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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	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 Supporting this KER

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

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.

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

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.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

The majority of research in support of this KER involves exposure to known TPO inhibitors and measurement of serum hormones. There are many in vivo studies that link decreases in serum TH concentrations with exposure to xenobiotics that inhibit thyroperoxidase (TPO) in mammals (Brucker-Davis, 1998; Hurley, 1998; Boas et al., 2006; Crofton, 2008; Kohrle, 2008; Pearce and Braverman, 2009; Murk et al., 2013).

While these studies support the connection between exposure to a known TPO inhibitor and decreased TH, many of these studies do not empirically measure TPO inhibition or decreased TH synthesis. Thus, many studies support the indirect linkage between TPO inhibition (for chemicals identified as TPO inhibitors in in vivo or ex vivo studies) and decreased TH, with the well accepted theory that these proceed via decreased TH synthesis. That exposure to TPO inhibitors leads to decreased serum TH concentrations, via decreased TH synthesis is strongly supported by decades of mechanistic research in a variety of species.

This indirect relationship is also evidenced by the use of clinically-relevant anti-hyperthyroidism drugs, MMI and PTU (Laurberg & Anderson, 2014; Sundaresh et al., 2013). These drugs are both recognized TPO inhibitors and are part of a standard drug-based regimen of care for clinically hyperthyroid patients including those with Grave's disease. Serum THs are measured as the bioindicator of successful treatment with anti-hyperthyroidism drugs; the actual decrease in TH synthesis in the thyroid gland is implied in the efficacious use of these drugs (Trepanier, 2006).

In rats, MMI and PTU are often used as control chemicals to decrease serum THs to study biological phenomena related to disruption of TH homeostasis (many examples, including Zoeller and Crofton, 2005; Morreale de Escobar et al, 2004; Schwartz et al., 1997; Herwig et al., 2014; Wu et al., 2013; Pathak et al., 2011). Further, MMI is recommended as a positive control for use in the Amphibian Metamorphosis (Frog) Assay within Tier 1 of the U.S. EPA Endocrine Disruptor Screening Program (US EPA, 2009; Coady et al., 2010), an assay used to evaluate the potential for chemicals to disrupt TH homeostasis. PTU has been suggested as positive control chemical in the guidance for the Comparative Developmental Thyroid Assay (US EPA, 2005), a non-guideline assay used to evaluate the potential for chemicals to disrupt TH homeostasis during gestation and early neonatal development.

Additionally, evidence is available from studies investigating responses to TPO inhibitors in fish. For example, Stinckens et al. (2020) showed reduced whole body T4 concentrations in zebrafish larvae exposed to 50 or 100 mg/L methimazole, a potent TPO inhibitor, from immediately after fertilization until 21 or 32 days of age. Exposure to 37 or 111 mg/L propylthiouracil also reduced T4 levels after exposure up to 14, 21 and 32 days in the same study. Walter et al. (2019) showed that propylthiouracil had no effect on T4 levels in 24h old zebrafish, but decreased T4 levels of 72h old zebrafish. This difference is probably due to the onset of embryonic TH production between the age of 24 and 72 hours (Opitz et al., 2011). Stinckens et al. (2016) showed that exposure to 2-mercaptobenzothiazole (MBT), an environmentally relevant TPO inhibitor, decreased whole body T4 levels in continuously exposed 5 and 32 day old zebrafish larvae. A high concentration of MBT also decreased whole body T4 levels in 6 day old fathead minnows, but recovery was observed at the age of 21 days although the fish were kept in the exposure medium (Nelson et al., 2016). Crane et al. (2006) showed decreased T4 levels in 28 day old fathead minnows continuously exposed to 32 or 100 µg/L methimazole.

Thus, an indirect key event relationship between TPO inhibition and decreased serum THs is strongly supported by a large database of clinical medicine and investigative research with whole animals (with a great deal of supporting evidence in rats and frogs).

