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Event: 1093

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Decreased, Thyroxine (T4) in tissues

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Decreased, Thyroxine (T4) in tissues
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Tissue

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
thyroxine increased
thyroxine decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
African clawed frog Xenopus laevis Moderate NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Development Moderate

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Unspecific Moderate

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Thyroxine (T4) is the pro-hormone form that is converted to the active hormone triiodothyronine (T3) via intracellular enzymatic outer ring deiodination by either type I or II deiodinases. The presence of T4 in cells/tissues is the predominant input into the biochemical pathway leading to regulation of gene expression by T3 and thyroid receptors. 

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Tissues typically contain low levels of thyroid hormones and are generally complex sample matrices, making analyses of thyroid hormones in tissues challenging. This requires special consideration for the composition of the specific tissue in order to employ the proper sample preparation technique. Ideally, analyses of tissue TH is a two-step process starting with extraction and then subsequent analyses. Extraction procedures for thyroid hormones, their precursors and analogues have been demonstrated in whole body homogenates of fish or tadpoles using ethanol extractions, tadpole and rat thyroid gland tissue using proteolytic digestions and rat peripheral tissues using methanol-chloroform extractions (see attached reference table for details). Analyses of sample extracts have been performed using radioimmunoassay (RIA), liquid-chromatography inductively coupled mass spectrometry (HPLC-ICP/MS) and liquid chromatography tandem mass spectrometry (UPLC/HPLC-MS/MS). These methods generally require addition of radioisotope labeled compounds (RIA) or stable isotope labeled compounds (LC-MS/MS) to samples prior to the extraction procedure in order to correct for recovery, so the extraction and analysis steps are not entirely independent of each other. Another consideration for the technique employed to measure thyroid hormones is that RIA methods are only capable of measuring a single analyte at a time and is typically either T3 or T4 whereas LC-ICP/MS and LC-MS/MS methods allow quantitation of thyroid hormones, precursors and metabolites all in the same sample (see attached reference table for details).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

The essentiality of this key event applies during thyroid-mediated metamorphosis in amphibians and especially African clawed frog (Xenopus laevis), which lends the basis for this key event leading to altered metamorphosis. However, direct measurements of this key event are not routine or typical. The support for this key event exists primarily as biological plausibility and thyroid endocrinology dogma.

Additionally, it is accepted that this key event can apply to mammalian pre and postnatal neurodevelopment but AOPs leading to this adverse outcome (e.g., AOP 42) specify neurological tissue in the key event title (KE 280), whereas this key event is applicable across tissue types.

References

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

Ackermans, M.T., Kettelarij‐Haas, Y., Boelen, A. and Endert, E., 2012. Determination of thyroid hormones and their metabolites in tissue using SPE UPLC‐tandem MS. Biomedical Chromatography, 26(4), pp.485-490.

Bastian, T.W., Prohaska, J.R., Georgieff, M.K. and Anderson, G.W., 2010. Perinatal iron and copper deficiencies alter neonatal rat circulating and brain thyroid hormone concentrations. Endocrinology, 151(8), pp.4055-4065.

Bastian, T.W., Anderson, J.A., Fretham, S.J., Prohaska, J.R., Georgieff, M.K. and Anderson, G.W., 2012. Fetal and neonatal iron deficiency reduces thyroid hormone-responsive gene mRNA levels in the neonatal rat hippocampus and cerebral cortex. Endocrinology, 153(11), pp.5668-5680.

Bastian, T.W., Prohaska, J.R., Georgieff, M.K. and Anderson, G.W., 2013. Fetal and neonatal iron deficiency exacerbates mild thyroid hormone insufficiency effects on male thyroid hormone levels and brain thyroid hormone-responsive gene expression. Endocrinology, 155(3), pp.1157-1167.

Crane, H.M., Pickford, D.B., Hutchinson, T.H. and Brown, J.A., 2004. Developmental changes of thyroid hormones in the fathead minnow, Pimephales promelas. General and comparative endocrinology, 139(1), pp.55-60.

