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Event: 289

Key Event Title

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

Decrease, Translocator protein (TSPO)

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
Decrease, Translocator protein (TSPO)
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Biological Context

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Level of Biological Organization
Cellular

Cell 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
Cell term
steroid hormone secreting cell

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
gene expression translocator protein 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
PPARα activation leading to impaired fertility KeyEvent Elise Grignard (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 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
Homo sapiens Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
Mus musculus Mus musculus Moderate NCBI

Life Stages

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

Sex Applicability

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

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

Biological state

Translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), is a mitochondrial outer membrane protein implicated in cholesterol import to the inner mitochondrial membrane (Besman et al. 1989).

Biological compartments

The TSPO is present in virtually all mammalian peripheral tissues (Zisterer and Williams 1997), however highly prominent TSPO protein expression has been identified in steroidogenic tissues (R. R. Anholt et al. 1985), (Wang, Fan, and Papadopoulos 2012). The presence of TSOP has been confirmed in Leydig and Sertoli cells (Morohaku, Phuong, and Selvaraj 2013), granulosa cells (Amsterdam and Suh 1991) and to a lesser extent in thecal cells (Morohaku, Phuong, and Selvaraj 2013). In subcellular fractions, binding sites for the TSOP have been identified to be present in the outer mitochondrial membrane (OMM) (R. R. Anholt et al. 1985), (R. Anholt et al. 1986). Transcriptional regulation of TSPO genes has been examined and recently reviewed (Morohaku, Phuong, and Selvaraj 2013).

General role in biology: regulation of lipid transport

TSPO mediates the delivery of the substrate cholesterol to the inner mitochondrial side chain cleavage enzyme P450scc (Besman et al. 1989). TSPO ligands stimulate steroidogenesis and induce cholesterol movement from the outer mitochondrial membrane (OMM) to the inner mitochondrial membrane (IMM) (Besman et al. 1989).

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

TSPO levels can be assayed by standard methods for assessment of gene expression levels like qPCR or direct protein levels by Western blot.

The level of TSPO as well as other steroidogenic protein can be measured in vitro cultured Leydig cells. The methods for culturing Leydig cells can be found in the Database Service on Alternative Methods to animal experimentation (DB-ALM): Leydig Cell-enriched Cultures [1], Testicular Organ and Tissue Culture Systems [2].

Uncertainties and Inconsistencies

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TSPO -knockout mice have shown embryonic lethality (Lacapère and Papadopoulos 2003); in contrast recent findings have shown no effect on viability of foetuses (Tu et al. 2014). Aberrant TSPO levels have been linked to multiple diseases, including cancer, endocrine disorders, brain injury, neurodegeneration, ischemia-reperfusion injury and inflammatory diseases (Wang, Fan, and Papadopoulos 2012). However, recent studies have shown opposite results. Peripheral benzodiazepine receptor/translocator protein global knock-out mice are viable and show no effects on steroid hormone biosynthesis (Tu et al. 2014), (Morohaku et al. 2014). As stated in a recent review "At this point in time, a functional designation for TSPO is still actively being sought" (Selvaraj, Stocco, and Tu 2015).

Domain of Applicability

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

TSPO is a protein that shows high DNA sequence conservation from bacteria to mammals. It is expressed ubiquitously, but most abundant in steroidogenic cells (Yeliseev, Krueger, and Kaplan 1997).

References

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

Amsterdam, A. & Suh, B.S., 1991. An inducible functional peripheral benzodiazepine receptor in mitochondria of steroidogenic granulosa cells. Endocrinology, 129(1), pp.503–10.

Anholt, R. et al., 1986. The peripheral-type benzodiazepine receptor. Localization to the mitochondrial outer membrane. J. Biol. Chem., 261(2), pp.576–583.

Anholt, R.R. et al., 1985. Peripheral-type benzodiazepine receptors: autoradiographic localization in whole-body sections of neonatal rats. The Journal of pharmacology and experimental therapeutics, 233(2), pp.517–26.

Besman, M.J. et al., 1989. Identification of des-(Gly-Ile)-endozepine as an effector of corticotropin-dependent adrenal steroidogenesis: stimulation of cholesterol delivery is mediated by the peripheral benzodiazepine receptor. Proceedings of the National Academy of Sciences of the United States of America, 86(13), pp.4897–901.

Lacapère, J.J. & Papadopoulos, V., 2003. Peripheral-type benzodiazepine receptor: structure and function of a cholesterol-binding protein in steroid and bile acid biosynthesis. Steroids, 68(7-8), pp.569–85.

Morohaku, K. et al., 2014. Translocator protein/peripheral benzodiazepine receptor is not required for steroid hormone biosynthesis. Endocrinology, 155(1), pp.89–97. Morohaku, K., Phuong, N.S. & Selvaraj, V., 2013. Developmental expression of translocator protein/peripheral benzodiazepine receptor in reproductive tissues. W. Yan, ed. PloS one, 8(9), p.e74509.

Papadopoulos, V. et al., 1997. Targeted disruption of the peripheral-type benzodiazepine receptor gene inhibits steroidogenesis in the R2C Leydig tumor cell line. The Journal of biological chemistry, 272(51), pp.32129–35.

Tu, L.N. et al., 2014. Peripheral benzodiazepine receptor/translocator protein global knock-out mice are viable with no effects on steroid hormone biosynthesis. The Journal of biological chemistry, 289(40), pp.27444–54.

Wang, H.-J., Fan, J. & Papadopoulos, V., 2012. Translocator protein (Tspo) gene promoter-driven green fluorescent protein synthesis in transgenic mice: an in vivo model to study Tspo transcription. Cell and tissue research, 350(2), pp.261–75.

Yeliseev, A.A., Krueger, K.E. & Kaplan, S., 1997. A mammalian mitochondrial drug receptor functions as a bacterial “oxygen” sensor. Proceedings of the National Academy of Sciences of the United States of America, 94(10), pp.5101–6. Zisterer, D.M. & Williams, D.C., 1997. Peripheral-type benzodiazepine receptors. General pharmacology, 29(3), pp.305–14.