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== Key Event Overview ==
 
== Key Event Overview ==
Please follow link to [//{{SERVERNAME}}/aopportal/events/{{PAGENAMEE}} widget page] to edit this section.
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Please follow link to [//{{SERVERNAME}}/events/{{PAGENAMEE}} widget page] to edit this section.
 +
 
 +
<span style="color:#FF0000">'''If you manually enter text in this section, it will get automatically altered or deleted in subsequent edits using the widgets.'''</span>
  
 
=== AOPs Including This Key Event ===
 
=== AOPs Including This Key Event ===
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|-
 
|-
  
|[[Aop:18|PPAR alpha activation leading to decreased fertility upon utero exposure in rodent males]]||MIE||[[Aop:18#Essentiality of the Key Events|Weak]]
+
|[[Aop:18|PPARα activation in utero leading to impaired fertility in males]]||MIE||[[Aop:18#Essentiality of the Key Events|Weak]]
  
 
|-
 
|-
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|[[Aop:61|NFE2L2/FXR activation leading to hepatic steatosis]]||KE||
 
|[[Aop:61|NFE2L2/FXR activation leading to hepatic steatosis]]||KE||
 +
 +
|-
 +
 +
|[[Aop:37|PPARalpha-dependent liver cancer]]||MIE||[[Aop:37#Essentiality of the Key Events|Strong]]
  
 
|-
 
|-
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=== Chemical Initiators ===
 
=== Chemical Initiators ===
The following are chemical initiators that operate through this AOP:
+
The following are chemical initiators that operate directly through this Event:
 +
 
 
#[[Chem_Init:65|Di(2-ethylhexyl) phthalate]]
 
#[[Chem_Init:65|Di(2-ethylhexyl) phthalate]]
 
#[[Chem_Init:64|Mono(2-ethylhexyl) phthalate]]
 
#[[Chem_Init:64|Mono(2-ethylhexyl) phthalate]]
 
  
 
=== Taxonomic Applicability ===
 
=== Taxonomic Applicability ===
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|-
 
|-
  
| rat || Rattus sp. || [[Event:227#Evidence Supporting Taxonomic Applicability|Strong]] || [http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10118 NCBI]
+
|rat||Rattus sp.||[[Event:227#Evidence Supporting Taxonomic Applicability|Strong]]||[http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10118 NCBI]
  
 
|-
 
|-
  
| mouse || Mus musculus || [[Event:227#Evidence Supporting Taxonomic Applicability|Weak]] || [http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090 NCBI]
+
|mouse||Mus musculus||[[Event:227#Evidence Supporting Taxonomic Applicability|Strong]]||[http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090 NCBI]
  
 
|-
 
|-
  
| human || Homo sapiens || [[Event:227#Evidence Supporting Taxonomic Applicability|Moderate]] || [http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606 NCBI]
+
|human||Homo sapiens||[[Event:227#Evidence Supporting Taxonomic Applicability|Strong]]||[http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606 NCBI]
  
 
|-
 
|-
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'''Biological state'''
 
'''Biological state'''
  
The Peroxisome Proliferator Activated receptor α (PPARα) belongs to [[Peroxisome Proliferator Activated receptors (PPARs; NR1C)]] steroid/thyroid/retinoid receptor superfamily of transcription factors.
+
The Peroxisome Proliferator Activated receptor α (PPARα) belongs to the  [[Peroxisome Proliferator Activated receptors (PPARs; NR1C)]] steroid/thyroid/retinoid receptor superfamily of transcription factors.
  
 
'''Biological compartments'''
 
'''Biological compartments'''
  
PPARα is expressed in high levels in tissues that perform significant catabolism of fatty acids (FAs), such as brown adipose tissue, liver, heart, kidney, and intestine (Michalik et al. 2006). The receptor is present in also in skeletal muscle, intestine, pancreas, lung, placenta and testes (Mukherjee et al. 1997), (Schultz et al. 1999).  
+
PPARα is expressed in high levels in tissues that perform significant catabolism of fatty acids (FAs), such as brown adipose tissue, liver, heart, kidney, and intestine (Michalik et al. 2006). The receptor is present also in skeletal muscle, intestine, pancreas, lung, placenta and testes (Mukherjee et al. 1997), (Schultz et al. 1999).  
  
