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Event: 280

Key Event Title

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

Thyroxine (T4) in neuronal tissue, Decreased

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
T4 in neuronal tissue, Decreased
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Biological Context

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Level of Biological Organization

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
Organ term

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; 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
regulation of hormone levels 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
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
TPO Inhibition and Altered Neurodevelopment KeyEvent Kevin Crofton (send email) Open for citation & comment WPHA/WNT Endorsed
NIS inhibition and learning and memory impairment KeyEvent Anna Price (send email) Open for citation & comment WPHA/WNT Endorsed
Nuclear receptor induced TH Catabolism and Developmental Hearing Loss KeyEvent Katie Paul Friedman (send email) Open for adoption Under Development
NIS and Neurodevelopment KeyEvent Kevin Crofton (send email) Not under active development
NIS and Cognitive Dysfunction KeyEvent Mary Gilbert (send email) Under Development: Contributions and Comments Welcome
Transthyretin interference KeyEvent Kristie Sullivan (send email) Under Development: Contributions and Comments Welcome Under Development
AhR activation in the liver leading to Adverse Neurodevelopmental Outcomes in Mammals KeyEvent Prakash Patel (send email) Under development: Not open for comment. Do not cite
AhR activation in the thyroid leading to Adverse Neurodevelopmental Outcomes in Mammals KeyEvent Prakash Patel (send email) Under development: Not open for comment. Do not cite

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
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
chicken Gallus gallus Low NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
During brain development High

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Female High
Male High

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

Thyroid hormones (TH) are present in brain tissue of most vertebrate species, and thyroxine (T4) is converted to triiodothyronine (T3) locally in this tissue.  The amount of THs in brain is known to vary during development and to differ among brain regions (Calvo et al., 1990; Kester et al., 2004; Tu et al., 1999). In human cerebral cortex, T3 increases steadily from 13-weeks, reaching adult levels by 20 weeks post conception. This occurs despite very low and unchanging levels in fetal serum T3, when fetal serum T4 increases 3-fold over the same period. This indicates that T3 in fetal brain is locally generated from serum-derived T4 via the activity of deiodinases, primarily DIO2. DIO2 serves to convert T4 to T3. During this time in fetal development DIO3 activity, which converts T3 to the inactive reverse T3 (rT3), remains very low in cortex.  In contrast, in other brain regions including hippocampus and cerebellum, T3 remains low throughout early and mid-gestation and corresponds with high activity of DIO3 in these brain regions. In late gestation and after birth, DIO3 levels drop in hippocampus and cerebellum with a corresponding increase in T3 concentrations (Kester et al., 2004). 

A similar spatial and temporal profile of deiodinase activity and corresponding brain hormone concentrations has been observed in rodent brain (Calvo et al., 1990; Tu et al., 1999). In the rat, either whole brain or cortex have been preferentially assessed due to the low levels of hormones present and the small tissue volumes make quantitification difficult. Brain T3 and T4 rise in parallel from gestational day 10 to gestational day 20 in rat. They are typically both quite low until gestational 17 with steep increases between GD18 and GD20 corresponding to the onset of fetal thyroid function (Calvo et al., 1990; Ruiz de Ono et al., 1988; Obergon et al., 1981). Just before birth, brain T3 and T4 concentrations are about one-third to one-half that of adult brain. Brain development in the early postnatal period in rat is roughly equivalent to the 3rd trimester in humans such that adult levels of T3 and T4 in brain are not reached in rodents until the 2nd-3rd postnatal week.

For THs to gain access to brain tissue they need to cross the blood brain barrier (BBB) which regulates the active transport of TH into neurons. Many transporter proteins have been identified, and the monocarboxylate transporters (Mct8, Mct10) and anion-transporting polypeptide (OATP1c1) show the highest degree of affinity towards TH and are prevalent in brain (Jansen et al., 2007; Mayer et al., 2014).  Transporters express a distinct distribution pattern that varies by tissue and age (Friesema et al., 2005; Henneman et al., 2001; Visser et al., 2007; Heuer et al., 2005; Muller and Heuer, 2007). Although several transporters have been identified, current knowledge of cell specific profile of transporters is limited. 