Temporal Evidence: In mammals, the temporal nature of this KER is applicable to all life stages, including development (Seed et al., 2005). The qualitative impact of TPO inhibition on serum hormones is similar across all ages in mammals. The temporal nature of the impact on serum THs by TPO inhibitors in developmental exposure studies is evidenced by the duration of exposure and developmental age (Goldey et al., 1995; Ahmed et al., 2010; Tietge et al., 2010), as well as recovery after cessation of exposure (Cooke et al., 1993; Goldey et al., 1995; Sawin et al., 1998; Axelstad et al., 2008; Shibutani et al., 2009; Lasley and Gilbert, 2011). The temporal relationship between TPO inhibitor exposure duration and serum hormone decreases in adult organisms has been widely demonstrated (e.g., Hood et al., 1999; Mannisto et al., 1979). In addition, MMI and PTU induced decreases in serum T4 are alleviated by TH replacement in both fetal and postnatal age rats (Calvo et al., 1990; Sack et al., 1995; Goldey and Crofton, 1998). Computational modeling of the thyroid also provides evidence for the indirect temporal relationship between these two KEs (e.g., Degon et al., 2008; Fisher et a., 2013).

In oviparous fish such as zebrafish and fathead minnow, the nature of this KER depends on the life stage since the earliest stages of embryonic development rely on maternal thyroid hormones transferred to the eggs. Embryonic thyroid hormone synthesis is activated later during embryo-larval development. (See Domain of applicability)

Dose-Response Evidence: Empirical data is available from enough studies in animals treated with TPO inhibitors during development to make it readily accepted dogma that a dose-response relationship exists between TPO inhibition and serum TH concentrations. Again, these studies do not empirically measure TPO inhibition or decreased TH synthesis, but rely on the strong support of decades of mechanistic research in a variety of species of the causative relationship between these KEs. Examples of dose-responsive changes in TH concentrations following developmental exposure to TPO inhibitors include studies a variety of species, including: rodents (Blake and Henning, 1985; Goldey et al., 1995; Sawin et al., 1998); frogs (Tietge et al., 2013); fish tissue levels (Elsalini and Rohr, 2003.); and, chickens (Wishe et al., 1979). Computational modeling of the thyroid also provides evidence for the indirect dose-response relationship between these two KEs (e.g., Leonard et al., 2016; Fisher et a., 2013).

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.

References

List of the literature that was cited for this KER description. More help

Ahmed OM, Abd El-Tawab SM, Ahmed RG. Effects of experimentally induced maternal hypothyroidism and hyperthyroidism on the development of rat offspring: I. The development of the thyroid hormones-neurotransmitters and adenosinergic system interactions. Int J Dev Neurosci. 2010 28(6):437-54

Axelstad M, Hansen PR, Boberg J, Bonnichsen M, Nellemann C, Lund SP, Hougaard KS, Hass U. Developmental neurotoxicity of propylthiouracil (PTU) in rats: relationship between transient hypothyroxinemia during development and long-lasting behavioural and functional changes. Toxicol Appl Pharmacol. 2008 232(1):1-13.

Blake HH, Henning SJ. Effect of propylthiouracil dose on serum thyroxine, growth, and weaning in young rats. Am J Physiol. 1985 248(5 Pt 2):R524-30.

Boas M, Feldt-Rasmussen U, Skakkebaek NE, Main KM. Environmental chemicals and thyroid function. Eur J Endocrinol. 2006 154:599-611.

Brucker-Davis F. Effects of environmental synthetic chemicals on thyroid function. Thyroid. 1998 8:827-56.

Calvo R, Obregón MJ, Ruiz de Oña C, Escobar del Rey F, Morreale de Escobar G. Congenital hypothyroidism, as studied in rats. Crucial role of maternal thyroxine but not of 3,5,3'-triiodothyronine in the protection of the fetal brain. J Clin Invest. 1990 Sep;86(3):889-99.