 
'''General role in biology'''
 
'''General role in biology'''
  
PPARs are activated by fatty acids and their derivatives; they are sensors of dietary lipids and are involved in lipid and carbohydrate metabolism; immune response and peroxisome proliferation (Wahli and Desvergne 1999), (Evans, Barish, & Wang, 2004). PAPRα is a also a target of hypothalamic hormone signalling and was found to play a role in embryonic development (Yessoufou and Wahli 2010).
+
PPARs are activated by fatty acids and their derivatives; they are sensors of dietary lipids and are involved in lipid and carbohydrate metabolism, immune response and peroxisome proliferation (Wahli and Desvergne 1999), (Evans, Barish, & Wang, 2004). PAPRα is a also a target of hypothalamic hormone signalling and was found to play a role in embryonic development (Yessoufou and Wahli 2010).
  
 
Fibrates, activators of PPARα, are commonly used to treat hypertriglyceridemia and other dyslipidemic states as they have been shown to decrease circulating lipid levels (Lefebvre et al. 2006).
 
Fibrates, activators of PPARα, are commonly used to treat hypertriglyceridemia and other dyslipidemic states as they have been shown to decrease circulating lipid levels (Lefebvre et al. 2006).
Line 100: Line 106:
 
== How it is Measured or Detected ==
 
== How it is Measured or Detected ==
  
Binding of ligands to PPARα is measured using binding assays in vitro and in silico, whereas the information about functional activation is derived from the transactivation assays (e.g. reporter assay with reporter gene) that demonstrates functional activation of a nuclear receptor by a specific compound. Binding of agonists within the ligand-binding site of PPARs causes a conformational change promoting binding to transcriptional coactivators. Conversely, binding of antagonists results in a conformation that favours the binding of corepressors (Yu and Reddy 2007) (Viswakarma et al. 2010).
+
Binding of ligands to PPARα is measured using binding assays in vitro and in silico, whereas the information about functional activation is derived from transactivation assays (e.g. transactivation assay with reporter gene) that demonstrate functional activation of a nuclear receptor by a specific compound. Binding of agonists within the ligand-binding site of PPARs causes a conformational change of nuclear receptor that promotes binding to transcriptional co-activators. Conversely, binding of antagonists results in a conformation that favours the binding of co-repressors (Yu and Reddy 2007), (Viswakarma et al. 2010).
Transactivation assays are performed using transient or stably transfected cells with the PPAR expression plasmid and a reporter plasmid, correspondingly.
+
Transactivation assays are performed using transient or stably transfected cells with the PPARα expression plasmid and a reporter plasmid, respectively. There are also other methods that have been used to measure PPARα activity, such as the Electrophoretic Mobility Shift Assay (EMSA) or commercially available PPARα transcription factor assay kits, see Table 1.
 +
The transactivation (stable transfection) assay provides the most applicable OECD Level 2 assay (i.e. In vitro assays providing mechanistic data) aimed at identifying the initiating event leading to an adverse outcome (LeBlanc, Norris, and Kloas 2011). Currently no internationally validated assays for regulatory purposes are available.
  
The transactivation assay provides the most applicable OECD Level 2 assay (i.e. In vitro assays providing mechanistic data) aimed at identifying the initiating event leading to adverse outcome (LeBlanc, Norris, and Kloas 2011). Currently no internationally validated assays are available.
 
  
Transactivation assays are performed using transient or stably transfected cells with the PPAR expression plasmid and a reporter plasmid, correspondingly. There are also other methods that have been used to measure PPAR activity, such as the Electrophoretic Mobility Shift Assay (EMSA) or commercially available PPARα transcription factor assay kits, for details see table 1.
 