Most of the hormone transported across the blood brain barrier is in the form of T4, primarily through the cellular membrane transporters (e.g., OATP1c1 transporter) into the astrocyte (Visser and Visser, 2012; Sugiyama et al., 2003; Tohyama et al., 2004). Within the astrocyte, T4 is converted into T3 via the local activity of deiodinase 2 (DIO2) (Guadano-Ferraz et al., 1997).  A small amount of T3 may cross the blood brain barrier directly via the T3-specific transporter, MCT8 (Heuer et al., 2005). Although in mature brain T3 derives partially from the circulation and from the deiodination of T4, in the fetal brain T3 is exclusively a product of T4 deiodination (Calvo et al., 1990; Grijota-Martinez et al., 2011). In both cases, only the required amount of T3 is utilized in neurons and the excess is degraded by the neuron-specific deiodinase DIO3 (Tu et al., 1999; St. Germain et al., 2009; Hernandez et al., 2010).

Both deiodinase and transporter expression in brain peak in different brain regions at different times in fetal and neonatal life (Kester et al., 2004; Bates et al., 1999; Muller and Heuer, 2014; Heuer, 2007). Collectively, these spatial and temporal patterns of transporter expression and deiodinase activity provide exquisite control of brain T3 available for nuclear receptor activation and regulated gene expression.

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

Radioimmunoassays (RIAs) are commonly used to detect TH in the brain (e.g., Obregon et al., 1982; Calvo et al., 1990; Morse et al., 1996; Bansal et al., 2005; Gilbert et al., 2013). The method (and minor variants) is well established in the published literature. However, it is not available in a simple 'kit' and requires technical knowledge of RIAs, thus has not been used in most routine toxicology studies. Evaluations in neuronal tissue are complicated by the difficulty of the fatty matrix, heterogeneity of regions within the brain, and low tissue concentrations and small tissue amounts especially in immature brain. Most often whole brain homogenates are assessed, obfuscating the known temporal and regional differences in brain hormone present. Two analytical techniques, LC- and HPLC-inductively coupled plasma–mass spectrometry have recently been used to measure brain concentrations of TH. These techniques have proven capable of measuring very low levels in whole-body homogenates of frog tadpoles at different developmental stages (e.g., Simon et al., 2002; Tietge et al., 2010). The assay detects I–, MIT, DIT, T4, T3, and rT3. More recently, Wang and Stapleton (2010) and Donzelli et al. (2016) used liquid chromatography-tandem mass spectrometry for the simultaneous analysis of five THs including thyroxine (T4), 3,3′,5-triidothyronine (T3), 3,3′,5′-triiodothyronine (rT3; reverse T3), 3,3′-diiodothyronine (3,3′-T2), and 3,5-diiodothyronine (3,5-T2) in serum and a variety of tissues including brain. These analytical methods require expensive equipment and technical expertise and as such are not routinely used.

Domain of Applicability

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

THs are critical for normal brain development in most vertebrates, primarily documented empirically in mammalian species (Bernal, 2013).  However, there is compelling data that demonstrates the need for TH in brain development for many other taxa, including: birds, fish and frogs (Van Herck et al., 2013; Denver, 1998; Power et al., 2001). The most well known non-mammalian action of TH is to induce metamorphosis in amphibians and some fish species. However, there is a fundamental difference in the mechanisms by which T3 affects amphibian metamorphosis vs its role in mammalian brain development (Galton, 1983). In the rat, brain development proceeds, even if defective, despite the absence of TH. By contrast, TH administration to tadpoles induces early metamorphosis, whereas in its absence, tadpoles grow to extremely large size, but the metamorphosis program is never activated (Galton, 1983).


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

Bansal R, You SH, Herzig CT, Zoeller RT (2005). Maternal thyroid hormone increases HES expression in the fetal rat brain: an effect mimicked by exposure to a mixture of polychlorinated biphenyls (PCBs). Brain Res Dev Brain Res 156:13-22.

