API

Event: 1093

Key Event Title

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Decreased, Thyroxine (T4) in tissues

Short name

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Decreased, Thyroxine (T4) in tissues

Biological Context

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Level of Biological Organization
Tissue


Organ term

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Key Event Components

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Process Object Action
thyroxine increased
thyroxine decreased

Key Event Overview


AOPs Including This Key Event

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Stressors

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Taxonomic Applicability

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Term Scientific Term Evidence Link
African clawed frog Xenopus laevis Moderate NCBI

Life Stages

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Life stage Evidence
Development Moderate

Sex Applicability

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Term Evidence
Unspecific Moderate

Key Event Description

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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

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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

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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.


Evidence for Perturbation by Stressor



Methimazole

Inferred given effect of reduced thyroid hormone synthesis on lack of metamorphic changes in tissues.


Propylthiouracil

Inferred given effect of reduced thyroid hormone synthesis on lack of metamorphic changes in tissues.


Mercaptobenzothiazole

Inferred given effect of reduced thyroid hormone synthesis on lack of metamorphic changes in tissues.


Perchlorate

Inferred given effect of reduced thyroid hormone synthesis on lack of metamorphic changes in tissues.


References

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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.