  
{| {{wikitable}} border="1" style="border-collapse:collapse;font-size:75%"
+
{| class="wikitable" id="Event227"
|-
+
! Key event
|
+
! colspan="7" | PPARα activation
Biological level of organisation
+
 
+
| colspan="7" |
+
Molecular
+
 
+
|-
+
|
+
Key event
+
 
+
| colspan="7" |
+
PPARα activation
+
  
 
|-
 
|-
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|
 
|
<center>In silico</center>
+
<center>''In silico''</center>
  
 
|
 
|
<center>In vitro</center>
+
<center>''In vitro''</center>
  
 
| colspan="3" |
 
| colspan="3" |
<center>In vitro</center>
+
<center>''In vitro''</center>
  
 
| colspan="2" |
 
| colspan="2" |
<center>In vitro, ex vivo</center>
+
<center>''In vitro, ex vivo''</center>
  
 
|-
 
|-
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| colspan="2" |
 
| colspan="2" |
PPARα once activated by a ligand, the receptor binds to a promoter element in the gene for target gene and activates its transcription. The bound (activated) to DNA PPAR is measured.
+
PPARα once activated by a ligand, the receptor binds to a promoter element in the gene for target gene and activates its transcription. The DNA-bound (activated) PPAR is measured.
  
 
|-
 
|-
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|
 
|
A binding interaction between a small molecule ligand and an enzyme protein may result in activation or inhibition of the enzyme. If the protein is a receptor, ligand binding may result in agonism or antagonism
+
A binding interaction between a small molecule ligand and an enzyme protein may result in activation or inhibition of the enzyme. If the protein is a receptor, ligand binding may result in agonism or antagonism of the normal activity of the receptor.
  
 
|
 
|
Assesses the ability of compounds to bind to human PPARα. Identifies the modulators of PPARα.
+
Assesses the ability of compounds to bind to PPARα. Identifies the modulators of PPARα.
  
 
| colspan="3" |
 
| colspan="3" |
The changes in activity of reporter gene levels functionally linked to a PPAR-responsive element/promoter gives information about the activity of the PPAR activation.
+
The changes in activity of reporter gene levels functionally linked to a PPAR-responsive element/promoter gives information about the nature of the PPAR activation.
  
 
| colspan="2" |
 
| colspan="2" |
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|
 
|
This assay determines whether compounds interact directly with PPARs. The type of beads that are involved in the SPA are microscopic in size and within the beads itself, there is a scintillant which emits light when it is stimulated. Stimulation occurs when radio-labelled molecules interact and bind to the surface of the bead and trigger the bead to emit light.
+
This assay determines whether compounds interact directly with PPARs. The type of beads that are involved in the SPA are microscopic in size and within the beads, there is a scintillant which emits light when it is stimulated. Stimulation occurs when radio-labelled molecules interact and bind to the surface of the bead and trigger the bead to emit light.
  
 
|
 
|
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|
 
|
In vitro screening
+
''In vitro'' screening
  
 
|
 
|
In vitro Screening, functional studies activity (reported use: agonist)
+
''In vitro'' Screening, functional studies activity (reported use: agonist)
  
 
|
 
|
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|
 
|
In vitro Screening functional activity (antagonist/agonist)
+
''In vitro'' Screening functional activity (antagonist/agonist)
  
 
|
 
|
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|
 
|
 
&nbsp;
 
&nbsp;
 
|-
 
|
 
Source
 
 
|
 
Research/
 
 
commercial
 
 
|
 
&nbsp;Research
 
 
|
 
Research
 
 
|
 
Research
 
 
|
 
commercial
 
 
|
 
&nbsp;commercial
 
 
|
 
Research/commercial
 
  
 
|-
 
|-
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|}
 
|}
 +
Table 1 Summary of the chosen methods to measure the PPARα activation.
  
 
== Evidence Supporting Taxonomic Applicability ==
 
== Evidence Supporting Taxonomic Applicability ==
  
PPARα have been identified in frog (Xenopus laevis), mouse, identified in human, rat, fish, hamster and chicken (reviewed in (Wahli and Desvergne 1999)).
+
PPARα has been identified in frog (Xenopus laevis), mouse, human, rat, fish, hamster and chicken (reviewed in (Wahli and Desvergne 1999)).
  
 
==Evidence for Chemical Initiation of this Molecular Initiating Event==
 
==Evidence for Chemical Initiation of this Molecular Initiating Event==
 +
 +
Fibrates are ligands of PPARα (Staels et al. 1998).
  