Bates JM, St Germain DL, Galton VA. Expression profiles of the three iodothyronine deiodinases, D1, D2, and D3, in the developing rat. Endocrinology. 1999 Feb;140(2):844-51.

Bernal J. (2013). Thyroid Hormones in Brain Development and Function.  In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, editors. Endotext [Internet]. South Dartmouth (MA):, Inc.; 2000-2015.

Calvo R, Obregón MJ, Ruiz de Oña C, Escobar del Rey F, Morreale de Escobar G. (1990). 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. 86:889-899.

Chatonnet F., Picou F., Fauquier T., and Flamant F., (2011). Thyroid Hormone Action in Cerebellum and Cerebral Cortex Development, Journal of Thyroid Research, Volume 2011, Article ID 145762, 8 pages

Denver, RJ 1998 The molecular basis of thyroid hormone-dependent central nervous system remodeling during amphibian metamorphosis. Comparative Biochemistry and Physiology Part C: Pharmacology, Toxicology and Endocrinology, 119:219-228.

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

Friesema EC, Jansen J, Milici C, Visser TJ (2005) Thyroid hormone transporters. Vitam Horm 70:137-167.

Galton VH 1983 Thyroid hormone action in amphibian metamorphosis. In: Oppenheimer JH, Samuels HH (eds) Molecular Basis of Thyroid Hormone Action. Academic Press, New York, pp 445–483.

Gilbert ME, Hedge JM, Valentin-Blasini L, Blount BC, Kannan K, Tietge J, Zoeller RT, Crofton KM, Jarrett JM, Fisher JW (2013) An animal model of marginal iodine deficiency during development: the thyroid axis and neurodevelopmental outcome. Toxicol Sci 132:177-195.

Grijota-Martinez C, Diez D, Morreale de Escobar G, Bernal J, Morte B. (2011). Lack of action of exogenously administered T3 on the fetal rat brain despite expression of the monocarboxylate transporter 8. Endocrinology. 152:1713-1721.

Guadano-Ferraz A, Obregon MJ, St Germain DL, Bernal J. (1997). The type 2 iodothyronine deiodinase is expressed primarily in glial cells in the neonatal rat brain. Proc Natl Acad Sci USA. 94: 10391–10396.

Hennemann G, Docter R, Friesema EC, de Jong M, Krenning EP, Visser TJ. (2001). Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocr Rev. 22:451-476.

Hernandez A, Quignodon L, Martinez ME, Flamant F, St Germain DL. Type 3 deiodinase deficiency causes spatial and temporal alterations in brain T3 signaling that are dissociated from serum thyroid hormone levels. Endocrinology. 2010 Nov;151(11):5550-8.

Heuer H. (2007). The importance of thyroid hormone transporters for brain development and function. Best Pract Res Clin Endocrinol Metab. 21:265–276.

Heuer H, Maier MK, Iden S, Mittag J, Friesema EC, Visser TJ, Bauer K. (2005). The monocarboxylate transporter 8 linked to human psychomotor retardation is highly expressed in thyroid hormone-sensitive neuron populations. Endocrinology 146:1701–1706.

Jansen J, Friesema EC, Kester MH, Milici C, Reeser M, Gruters A, Barrett TG, Mancilla EE, Svensson J, Wemeau JL, Busi da Silva Canalli MH, Lundgren J, McEntagart ME, Hopper N, Arts WF, Visser TJ (2007) Functional analysis of monocarboxylate transporter 8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothyronine. J Clin Endocrinol Metab 92:2378-2381.

Kester MH, Martinez de Mena R, Obregon MJ, Marinkovic D, Howatson A, Visser TJ, Hume R, Morreale de Escobar G. (2004). Iodothyronine levels in the human developing brain: major regulatory roles of iodothyronine deiodinases in different areas. J Clin Endocrinol Metab 89:3117–3128.

Mayer S, Müller J, Bauer R, Richert S, Kassmann CM, Darras VM, Buder K, Boelen A, Visser TJ, Heuer H. Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. J Clin Invest. 2014 May 1;124(5):1987-99.