Chang J, Wang M, Gui W, Zhao Y, Yu L, Zhu G. 2012. Changes in thyroid hormone levels during zebrafish development. Zoological Science. 29(3):181-184.

Coady K, Marino T, Thomas J, Currie R, Hancock G, Crofoot J, McNalley L, McFadden L, Geter D, Klecka G. 2010. Evaluation of the amphibian metamorphosis assay: exposure to the goitrogen methimazole and the endogenous thyroid hormone L-thyroxine. Environmental toxicology and chemistry / SETAC. Apr;29:869-880.

Cooke PS, Kirby JD, Porcelli J. Increased testis growth and sperm production in adult rats following transient neonatal goitrogen treatment: optimization of the propylthiouracil dose and effects of methimazole. J Reprod Fertil. 1993 97(2):493-9

Cooper DS, Kieffer JD, Halpern R, Saxe V, Mover H, Maloof F, Ridgway EC (1983) Propylthiouracil (PTU) pharmacology in the rat. II. Effects of PTU on thyroid function. Endocrinology 113:921-928.

Crane, H.M., Pickford, D.B., Hutchinson, T.H., Brown, J.A., 2006. The effects of methimazole on development of the fathead minnow, pimephales promelas, from embryo to adult. Toxicological Sciences 93, 278-285.

Crofton KM Thyroid disrupting chemicals: mechanisms and mixtures. Int J Androl. 2008 31:209-23

Degon, M., Chipkin, S.R., Hollot, C.V., Zoeller, R.T., and Chait, Y. (2008). A computational model of the human thyroid. Mathematical Biosciences 212: 22–53.

Ekerot P, Ferguson D, Glämsta EL, Nilsson LB, Andersson H, Rosqvist S, Visser SA. Systems pharmacology modeling of drug-induced modulation of thyroid hormones in dogs and translation to human. Pharm Res. 2013 Jun;30(6):1513-24.

Elsalini OA, Rohr KB.: Phenylthiourea disrupts thyroid function in developing zebrafish. Dev Genes Evol 212, 593-8, 2003.

Emiliano, A.B., Governale, L., Parks, M., Cooper, D.S., 2010. Shifts in propylthiouracil and methimazole prescribing practices: antithyroid drug use in the United States from 1991 to 2008. J. Clin. Endocrinol. Metab. 95, 2227–2233.

Fisher JW, Li S, Crofton K, Zoeller RT, McLanahan ED, Lumen A, Gilbert ME. Evaluation of iodide deficiency in the lactating rat and pup using a biologically based dose-response model. Toxicol Sci. 2013 132(1):75-86.

Gilbert ME. 2011. Impact of low-level thyroid hormone disruption induced by propylthiouracil on brain development and function. Toxicol Sci. 124:432-445.

Goldey ES, Crofton KM. Thyroxine replacement attenuates hypothyroxinemia, hearing loss, and motor deficits following developmental exposure to Aroclor 1254 in rats. Toxicol Sci. 1998 Sep;45(1):94-105.

Goldey ES, Kehn LS, Rehnberg GL, Crofton KM. Effects of developmental hypothyroidism on auditory and motor function in the rat. Toxicol Appl Pharmacol. 1995 135(1):67-76.

Grommen, S.V., Iwasawa, A., Beck, V., Darras, V.M., De Groef, B., 2011. Ontogenic expression profiles of thyroid-specific genes in embryonic and hatching chicks. Domest. Anim. Endocrinol. 40, 10–18.

Handa S, Hassan I, Gilbert M, El-Masri H. 2021. Mechanistic Computational Model for Extrapolating In Vitro Thyroid Peroxidase (TPO) Inhibition Data to Predict Serum Thyroid Hormone Levels in Rats. Toxicological Sciences 183(1):36-48.