 
Phthalates  
 
Phthalates  
  
MHEP (CAS 4376-20-9) directly binds in vitro to PPARα (Lapinskas et al. 2005) and activates this receptor in transactivation assays PPARα (Lapinskas et al. 2005), (Maloney and Waxman 1999), (Hurst and Waxman 2003), (Bility et al. 2004), (Lampen, Zimnik, and Nau 2003), (Venkata et al. 2006) ].  
+
MHEP (CAS 4376-20-9) directly binds ''in vitro'' to PPARα (Lapinskas et al. 2005) and activates this receptor in transactivation assays PPARα (Lapinskas et al. 2005), (Maloney and Waxman 1999), (Hurst and Waxman 2003), (Bility et al. 2004), (Lampen, Zimnik, and Nau 2003), (Venkata et al. 2006) ].  
DEHP (CAS 117-81-7) has not been found to bind and activate PPARα (Lapinskas et al. 2005), (Maloney and Waxman 1999). However, the recent studies shown activation of PPARα (ToxCast).  
+
DEHP (CAS 117-81-7) has not been found to bind and activate PPARα (Lapinskas et al. 2005), (Maloney and Waxman 1999). However, the recent studies shown activation of PPARα (ToxCastTM Data).  
  
Notably, PPARα are responsive to DEHP in vitro as they are translocated to the nucleus (in primary Sertoli cells) (Dufour et al. 2003), (Bhattacharya et al. 2005).
+
Notably, PPARα are responsive to DEHP ''in vitro'' as they are translocated to the nucleus (in primary Sertoli cells) (Dufour et al. 2003), (Bhattacharya et al. 2005).
Expression of PPARα [mRNA and protein] have been also reported modulated by phthtalates: (to be upregulated in vivo upon DEHP treatment (Xu et al. 2010), downregulated by Diisobutyl phthalate (DiBP) (Boberg et al. 2008)).
+
Expression of PPARα [mRNA and protein] has been reported to be also modulated by phthtalates: (to be up-regulated ''in vivo'' upon DEHP treatment (Xu et al. 2010) and down-regulated by Diisobutyl phthalate (DiBP) (Boberg et al. 2008)).
  
 +
 +
Perfluorooctanoic Acid (PFOA) is known to activate PPARα (Vanden Heuvel et al. 2006).
  
 
Organotin  
 
Organotin  
Line 404: Line 376:
  
 
Mukherjee, R, L Jow, G E Croston, and J R Paterniti. 1997. “Identification, Characterization, and Tissue Distribution of Human Peroxisome Proliferator-Activated Receptor (PPAR) Isoforms PPARgamma2 versus PPARgamma1 and Activation with Retinoid X Receptor Agonists and Antagonists.” The Journal of Biological Chemistry 272 (12) (March 21): 8071–6.
 
Mukherjee, R, L Jow, G E Croston, and J R Paterniti. 1997. “Identification, Characterization, and Tissue Distribution of Human Peroxisome Proliferator-Activated Receptor (PPAR) Isoforms PPARgamma2 versus PPARgamma1 and Activation with Retinoid X Receptor Agonists and Antagonists.” The Journal of Biological Chemistry 272 (12) (March 21): 8071–6.
 +
 
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.
 
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.
 +
 +
Staels, B., J. Dallongeville, J. Auwerx, K. Schoonjans, E. Leitersdorf, and J.-C. Fruchart. 1998. “Mechanism of Action of Fibrates on Lipid and Lipoprotein Metabolism.” Circulation 98 (19) (November 10): 2088–2093. doi:10.1161/01.CIR.98.19.2088.
 +
 +
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.
  
 
Venkata, Nagaraj Gopisetty, Jodie a Robinson, Peter J Cabot, Barbara Davis, Greg R Monteith, and Sarah J Roberts-Thomson. 2006. “Mono(2-Ethylhexyl)phthalate and Mono-N-Butyl Phthalate Activation of Peroxisome Proliferator Activated-Receptors Alpha and Gamma in Breast.” Toxicology Letters 163 (3) (June 1): 224–34. doi:10.1016/j.toxlet.2005.11.001.
 
Venkata, Nagaraj Gopisetty, Jodie a Robinson, Peter J Cabot, Barbara Davis, Greg R Monteith, and Sarah J Roberts-Thomson. 2006. “Mono(2-Ethylhexyl)phthalate and Mono-N-Butyl Phthalate Activation of Peroxisome Proliferator Activated-Receptors Alpha and Gamma in Breast.” Toxicology Letters 163 (3) (June 1): 224–34. doi:10.1016/j.toxlet.2005.11.001.