Moog N.K., Entringer S., Heim Ch., Wadhwa PD., Kathmann N., Buss C. (2017). Influence of maternal thyroid hormones during gestation on fetal  brain development. Neuroscience, 2017, 342: 68–100. doi:10.1016/j.neuroscience.2015.09.0

Morse DC, Wehler EK, Wesseling W, Koeman JH, Brouwer A. Alterations in rat brain thyroid hormone status following pre- and postnatal exposure to polychlorinated biphenyls (Aroclor 1254). Toxicol Appl Pharmacol. 1996 Feb;136(2):269-79

Müller J, Heuer H. Expression pattern of thyroid hormone transporters in the postnatal mouse brain. Front Endocrinol (Lausanne). 2014 Jun 18:5:92.

Obregon MJ, Mallol J, Escobar del Rey F, Morreale de Escobar G. (1981). Presence of l-thyroxine and 3,5,3-triiodo-l-thyronine in tissues from thyroidectomised rats. Endocrinology 109:908-913.

Power DM, Llewellyn L, Faustino M, Nowell MA, Björnsson BT, Einarsdottir IE, Canario AV, Sweeney GE. Thyroid hormones in growth and development of fish. Comp Biochem Physiol C Toxicol Pharmacol. 2001 Dec;130(4):447-59.

Ruiz de Oña C, Obregón MJ, Escobar del Rey F, Morreale de Escobar G. Developmental changes in rat brain 5'-deiodinase and thyroid hormones during the fetal period: the effects of fetal hypothyroidism and maternal thyroid hormones. Pediatr Res. 1988 Nov;24(5):588-94.

Simon R, Tietge JE, Michalke B, Degitz S, Schramm KW. Iodine species and the endocrine system: thyroid hormone levels in adult Danio rerio and developing Xenopus laevis. Anal Bioanal Chem. 2002 Feb;372(3):481-5.

St Germain DL, Galton VA, Hernandez A. (2009). Minireview: Defining the roles of the iodothyronine deiodinases: current concepts and challenges. Endocrinology. 150:1097-107.

Sugiyama D, Kusuhara H, Taniguchi H, Ishikawa S, Nozaki Y, Aburatani H, Sugiyama Y. (2003). Functional characterization of rat brain-specific organic anion transporter (Oatp14) at the blood–brain barrier: high affinity transporter for thyroxine. J Biol Chem. 278:43489–43495.

Tietge JE, Butterworth BC, Haselman JT, Holcombe GW, Hornung MW, Korte JJ, Kosian PA, Wolfe M, Degitz SJ. Early temporal effects of three thyroid hormone synthesis inhibitors in Xenopus laevis. Aquat Toxicol. 2010 Jun 1;98(1):44-50.

Tohyama K, Kusuhara H, Sugiyama Y. (2004). Involvement of multispecific organic anion transporter, Oatp14 (Slc21a14), in the transport of thyroxine across the blood-brain barrier. Endocrinology. 145: 4384–4391.

Tu HM, Legradi G, Bartha T, Salvatore D, Lechan RM, Larsen PR. (1999). Regional expression of the type 3 iodothyronine deiodinase messenger ribonucleic acid in the rat central nervous system and its regulation by thyroid hormone. Endocrinology. 140: 784–790.

Van Herck SL, Geysens S, Delbaere J, Darras VM. Regulators of thyroid hormone availability and action in embryonic chicken brain development. Gen Comp Endocrinol. 2013.190:96-104.

Visser EW, Visser TJ. (2012). Finding the way into the brain without MCT8. J Clin Enodcrinol Metab. 97:4362-4365.

Visser WE, Friesema EC, Jansen J, Visser TJ. (2007). Thyroid hormone transport by monocarboxylate transporters. Best Pract Res Clin Endocrinol Metab. 21:223–236.

Wang, D. and Stapleton, HM. (2010) Analysis of thyroid hormones in serum by liquid chromatography -tandem mass spectrometry. Anal Bioanal Chem. 2010 Jul; 397(5): 1831–1839