API

Relationship: 369

Title

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Activation, PPARα leads to Decrease, Steroidogenic acute regulatory protein (STAR)

Upstream event

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Activation, PPARα

Downstream event

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Decrease, Steroidogenic acute regulatory protein (STAR)

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Directness Weight of Evidence Quantitative Understanding
PPARα activation in utero leading to impaired fertility in males indirectly leads to Moderate

Taxonomic Applicability

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Term Scientific Term Evidence Link
rat Rattus norvegicus Strong NCBI
mouse Mus musculus Moderate NCBI
human Homo sapiens Weak NCBI

Sex Applicability

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Life Stage Applicability

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How Does This Key Event Relationship Work

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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)).

Weight of Evidence

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Biological Plausibility

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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.

Empirical Support for Linkage

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PPARα agonists can suppress Leydig cell steroidogenesis (Gazouli 2002), and downregulate steroidogenic genes including StAR (Borch et al. 2006), (Lehmann et al. 2004), (Liu et al. 2005), for details see Table 1. Moreover, PPARα agonists, which do not directly transrepress the StAR promoter, have been found to downregulate the expression of this gene in steroidogenic tissues (in mice ovaries) (Toda et al. 2003).

 

Compound

species

KE: PPARα, Activation

KE: StAR, Decrease

Phthalate (MBzP )

human

EC50 = 30 μM human (Hurst and Waxman 2003)

n.a.

Phthalate (DBP)

rodent

EC50 = 21 μM MBzP

EC50 = 63 μM (Hurst and Waxman 2003) MBuP

LOEC=50 mg/kg/day (Borch et al. 2006) (Lehmann et al. 2004), (Shultz 2001)

Phthalate (MEHP)

rodent

LOEC=30 μM (Bility et al. 2004)

LOEC=300 mg/kg/day (Borch et al. 2006)

Phthalate (MEHP)

human

Ki=15 µM (Lapinskas et al. 2005)

EC50 = 3.2 μM

(Hurst and Waxman 2003)

n.a.

Phthalate (DiBP)

rat

LOEC=600 mg/kg/day, decrease of PPARα mRNA, at GD 19 and 21 in testes of foetuses (Boberg et al. 2008)

LOEC=600 mg/kg/day, decrease of StAR mRNA at GD 19 and 21 in testes of foetuses (Boberg et al. 2008)

Econazole

rodent

AC50=0.0729 μM (ToxCastTM Data)

LOEC=25 μM, mouse MA-10 Leydig tumor cell line, Decrease in StAR activity and/or expression (Walsh, Kuratko, and Stocco 2000)

Perfluorooctanoate (PFOA)

mice

3T3-L1 cells transfected with human, mouse and rat PPARα (Vanden Heuvel et al. 2006)

LOEC= 5.0 mg/kg/day mRNA StAR decrease in the testis of wild-type mice, LOEC=1.0 mg/kg/day mRNA StAR decrease in testis of

PPARα-humanized mice (not in the PPARα –null mice) (Li et al. 2011)

Fenofibrate

mice

PPAR agonist

Increase PPARα protein (Toda et al. 2003).

Decrease of StAR (protein level, in mice ovaries) (Toda et al. 2003)

Table 1. Summary table for empirical support of KER. ED50 - half maximal effective concentration, LOEC-lowest observed effect concentration, Bis(2-ethylhexyl) phthalate (DEHP), Dibutyl phthalate (DBP), diisobutyl phthalate (DiBP), mono-sec-butyl phthalate (MBuP), n.a - not available.

Uncertainties or Inconsistencies

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Uncertainties

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).

Quantitative Understanding of the Linkage

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Evidence Supporting Taxonomic Applicability

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See Table 1.

References

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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.

Borch, Julie, Stine Broeng Metzdorff, Anne Marie Vinggaard, Leon Brokken, and Majken Dalgaard. 2006. “Mechanisms Underlying the Anti-Androgenic Effects of Diethylhexyl Phthalate in Fetal Rat Testis.” Toxicology 223 (1-2) (June 1): 144–55. doi:10.1016/j.tox.2006.03.015. http://www.sciencedirect.com/science/article/pii/S0300483X0600165X.

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.

Hannas, Bethany R, Christy S Lambright, Johnathan Furr, Nicola Evans, Paul M D Foster, Earl L Gray, and Vickie S Wilson. 2012. “Genomic Biomarkers of Phthalate-Induced Male Reproductive Developmental Toxicity: A Targeted RT-PCR Array Approach for Defining Relative Potency.” Toxicological Sciences : An Official Journal of the Society of Toxicology 125 (2) (February): 544–57. doi:10.1093/toxsci/kfr315. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3262859&tool=pmcentrez&rendertype=abstract.

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.

Sugawara, T, J A Holt, M Kiriakidou, and J F Strauss. 1996. “Steroidogenic Factor 1-Dependent Promoter Activity of the Human Steroidogenic Acute Regulatory Protein (StAR) Gene.” Biochemistry 35 (28) (July 16): 9052–9. doi:10.1021/bi960057r. http://www.ncbi.nlm.nih.gov/pubmed/8703908.

Toda, Katsumi, Teruhiko Okada, Chisata Miyaura, and Toshiji Saibara. 2003. “Fenofibrate, a Ligand for PPARalpha, Inhibits Aromatase Cytochrome P450 Expression in the Ovary of Mouse.” Journal of Lipid Research 44 (2) (February): 265–70. doi:10.1194/jlr.M200327-JLR200. http://www.ncbi.nlm.nih.gov/pubmed/12576508. ToxCastTM Data. “ToxCastTM Data.” US Environmental Protection Agency. http://www.epa.gov/ncct/toxcast/data.html.

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.