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Relationship: 369

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

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

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 non-adjacent Moderate 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 High NCBI
mouse Mus musculus Moderate NCBI
human Homo sapiens Low NCBI

Sex Applicability

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

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

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

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 Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

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 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
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

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).

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

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

See Table 1.

References

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

Bility, Moses T, Jerry T Thompson, Richard H McKee, Raymond M David, John H Butala, John P Vanden Heuvel, and Jeffrey M Peters. 2004. “Activation of Mouse and Human Peroxisome Proliferator-Activated Receptors (PPARs) by Phthalate Monoesters.” Toxicological Sciences : An Official Journal of the Society of Toxicology 82 (1) (November): 170–82. doi:10.1093/toxsci/kfh253. http://www.ncbi.nlm.nih.gov/pubmed/15310864.

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.