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Activation, PPARα leads to Decrease, Steroidogenic acute regulatory protein (STAR)
Key Event Relationship Overview
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||non-adjacent||Moderate||Arthur Author (send email)||Open for citation & comment||EAGMST Under Review|
Life Stage Applicability
Key Event Relationship Description
The direct link of PPARα in regulation of the cholesterol transport in mitochondria and hormone synthesis derives from studies demonstrating that PPARα may act as indirect transrepressor of the key steroidogenic factor-1 (SF-1) (S. Plummer et al. 2007), (S. M. Plummer et al. 2013). SF-1 is a transcription factor essential for expression of genes involved in steroidogenesis (including Steroidogenic acute regulatory protein (StAR)).
Evidence Supporting this KER
The PPARα is expressed in foetal rat Leydig cells (Boberg et al. 2008), (S. M. Plummer et al. 2013) and in adult rat Leydig cells (Schultz et al. 1999). Recent studies have shown that foetal testes contained PPARα protein–binding peaks in CYP11a, StAR, and CYP17a regulatory regions (S. M. Plummer et al. 2013). Binding of PPARα to promoter of steroidogenic gene occurs at binding sites different from those of SF-1, indicating that PPARα may be an indirect repressor of SF1 binding. Moreover, it is possible that PPARα could act via sequestration of the shared coactivator CBP (S. M. Plummer et al. 2013). PPARα and SF-1 share a common coactivator, CREB-binding protein (CBP), which is present in limited concentrations (McCampbell 2000). Binding of CBP to PPARα could therefore starve SF-1 from a cofactor essential for its transactivation functions. SF-1 controls transcription of the StAR gene (Sugawara et al. 1996). Steroidogenic acute regulatory (StAR) protein plays a critical role in the movement of cholesterol from the outer to the inner mitochondrial membrane (Stocco 2001). Hence, it seems likely that the ability of PPARα to interfere with SF-1 binding/transactivation caused by exposure to chemicals (e.g. phthalates) could affect the StAR expression and the cholesterol transport in mitochondria.
Uncertainties and Inconsistencies
PPARα was also shown to regulate Translator protein (TSPO), which is a mitochondrial outer membrane protein implicated in cholesterol import to the inner mitochondrial (for details see Relationship:370). Moreover, there is evidence that activated PPARα regulates the expression of enzymes involved in steroid metabolism (17β-hydroxysteroid dehydrogenase IV, 11β-hydroxysteroid dehydrogenase I, and 3β-hydroxysteroid dehydrogenase V (Hermanowski-Vosatka et al. 2000), (Corton et al. 1996), (Wong et al. 2002)).
Inconsistencies In utero rat exposure to the PPARα agonist Wy-14,643 did not reduce fetal testis steroidogenic gene expression or testosterone production (Hannas et al. 2012).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
See Table 1.
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Boberg, Julie, Stine Metzdorff, Rasmus Wortziger, Marta Axelstad, Leon Brokken, Anne Marie Vinggaard, Majken Dalgaard, and Christine Nellemann. 2008. “Impact of Diisobutyl Phthalate and Other PPAR Agonists on Steroidogenesis and Plasma Insulin and Leptin Levels in Fetal Rats.” Toxicology 250 (2-3) (September 4): 75–81. doi:10.1016/j.tox.2008.05.020. http://www.ncbi.nlm.nih.gov/pubmed/18602967.
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Corton, JC, C Bocos, ES Moreno, A Merritt, DS Marsman, PJ Sausen, RC Cattley, and JA Gustafsson. 1996. “Rat 17 Beta-Hydroxysteroid Dehydrogenase Type IV Is a Novel Peroxisome Proliferator-Inducible Gene.” Mol. Pharmacol. 50 (5) (November 1): 1157–1166. http://molpharm.aspetjournals.org/content/50/5/1157.abstract?ijkey=a767a7a5a99dd83cc9fe3e4b601372c7ea4caa62&keytype2=tf_ipsecsha.
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) (July 1): 2571–2583. doi:10.1210/en.143.7.2571. http://endo.endojournals.org/content/143/7/2571.
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Hermanowski-Vosatka, A, D Gerhold, S S Mundt, V A Loving, M Lu, Y Chen, A Elbrecht, et al. 2000. “PPARalpha Agonists Reduce 11beta-Hydroxysteroid Dehydrogenase Type 1 in the Liver.” Biochemical and Biophysical Research Communications 279 (2) (December 20): 330–6. doi:10.1006/bbrc.2000.3966. http://www.ncbi.nlm.nih.gov/pubmed/11118287.
Hurst, Christopher H, and David J Waxman. 2003. “Activation of PPARalpha and PPARgamma by Environmental Phthalate Monoesters.” Toxicological Sciences : An Official Journal of the Society of Toxicology 74 (2) (August): 297–308. doi:10.1093/toxsci/kfg145. http://www.ncbi.nlm.nih.gov/pubmed/12805656.
Lapinskas, Paula J., Sherri Brown, Lisa M. Leesnitzer, Steven Blanchard, Cyndi Swanson, Russell C. Cattley, and J. Christopher Corton. 2005. “Role of PPARα in Mediating the Effects of Phthalates and Metabolites in the Liver.” Toxicology 207 (1): 149–163. http://www.sciencedirect.com/science/article/pii/S0300483X04005633.
