Relationship:370

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Key Event Relationship Overview

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Description of Relationship

Upstream Event Downstream Event/Outcome
PPARα, Activation Translocator protein (TSPO), Decrease

AOPs Referencing Relationship

AOP Name Type of Relationship Weight of Evidence Quantitative Understanding
PPARα activation in utero leading to impaired fertility in males Indirectly Leads to Weak

Taxonomic Applicability

Name Scientific Name Evidence Links
rat Rattus sp. Strong NCBI
mice Mus musculus Weak NCBI
human Homo sapiens Weak NCBI

How Does This Key Event Relationship Work

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).

Weight of Evidence

Biological Plausibility

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.

Empirical Support for Linkage

Gazouli et al showed that PPAR activators (Bezafibrate , MEHP ) inhibited the transfer or loading of cholesterol to the inner mitochondrial membrane in MA-10 mouse Leydig tumor cells and decreased levels of TSOP protein. Additionally, in R2C (Leydig tumor cell line) inhibited the formation of progesterone. The levels of the TSPO protein were decreased in testes of adult mice exposed to and DEHP (Gazouli 2002). Moreover, the finding that benzafibrate and phthalates inhibit the hormone-induced and constitutively sustained steroidogenesis with similar IC50 values indicates that these compounds act on a common regulatory component of the steroidogenic pathway (Gazouli 2002). In in vivo studies with rats exposed to DEHP the levels of TSOP (mRNA) were decreased dose-dependently in foetal testes (GD 21 testes), also on protein levels in Leydig cells (Borch et al. 2006). For details see Table1.

Compound
KE: PPARα,
Activation
KE: TSPO,
Decrease
species
Details
References
Phthalate (DBP)
EC50=30μM
n.a.
human

Monobenzyl phthalate (MBzP) metabolite of DBP

(Hurst and Waxman 2003)

Phthalate (DBP)
EC50=21μM *
EC50=63μM**
LOEC=100 μM
rodent

*MBzP

**mono-sec-butyl phthalate (MBuP) metabolite of DBP

(Hurst and Waxman 2003),(Gazouli 2002)

Phthalate (DEHP)
LOEC=30μM
LOEC=300 mg/kg /d


rodent

MEHP metabolite of DEHP

(Bility et al. 2004), (Gazouli 2002), (Borch et al. 2006)

Phthalate (DEHP)
Ki=15µM;
EC50 = 3.2μM
n.a.
human

MEHP metabolite of DEHP

(Lapinskas et al. 2005), (Hurst and Waxman 2003)

Bezafibrate
EC50=55μM
LOEC=100 μM
rodent

TSPO decreased by 80% in MA-10 Leydig cells

(Willson et al. 2000), (Gazouli 2002)

WY-14,643
EC50=0.00027μM
LOEC=50 mg/kg/d
rodent


(Pinelli et al. 2005), (Gazouli 2002)

Table 1. Summary table of empirical support for this KER. ED50 - half maximal effective dose, LOEC-lowest observed effect concentration, Bis(2-ethylhexyl) phthalate (DEHP), Dibutyl phthalate (DBP), WY-14,643 and Bezafibrate ligands of PPARα, n.a.- not available

Uncertainties or Inconsistencies

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).

Quantitative Understanding of the Linkage

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

Evidence Supporting Taxonomic Applicability

See Table 1.

References

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.