Hassan I, El-Masri H, Ford J, Brennan A, Handa S, Friedman KP, Gilbert ME. 2020. Extrapolating In Vitro Screening Assay Data for Thyroperoxidase Inhibition to Predict Serum Thyroid Hormones in the Rat. Toxicological Sciences 173(2):280-292.

Hassan I, El-Masri H, Kosian PA, Ford J, Degitz SJ, Gilbert ME. 2017. Neurodevelopment and Thyroid Hormone Synthesis Inhibition in the Rat: Quantitative Understanding Within the Adverse Outcome Pathway Framework. Toxicological Sciences 160(1):57-73.

Hernandez-Mariano JA, Torres-Sanchez L, Bassol-Mayagoitia S, Escamilla-Nunez M, Cebrian ME, Villeda-Gutierrez EA, Lopez-Rodriguez G, Felix-Arellano EE, Blanco-Munoz J. 2017. Effect of exposure to p,p '-dde during the first half of pregnancy in the maternal thyroid profile of female residents in a mexican floriculture area. Environmental Research. 156:597-604.

Herwig A, Campbell G, Mayer CD, Boelen A, Anderson RA, Ross AW, Mercer JG, Barrett P. 2014. A thyroid hormone challenge in hypothyroid rats identifies T3 regulated genes in the hypothalamus and in models with altered energy balance and glucose homeostasis. Thyroid: Nov;24:1575-1593.

Hood A, Liu YP, Gattone VH, 2nd, Klaassen CD (1999) Sensitivity of thyroid gland growth to thyroid stimulating hormone (TSH) in rats treated with antithyroid drugs. Toxicol Sci 49:263-271.

Hurley PM. Mode of carcinogenic action of pesticides inducing thyroid follicular cell tumors in rodents. Environ Health Perspect. 1998 106:437-45.

Köhrle J. Environment and endocrinology: the case of thyroidology. Ann Endocrinol (Paris). 2008 69:116-22.

Lasley SM, Gilbert ME. Developmental thyroid hormone insufficiency reduces expression of brain-derived neurotrophic factor (BDNF) in adults but not in neonates. Neurotoxicol Teratol. 2011 33(4):464-72

Laurberg P, Andersen SL. 2014. Therapy of endocrine disease: antithyroid drug use in early pregnancy and birth defects: time windows of relative safety and high risk? Eur J Endocrinol. 2014 Jul;171(1):R13-20.

Leonard JA, Tan YM, Gilbert M, Isaacs K, El-Masri H. Estimating margin of exposure to thyroid peroxidase inhibitors using high-throughput in vitro data, high-throughput exposure modeling, and physiologically based pharmacokinetic/pharmacodynamic modeling. Toxicol Sci. 2016 151(1):57-70.

Liu XS, Cai Y, Wang Y, Xu SH, Ji K, Choi K. 2019. Effects of tris(1,3-dichloro-2-propyl) phosphate (tdcpp) and triphenyl phosphate (tpp) on sex-dependent alterations of thyroid hormones in adult zebrafish. Ecotoxicology and Environmental Safety. 170:25-32.

Männistö PT, Ranta T, Leppäluoto J. Effects of methylmercaptoimidazole (MMI), propylthiouracil (PTU), potassium perchlorate (KClO4) and potassium iodide (KI) on the serum concentrations of thyrotrophin (TSH) and thyroid hormones in the rat. Acta Endocrinol (Copenh). 1979 91(2):271-81.

Morreale de Escobar G, Obregon MJ, Escobar del Rey F (2004) Role of thyroid hormone during early brain development. Eur J Endocrinol 151 Suppl 3:U25-37.

Murk AJ, Rijntjes E, Blaauboer BJ, Clewell R, Crofton KM, Dingemans MM, Furlow JD, Kavlock R, Köhrle J, Opitz R, Traas T, Visser TJ, Xia M, Gutleb AC. Mechanism-based testing strategy using in vitro approaches for identification of thyroid hormone disrupting chemicals. Toxicol In Vitro. 2013 27:1320-46.