Lehmann, Kim P, Suzanne Phillips, Madhabananda Sar, Paul M D Foster, and Kevin W Gaido. 2004. “Dose-Dependent Alterations in Gene Expression and Testosterone Synthesis in the Fetal Testes of Male Rats Exposed to Di (n-Butyl) Phthalate.” Toxicological Sciences : An Official Journal of the Society of Toxicology 81 (1) (September 1): 60–8. doi:10.1093/toxsci/kfh169. http://toxsci.oxfordjournals.org/content/81/1/60.abstract?ijkey=99364980d6548f969a82406deb6600873a38be36&keytype2=tf_ipsecsha.
Li, Yufei, Doni Hikmat Ramdhan, Hisao Naito, Nozomi Yamagishi, Yuki Ito, Yumi Hayashi, Yukie Yanagiba, et al. 2011. “Ammonium Perfluorooctanoate May Cause Testosterone Reduction by Adversely Affecting Testis in Relation to PPARα.” Toxicology Letters 205 (3) (September 10): 265–72. doi:10.1016/j.toxlet.2011.06.015. http://www.ncbi.nlm.nih.gov/pubmed/21712084.
Liu, Kejun, Kim P Lehmann, Madhabananda Sar, S Stanley Young, and Kevin W Gaido. 2005. “Gene Expression Profiling Following in Utero Exposure to Phthalate Esters Reveals New Gene Targets in the Etiology of Testicular Dysgenesis.” Biology of Reproduction 73 (1) (July): 180–92. doi:10.1095/biolreprod.104.039404. http://www.ncbi.nlm.nih.gov/pubmed/15728792.
McCampbell, A. 2000. “CREB-Binding Protein Sequestration by Expanded Polyglutamine.” Human Molecular Genetics 9 (14) (September 1): 2197–2202. doi:10.1093/hmg/9.14.2197. http://hmg.oxfordjournals.org/content/9/14/2197.abstract?ijkey=c35580e57df64d1fc98fb242bf4ed19362a4a3ce&keytype2=tf_ipsecsha.
Plummer, Simon M, Dhritiman Dan, Joanne Quinney, Nina Hallmark, Richard D Phillips, Michael Millar, Sheila Macpherson, and Clifford R Elcombe. 2013. “Identification of Transcription Factors and Coactivators Affected by Dibutylphthalate Interactions in Fetal Rat Testes.” Toxicological Sciences : An Official Journal of the Society of Toxicology 132 (2) (April): 443–57. doi:10.1093/toxsci/kft016. http://www.ncbi.nlm.nih.gov/pubmed/23358192.
Plummer, Simon, Richard M Sharpe, Nina Hallmark, Isobel Kim Mahood, and Cliff Elcombe. 2007. “Time-Dependent and Compartment-Specific Effects of in Utero Exposure to Di(n-Butyl) Phthalate on Gene/protein Expression in the Fetal Rat Testis as Revealed by Transcription Profiling and Laser Capture Microdissection.” Toxicological Sciences : An Official Journal of the Society of Toxicology 97 (2) (June 1): 520–32. doi:10.1093/toxsci/kfm062. http://www.ncbi.nlm.nih.gov/pubmed/17379624.
Schultz, R, W Yan, J Toppari, A Völkl, J A Gustafsson, and M Pelto-Huikko. 1999. “Expression of Peroxisome Proliferator-Activated Receptor Alpha Messenger Ribonucleic Acid and Protein in Human and Rat Testis.” Endocrinology 140 (7) (July): 2968–75. doi:10.1210/endo.140.7.6858. http://www.ncbi.nlm.nih.gov/pubmed/10385388.
Shultz, V. D. 2001. “Altered Gene Profiles in Fetal Rat Testes after in Utero Exposure to Di(n-Butyl) Phthalate.” Toxicological Sciences 64 (2) (December 1): 233–242. doi:10.1093/toxsci/64.2.233. http://toxsci.oxfordjournals.org/content/64/2/233.abstract?ijkey=b8af27acfe10695847a4e8a9b568882405d071ae&keytype2=tf_ipsecsha. Stocco, D M. 2001. “StAR Protein and the Regulation of Steroid Hormone Biosynthesis.” Annual Review of Physiology 63 (January): 193–213. doi:10.1146/annurev.physiol.63.1.193. http://www.ncbi.nlm.nih.gov/pubmed/11181954.
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Vanden Heuvel, John P, Jerry T Thompson, Steven R Frame, and Peter J Gillies. 2006. “Differential Activation of Nuclear Receptors by Perfluorinated Fatty Acid Analogs and Natural Fatty Acids: A Comparison of Human, Mouse, and Rat Peroxisome Proliferator-Activated Receptor-Alpha, -Beta, and -Gamma, Liver X Receptor-Beta, and Retinoid X Rec.” Toxicological Sciences : An Official Journal of the Society of Toxicology 92 (2) (August): 476–89. doi:10.1093/toxsci/kfl014. http://www.ncbi.nlm.nih.gov/pubmed/16731579.
Walsh, L P, C N Kuratko, and D M Stocco. 2000. “Econazole and Miconazole Inhibit Steroidogenesis and Disrupt Steroidogenic Acute Regulatory (StAR) Protein Expression Post-Transcriptionally.” The Journal of Steroid Biochemistry and Molecular Biology 75 (4-5) (December 31): 229–36. http://www.ncbi.nlm.nih.gov/pubmed/11282276.
Wong, Jean S, Xiaoqin Ye, Christy R Muhlenkamp, and Sarjeet S Gill. 2002. “Effect of a Peroxisome Proliferator on 3 Beta-Hydroxysteroid Dehydrogenase.” Biochemical and Biophysical Research Communications 293 (1) (April 26): 549–53. doi:10.1016/S0006-291X(02)00235-8. http://www.ncbi.nlm.nih.gov/pubmed/12054636.