- 1 Key Event Relationship Overview
- 2 How Does This Key Event Relationship Work
- 3 Weight of Evidence
- 4 Quantitative Understanding of the Linkage
- 5 Evidence Supporting Taxonomic Applicability
- 6 References
Key Event Relationship Overview
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Description of Relationship
|Upstream Event||Downstream Event/Outcome|
|Translocator protein (TSPO), Decrease||Cholesterol transport in mitochondria, Reduction|
AOPs Referencing Relationship
|AOP Name||Type of Relationship||Weight of Evidence||Quantitative Understanding|
|PPARα activation in utero leading to impaired fertility in males||Directly Leads to||Weak|
How Does This Key Event Relationship Work
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.
Weight of Evidence
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).
Empirical Support for Linkage
The decreased TSPO protein levels leads to decreased cholesterol transport into Leydig cells (Gazouli 2002), (Borch et al. 2006). Moreover, Thompson et al., observed decreased uptake of cholesterol in Leydig cell mitochondria upon exposure to phthalates (Thompson, Ross, and Gaido 2004).
Uncertainties or Inconsistencies
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).
Quantitative Understanding of the Linkage
Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?
Evidence Supporting Taxonomic Applicability
Rat (Papadopoulos et al., 1997)
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.