Latest revision as of 18:02, 8 September 2016



Event Title

PPARα, Activation
Short name: PPARα, Activation

Key Event Overview

Please follow link to widget page to edit this section.

If you manually enter text in this section, it will get automatically altered or deleted in subsequent edits using the widgets.

AOPs Including This Key Event

AOP Name Event Type Essentiality
PPARα activation in utero leading to impaired fertility in males MIE Weak
PPARα activation leading to impaired fertility in adult male rodents MIE Weak
NFE2L2/FXR activation leading to hepatic steatosis KE
PPARalpha-dependent liver cancer MIE Strong

Chemical Initiators

The following are chemical initiators that operate directly through this Event:

  1. Di(2-ethylhexyl) phthalate
  2. Mono(2-ethylhexyl) phthalate

Taxonomic Applicability

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

Level of Biological Organization

Biological Organization
Molecular

How this Key Event works

Biological state

The Peroxisome Proliferator Activated receptor α (PPARα) belongs to the Peroxisome Proliferator Activated receptors (PPARs; NR1C) steroid/thyroid/retinoid receptor superfamily of transcription factors.

Biological compartments

PPARα is expressed in high levels in tissues that perform significant catabolism of fatty acids (FAs), such as brown adipose tissue, liver, heart, kidney, and intestine (Michalik et al. 2006). The receptor is present also in skeletal muscle, intestine, pancreas, lung, placenta and testes (Mukherjee et al. 1997), (Schultz et al. 1999).

General role in biology

PPARs are activated by fatty acids and their derivatives; they are sensors of dietary lipids and are involved in lipid and carbohydrate metabolism, immune response and peroxisome proliferation (Wahli and Desvergne 1999), (Evans, Barish, & Wang, 2004). PAPRα is a also a target of hypothalamic hormone signalling and was found to play a role in embryonic development (Yessoufou and Wahli 2010).

Fibrates, activators of PPARα, are commonly used to treat hypertriglyceridemia and other dyslipidemic states as they have been shown to decrease circulating lipid levels (Lefebvre et al. 2006).

How it is Measured or Detected

Binding of ligands to PPARα is measured using binding assays in vitro and in silico, whereas the information about functional activation is derived from transactivation assays (e.g. transactivation assay with reporter gene) that demonstrate functional activation of a nuclear receptor by a specific compound. Binding of agonists within the ligand-binding site of PPARs causes a conformational change of nuclear receptor that promotes binding to transcriptional co-activators. Conversely, binding of antagonists results in a conformation that favours the binding of co-repressors (Yu and Reddy 2007), (Viswakarma et al. 2010). Transactivation assays are performed using transient or stably transfected cells with the PPARα expression plasmid and a reporter plasmid, respectively. There are also other methods that have been used to measure PPARα activity, such as the Electrophoretic Mobility Shift Assay (EMSA) or commercially available PPARα transcription factor assay kits, see Table 1. The transactivation (stable transfection) assay provides the most applicable OECD Level 2 assay (i.e. In vitro assays providing mechanistic data) aimed at identifying the initiating event leading to an adverse outcome (LeBlanc, Norris, and Kloas 2011). Currently no internationally validated assays for regulatory purposes are available.


Key event PPARα activation

What is measured?

Ligand Binding
Transcriptional activity

Method/test category

molecular modelling
binding assay
transactivation reporter gene assay
transcription factor assay

Method/test

name

molecular modelling; docking

Scintillation proximity binding assay

luciferase reporter gene assay

PPARα (mouse/rat) Reporter Assay Kit

Electrophoretic Mobility Shift Assay (EMSA)

Test environment

In silico
In vitro
In vitro
In vitro, ex vivo

Test principle

Computational simulation of a candidate ligand binding to a receptor, Predicts the strength of association or binding affinity.

Direct binding indicating the mode of action for PPARα

Quantifying changes in luciferase expression in the treated reporter cells provides a sensitive surrogate measure of the changes in PPAR functional activity.

