyroperoxidase inhibition leading to altered amphibian metamorphosis	non-adjacent	High	High	Brendan Ferreri-Hanberry (send email)	Under Development: Contributions and Comments Welcome
Thyroperoxidase inhibition leading to altered visual function via altered retinal layer structure	non-adjacent	High	Moderate	Allie Always (send email)	Open for citation & comment	EAGMST Under Review

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
Xenopus laevis	Xenopus laevis	High	NCBI
rat	Rattus norvegicus	High	NCBI
chicken	Gallus gallus	Moderate	NCBI
human	Homo sapiens	High	NCBI
zebrafish	Danio rerio	High	NCBI
fathead minnow	Pimephales promelas	Moderate	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Male	High
Female	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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 Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Map 2.0

ID	Experimental Design	Species	Upstream Observation	Downstream Observation	Citation (first author, year)	Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Title	First Author	Biological Plausibility	Dose Concordance	Temporal Concordance	Incidence Concordance

Biological Plausibility

Dose Concordance Evidence

Temporal Concordance Evidence

Incidence Concordance Evidence

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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 rats and humans is derived from a chemical's effect on the maternal thyroid gland as well as the fetal thyroid gland.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Hassan et al. (2017, 2020) and Handa et al. (2021) worked out a quantitative model to predict serum T4 levels based on TPO inhibition in rats.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

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 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 TH 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.

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Taxonomic: 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. Therefore, this KER is plausibly applicable across vertebrate species. Therefore, this KER is plausibly applicable across vertebrates.

Life stage: Applicability to certain life stages may depend on the species and their dependence on maternally transferred thyroid hormones during the earliest phases of development. The earliest life stages of teleost fish rely on maternally transferred THs to regulate certain developmental processes until embryonic TH synthesis is active (Power et al., 2001). As a result, TPO inhibition is not expected to decrease TH synthesis during these earliest stages of development. In zebrafish, Opitz et al. (2011) showed the formation of a first thyroid follicle at 55 hours post fertilization (hpf), Chang et al. (2012) showed a first significant TH increase at 120 hpf and Walter et al. (2019) showed clear TH production already at 72 hpf but did not analyse time points between 24 and 72 hpf. In fathead minnows, a significant increase of whole body TH levels was already observed between 1 and 2 dpf, which corresponds to the appearance of the thyroid anlage at 35 hpf prior to the first observation of thyroid follicles at 58 hpf (Wabuke-Bunoti and Firling, 1983). Therefore, iIt is still uncertain when exactly embryonic TH synthesis is activated and how this determines sensitivity to TH system disruptors.

Sex: The KE is plausibly applicable to both sexes. THs are essential in both sexes and the components of the HPT-axis are identical in both sexes. There can however be sex-dependent differences in the sensitivity to the disruption of TH levels and the magnitude of the response. In humans, females appear more susceptible to hypothyroidism compared to males when exposed to certain halogenated chemicals (Hernandez‐Mariano et al., 2017; Webster et al., 2014). In adult zebrafish, Liu et al. (2019) showed sex-dependent changes in TH levels and mRNA expression of regulatory genes including corticotropin releasing hormone (crh), thyroid stimulating hormone (tsh) and deiodinase 2 after exposure to organophosphate flame retardants. The underlying mechanism of any sex-related differences remains unclear.