Relationship: 369



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

Upstream event


Activation, PPARα

Downstream event


Decrease, Steroidogenic acute regulatory protein (STAR)

Key Event Relationship Overview


AOPs Referencing Relationship


AOP Name Adjacency Weight of Evidence Quantitative Understanding
PPARα activation in utero leading to impaired fertility in males non-adjacent Moderate

Taxonomic Applicability


Term Scientific Term Evidence Link
rat Rattus norvegicus High NCBI
mouse Mus musculus Moderate NCBI
human Homo sapiens Low NCBI

Sex Applicability


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


Biological Plausibility


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 Evidence


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).




KE: PPARα, Activation

KE: StAR, Decrease

Phthalate (MBzP )


EC50 = 30 μM human (Hurst and Waxman 2003)


Phthalate (DBP)


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)


LOEC=30 μM (Bility et al. 2004)

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

Phthalate (MEHP)


Ki=15 µM (Lapinskas et al. 2005)

EC50 = 3.2 μM

(Hurst and Waxman 2003)


Phthalate (DiBP)


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)



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)


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)



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 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).

Quantitative Understanding of the Linkage


Response-response Relationship




Known modulating factors


Known Feedforward/Feedback loops influencing this KER


Domain of Applicability


See Table 1.



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