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Relationship: 370


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, Translocator protein (TSPO)

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 Low Arthur Author (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
mice Mus sp. Low 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

Activation of PPARα leads to decreased expression of cholesterol transport (TSPO) gene in steroidogenic cells (e.g. Leydig cell) and as a consequence the amount of cholesterol transported into mitochondria decreases (impact on steroid production).

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

PPARs are nuclear receptors that among many other functions regulate genes involved in cholesterol uptake and transport (Xie, Yang, and DePierre 2002), (Gazouli 2002), (Campioli et al. 2011). The indirect link of PPAR receptors in regulation of the cholesterol transport in mitochondria derives from studies demonstrating PPARα dependent control of TSOP (Gazouli 2002), (Campioli et al. 2011). PPARα is present in steroidogenic cells e.g. of the testes during its development as well as in adult testes (Schultz et al. 1999), (Boberg et al. 2008) and modulation of its activity has been shown to impact on TSOP transcriptional activity (Gazouli 2002). The exact mechanisms of this relationship are not known.

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

The exact mechanisms of this relationship are not known.

Treatment of adult mice with PPARα activator (DEHP or WY-14,643) resulted in reduced levls of circulating testosterone and testis TSPO mRNA, consistent with the in vitro effects (Gazouli 2002). In contrast, liver TSPO mRNA levels have been increased, indicating a tissue-specific regulation of TSOP expression by PPARα activator (Gazouli 2002). In the PPARα-null mice, compared with the wild-type controls, circulating testosterone levels were decreased suggesting a positive constitutive role for PPARα in maintaining Leydig cell steroid formation. Surprisingly, treatment of the PPARα-null mice with PPARα activators (DEHP and WY-14,643) restored testosterone formation and TSPO mRNA returned to normal levels, suggesting PPARα-independent pathways might be involved in the regulation of TSPO genes and steroidogenesis (Gazouli 2002). In support of this hypothesis, an other study demonstrated that part of the toxic effect of phthalate (DEHP) on testis was retained in PPARα-null mice (Ward et al. 1998).

There is some evidence involving additional PPARs in transcriptional regulation of TSPO:

  • PPARβ/δ (Campioli et al. 2011);
  • PPARγ isoform was also detected in testes (Boberg et al. 2008) and it was reduced by treatment of DEHP in parallel with the reduction of TSPO regulation (Borch et al. 2006).

A genomic study does not support the hypothesis that activation of PPARα/γ pathways is involved in the effects of phthalates on sexual differentiation of the male rat, as Wy-14,643 (PPARα activator) has no effect on testosterone production and the PPARγ isoform has not been detected in testes at gestation day 14-18 (Hannas et al. 2012). Differential patterns of TSPO expression in the foetal rat testis have been observed upon phthalate (DBP) treatment, whereas TSPO mRNA up-regulated protein levels were decreased in Leydig cells (Lehmann et al. 2004).

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
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.


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.

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.

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.

Campioli, Enrico, Amani Batarseh, Jiehan Li, and Vassilios Papadopoulos. 2011. “The Endocrine Disruptor Mono-(2-Ethylhexyl) Phthalate Affects the Differentiation of Human Liposarcoma Cells (SW 872).” Edited by Vasu D. Appanna. PloS One 6 (12) (January 21): e28750. doi:10.1371/journal.pone.0028750.

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.

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.

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.

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.

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.

Pinelli, Alessandra, Cristina Godio, Antonio Laghezza, Nico Mitro, Giuseppe Fracchiolla, Vincenzo Tortorella, Antonio Lavecchia, et al. 2005. “Synthesis, Biological Evaluation, and Molecular Modeling Investigation of New Chiral Fibrates with PPARalpha and PPARgamma Agonist Activity.” Journal of Medicinal Chemistry 48 (17) (August 25): 5509–19. doi:10.1021/jm0502844.

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.

Ward, J M, J M Peters, C M Perella, and F J Gonzalez. 1998. “Receptor and Nonreceptor-Mediated Organ-Specific Toxicity of di(2-Ethylhexyl)phthalate (DEHP) in Peroxisome Proliferator-Activated Receptor Alpha-Null Mice.” Toxicologic Pathology 26 (2): 240–6.

Willson, T M, P J Brown, D D Sternbach, and B R Henke. 2000. “The PPARs: From Orphan Receptors to Drug Discovery.” Journal of Medicinal Chemistry 43 (4) (February 24): 527–50.

Xie, Yi, Qian Yang, and Joseph W DePierre. 2002. “The Effects of Peroxisome Proliferators on Global Lipid Homeostasis and the Possible Significance of These Effects to Other Responses to These Xenobiotics: An Hypothesis.” Annals of the New York Academy of Sciences 973 (November): 17–25.