Nelson, K., Schroeder, A., Ankley, G., Blackwell, B., Blanksma, C., Degitz, S., Flynn, K., Jensen, K., Johnson, R., Kahl, M., Knapen, D., Kosian, P., Milsk, R., Randolph, E., Saari, T., Stinckens, E., Vergauwen, L., Villeneuve, D., 2016. Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part I: Fathead minnow. Aquatic Toxicology 173, 192-203.

Opitz, R., Maquet, E., Zoenen, M., Dadhich, R., Costagliola, S., 2011. TSH Receptor Function Is Required for Normal Thyroid Differentiation in Zebrafish. Molecular Endocrinology 25, 1579-1599.

Pathak A, Sinha RA, Mohan V, Mitra K, Godbole MM. 2011. Maternal thyroid hormone before the onset of fetal thyroid function regulates reelin and downstream signaling cascade affecting neocortical neuronal migration. Cerebral Cortex. 21:11-21.

Pearce EN, Braverman LE. Environmental pollutants and the thyroid. Best Pract Res Clin Endocrinol Metab. 2009 23:801-1.

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Rosebrough, R.W., Russell, B.A., McMurtry, J.P., 2006. Studies on doses of methimazole (MMI) and its administration regimen on broiler metabolism. Comp. Biochem. Physiol. A: Mol. Integr. Physiol. 143, 35–41.

Sack J, Weller A, Rigler O, Rozin A.A simple model for studying the correction of in utero hypothyroidism in the rat. Pediatr Res. 1995 37(4 Pt 1):497-501.

Sawin S, Brodish P, Carter CS, Stanton ME, Lau C. Development of cholinergic neurons in rat brain regions: dose-dependent effects of propylthiouracil-induced hypothyroidism. Neurotoxicol Teratol. 1998 20(6):627-35

Schwartz HL, Ross ME, Oppenheimer JH (1997) Lack of effect of thyroid hormone on late fetal rat brain development. Endocrinology 138:3119-3124.

Seed J, Carney EW, Corley RA, Crofton KM, DeSesso JM, Foster PM, Kavlock R, Kimmel G, Klaunig J, Meek ME, Preston RJ, Slikker W Jr, Tabacova S, Williams GM, Wiltse J, Zoeller RT, Fenner-Crisp P, Patton DE. Overview: Using mode of action and life stage information to evaluate the human relevance of animal toxicity data. Crit Rev Toxicol. 2005 35(8-9):664-72.

Shibutani M, Woo GH, Fujimoto H, Saegusa Y, Takahashi M, Inoue K, Hirose M, Nishikawa A. Assessment of developmental effects of hypothyroidism in rats from in utero and lactation exposure to anti-thyroid agents. Reprod Toxicol. 2009 Nov;28(3):297-307

Stinckens, E., Vergauwen, L., Blackwell, B.R., Anldey, G.T., Villeneuve, D.L., Knapen, D., 2020. Effect of Thyroperoxidase and Deiodinase Inhibition on Anterior Swim Bladder Inflation in the Zebrafish. Environmental Science & Technology 54, 6213-6223.

Stinckens, E., Vergauwen, L., Schroeder, A., Maho, W., Blackwell, B., Witters, H., Blust, R., Ankley, G., Covaci, A., Villeneuve, D., Knapen, D., 2016. Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-mercaptobenzothiazole part II: Zebrafish. Aquatic Toxicology 173, 204-217.

Sundaresh V, Brito JP, Wang Z, Prokop LJ, Stan MN, Murad MH, Bahn RS. 2013. Comparative effectiveness of therapies for Graves' hyperthyroidism: a systematic review and network meta-analysis. The Journal of clinical endocrinology and metabolism. 98:3671-3677.

Taurog A. 2005. Hormone synthesis. In: Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text (Braverman LE, Utiger RD, eds). Philadelphia:Lippincott, Williams and Wilkins, 47–81

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