Donzelli, R., Colligiani, D., Kusmic, C., Sabatini, M., Lorenzini, L., Accorroni, A., Nannipieri, M., Saba, A., Iervasi, G. and Zucchi, R., 2016. Effect of Hypothyroidism and Hyperthyroidism on Tissue Thyroid Hormone Concentrations in Rat. European thyroid journal, 5(1), pp.27-34.

ESCOBAR, G.M.D., Pastor, R., Obregón, M.J. and REY, F.E.D., 1985. Effects of Maternal Hypothyroidism on the Weight and Thyroid Hormone Content of Rat Embryonic Tissues, before and after Onset of Fetal Thyroid Function*. Endocrinology, 117(5), pp.1890-1900.

Gilbert, M.E., Hedge, J.M., Valentín-Blasini, L., Blount, B.C., Kannan, K., Tietge, J., Zoeller, R.T., Crofton, K.M., Jarrett, J.M. and Fisher, J.W., 2013. An animal model of marginal iodine deficiency during development: the thyroid axis and neurodevelopmental outcome. toxicological sciences, p.kfs335.

Hornung, M.W., Kosian, P.A., Haselman, J.T., Korte, J.J., Challis, K., Macherla, C., Nevalainen, E. and Degitz, S.J., 2015. In vitro, ex vivo, and in vivo determination of thyroid hormone modulating activity of benzothiazoles. Toxicological Sciences, 146(2), pp.254-264.

Kunisue, T., Fisher, J.W., Fatuyi, B. and Kannan, K., 2010. A method for the analysis of six thyroid hormones in thyroid gland by liquid chromatography–tandem mass spectrometry. Journal of Chromatography B, 878(21), pp.1725-1730.

Kunisue, T., Fisher, J.W. and Kannan, K., 2011. Determination of six thyroid hormones in the brain and thyroid gland using isotope-dilution liquid chromatography/tandem mass spectrometry. Analytical chemistry, 83(1), pp.417-424.

Lavado-Autric, R., Calvo, R.M., de Mena, R.M., de Escobar, G.M. and Obregon, M.J., 2012. Deiodinase activities in thyroids and tissues of iodine-deficient female rats. Endocrinology, 154(1), pp.529-536.

Pinna, G., Hiedra, L., Prengel, H., Broedel, O., Eravci, M., Meinhold, H. and Baumgartner, A., 1999. Extraction and quantification of thyroid hormones in selected regions and subcellular fractions of the rat brain. Brain Research Protocols, 4(1), pp.19-28.

Simon, R., Tietge, J., Michalke, B., Degitz, S. and Schramm, K.W., 2002. Iodine species and the endocrine system: thyroid hormone levels in adult Danio rerio and developing Xenopus laevis. Analytical and bioanalytical chemistry, 372(3), pp.481-485.

Saba, A., Donzelli, R., Colligiani, D., Raffaelli, A., Nannipieri, M., Kusmic, C., Dos Remedios, C.G., Simonides, W.S., Iervasi, G. and Zucchi, R., 2014. Quantification of thyroxine and 3, 5, 3′-triiodo-thyronine in human and animal hearts by a novel liquid chromatography-tandem mass spectrometry method. Hormone and Metabolic Research, 46(09), pp.628-634.

Tietge, J.E., Butterworth, B.C., Haselman, J.T., Holcombe, G.W., Hornung, M.W., Korte, J.J., Kosian, P.A., Wolfe, M. and Degitz, S.J., 2010. Early temporal effects of three thyroid hormone synthesis inhibitors in Xenopus laevis. Aquatic Toxicology, 98(1), pp.44-50.

Tietge, J.E., Degitz, S.J., Haselman, J.T., Butterworth, B.C., Korte, J.J., Kosian, P.A., Lindberg-Livingston, A.J., Burgess, E.M., Blackshear, P.E. and Hornung, M.W., 2013. Inhibition of the thyroid hormone pathway in Xenopus laevis by 2-mercaptobenzothiazole. Aquatic toxicology, 126, pp.128-136.