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Relationship: 437

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

Decrease, Translocator protein (TSPO) leads to Reduction, Cholesterol transport in mitochondria

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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
PPARα activation in utero leading to impaired fertility in males adjacent Low 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 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
rat Rattus norvegicus Moderate NCBI
human Homo sapiens Low NCBI
mice Mus sp. Low NCBI

Sex Applicability

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

Life Stage Applicability

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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

Translocator Protein (TSPO) mediates the first step of cholesterol transport to the inner mitochondrial membrane cytochrome P-450 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). Therefore reduced amount/activity of the TSPO impairs the cholesterol delivery that is necessary for the hormone biosynthesis.

Evidence Collection Strategy

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Evidence Supporting this KER

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

The TSPO was first identified as a peripheral tissue diazepam binding site [known as peripheral-type benzodiazepine receptor (PBR)] and since then it has been implicated in many cellular processes. Amongst these are steroid biosynthesis, protein import, heme biosynthesis, immunomodulation, cellular respiration and oxidative processes. 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 TSPO was confirmed in Leydig and Sertoli cells (Morohaku, Phuong, and Selvaraj 2013), granulosa cells (Amsterdam and Suh 1991) and to lesser extent in thecal cells (Morohaku, Phuong, and Selvaraj 2013). In subcellular fractions, binding sites for the TSPO were identified to be present in the OMM (R. R. Anholt et al. 1985), (R. Anholt et al. 1986).

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

Targeted disruption of TSPO in rat Leydig R2C cells reduced steroidogenesis (Papadopoulos et al. 1997). However, recent experiments with TSPO knockdown in steroidogenic cells was not shown to affect steroid hormone biosynthesis (Tu et al. 2014) as well as in a specific deletion of TSPO in steroidogenic Leydig cells did not impair their synthesis of testosterone (Morohaku et al. 2014). As stated in the recent review "At this point in time, a functional designation for TSPO is still actively being sought" (Selvaraj, Stocco, and Tu 2015).

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
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
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

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Rat (Papadopoulos et al., 1997)

References

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

Amsterdam, A., & Suh, B. S. (1991). An inducible functional peripheral benzodiazepine receptor in mitochondria of steroidogenic granulosa cells. Endocrinology, 129(1), 503–10. doi:10.1210/endo-129-1-503 Anholt, R., Pedersen, P., De Souza, E., & Snyder, S. (1986). The peripheral-type benzodiazepine receptor. Localization to the mitochondrial outer membrane. J. Biol. Chem., 261(2), 576–583. Anholt, R. R., De Souza, E. B., Oster-Granite, M. L., & Snyder, S. H. (1985). Peripheral-type benzodiazepine receptors: autoradiographic localization in whole-body sections of neonatal rats. The Journal of Pharmacology and Experimental Therapeutics, 233(2), 517–26.

Besman, M. J., Yanagibashi, K., Lee, T. D., Kawamura, M., Hall, P. F., & Shively, J. E. (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), 4897–901.

Borch, J., Metzdorff, S. B., Vinggaard, A. M., Brokken, L., & Dalgaard, M. (2006). Mechanisms underlying the anti-androgenic effects of diethylhexyl phthalate in fetal rat testis. Toxicology, 223(1-2), 144–55. doi:10.1016/j.tox.2006.03.015

Gazouli, M. (2002). Effect of Peroxisome Proliferators on Leydig Cell Peripheral-Type Benzodiazepine Receptor Gene Expression, Hormone-Stimulated Cholesterol Transport, and Steroidogenesis: Role of the Peroxisome Proliferator-Activator Receptor . Endocrinology, 143(7), 2571–2583. doi:10.1210/en.143.7.2571

Morohaku, K., Pelton, S. H., Daugherty, D. J., Butler, W. R., Deng, W., & Selvaraj, V. (2014). Translocator protein/peripheral benzodiazepine receptor is not required for steroid hormone biosynthesis. Endocrinology, 155(1), 89–97. doi:10.1210/en.2013-1556

Morohaku, K., Phuong, N. S., & Selvaraj, V. (2013). Developmental expression of translocator protein/peripheral benzodiazepine receptor in reproductive tissues. PloS One, 8(9), e74509. doi:10.1371/journal.pone.0074509

Papadopoulos, V., Amri, H., Li, H., Boujrad, N., Vidic, B., & Garnier, M. (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), 32129–35.

Selvaraj, V., Stocco, D. M., & Tu, L. N. (2015). TRANSLOCATOR PROTEIN (TSPO) AND STEROIDOGENESIS: A REAPPRAISAL. Molecular Endocrinology (Baltimore, Md.), me20151033. doi:10.1210/me.2015-1033

Thompson, C. J., Ross, S. M., & Gaido, K. W. (2004). Di(n-butyl) phthalate impairs cholesterol transport and steroidogenesis in the fetal rat testis through a rapid and reversible mechanism. Endocrinology, 145(3), 1227–37. doi:10.1210/en.2003-1475

Tu, L. N., Morohaku, K., Manna, P. R., Pelton, S. H., Butler, W. R., Stocco, D. M., & Selvaraj, V. (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), 27444–54. doi:10.1074/jbc.M114.578286

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), 261–75. doi:10.1007/s00441-012-1478-5

Zisterer, D. M., & Williams, D. C. (1997). Peripheral-type benzodiazepine receptors. General Pharmacology, 29(3), 305–14.