Relationship:437

From AOP-Wiki
Revision as of 13:30, 10 March 2015 by Wikibot (Talk | contribs)

Jump to: navigation, search


Key Event Relationship Overview

Please follow link to widget page to edit this section.

Description of Relationship

Upstream Event Downstream Event/Outcome
Translator protein (TSPO), Decrease Cholesterol transport in mitochondria, Reduction

AOPs Referencing Relationship

AOP Name Type of Relationship Weight of Evidence Quantitative Understanding
PPARα activation leading to impaired fertility in adult male rodents Directly Leads to Moderate

Taxonomic Applicability

Name Scientific Name Evidence Links

How Does This Key Event Relationship Work

Translocator Protein (TSPO) mediates the first step in the delivery of cholesterol 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 will impair the cholesterol delivery necessary for the hormone biosynthesis.

Weight of Evidence

Biological Plausibility

Empirical Support for Linkage

The effects of altered TSPO are to decrease cholesterol transport into Leydig cells (Gazouli, 2002), (Borch, Metzdorff, Vinggaard, Brokken, & Dalgaard, 2006). Additionally, Thompson et al observed decreased uptake of cholesterol in Leydig cell mitochondria upon exposure to phthalates (Thompson, Ross, & 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 does not 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, & 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)

References

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.