PPARα once activated by a ligand, the receptor binds to a promoter element in the gene for target gene and activates its transcription. The DNA-bound (activated) PPAR is measured.

Test outcome

A binding interaction between a small molecule ligand and an enzyme protein may result in activation or inhibition of the enzyme. If the protein is a receptor, ligand binding may result in agonism or antagonism of the normal activity of the receptor.

Assesses the ability of compounds to bind to PPARα. Identifies the modulators of PPARα.

The changes in activity of reporter gene levels functionally linked to a PPAR-responsive element/promoter gives information about the nature of the PPAR activation.

Protein: DNA binding, DNA binding activity  

Test background

Predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex. Knowledge of the preferred orientation in turn may be used to predict the strength of association or binding affinity between two molecules using, for example, scoring functions.

This assay determines whether compounds interact directly with PPARs. The type of beads that are involved in the SPA are microscopic in size and within the beads, there is a scintillant which emits light when it is stimulated. Stimulation occurs when radio-labelled molecules interact and bind to the surface of the bead and trigger the bead to emit light.

PPARα/γ COS-1cell transactivation assay (transient transfection with human or mouse PPARα/γ expression plasmid and pHD(x3)-Luc reporter plasmid

(PPRE)3- luciferase reporter construct C2C12

Proprietary rodent cell line expressing the mouse/rat PPARα

Transcriptional activity of PPARα can be assessed using commercially available kits like e.g. PPAR-α transcription factor assay kit.

Gene regulation and determining protein: DNA interactions are detected by the EMSA. EMSA can be used qualitatively to identify sequence-specific DNA-binding proteins (such as transcription factors) in crude lysates and, in conjunction with mutagenesis, to identify the important binding sequences within a given gene upstream regulatory region. EMSA can also be utilized quantitatively to measure thermodynamic and kinetic parameters.

Assay type

Quantitative
Qualitative
Quantitative
Quantitative
Quantitative

Quantitative

Quantitative

Application domain

Virtual screening

In vitro screening

In vitro Screening, functional studies activity (reported use: agonist)

 

In vitro Screening functional activity (antagonist/agonist)

 

 

Ref

(Feige et al. 2007), (Kaya et al. 2006)
(Lapinskas et al. 2005), (Wu, Gao, and Wang 2005)
(Maloney and Waxman 1999)
(Feige et al. 2007)
Indigobiosciences
Abcam

Table 1 Summary of the chosen methods to measure the PPARα activation.

Evidence Supporting Taxonomic Applicability

PPARα has been identified in frog (Xenopus laevis), mouse, human, rat, fish, hamster and chicken (reviewed in (Wahli and Desvergne 1999)).

Evidence for Chemical Initiation of this Molecular Initiating Event

Fibrates are ligands of PPARα (Staels et al. 1998).

Phthalates

MHEP (CAS 4376-20-9) directly binds in vitro to PPARα (Lapinskas et al. 2005) and activates this receptor in transactivation assays PPARα (Lapinskas et al. 2005), (Maloney and Waxman 1999), (Hurst and Waxman 2003), (Bility et al. 2004), (Lampen, Zimnik, and Nau 2003), (Venkata et al. 2006) ]. DEHP (CAS 117-81-7) has not been found to bind and activate PPARα (Lapinskas et al. 2005), (Maloney and Waxman 1999). However, the recent studies shown activation of PPARα (ToxCastTM Data).

Notably, PPARα are responsive to DEHP in vitro as they are translocated to the nucleus (in primary Sertoli cells) (Dufour et al. 2003), (Bhattacharya et al. 2005). Expression of PPARα [mRNA and protein] has been reported to be also modulated by phthtalates: (to be up-regulated in vivo upon DEHP treatment (Xu et al. 2010) and down-regulated by Diisobutyl phthalate (DiBP) (Boberg et al. 2008)).


Perfluorooctanoic Acid (PFOA) is known to activate PPARα (Vanden Heuvel et al. 2006).

Organotin

Tributyltin (TBT) activates all three heterodimers of PPAR with RXR, primarily through its interaction with RXR (le Maire et al. 2009)

References

Bhattacharya, Nandini, Jannette M Dufour, My-Nuong Vo, Janice Okita, Richard Okita, and Kwan Hee Kim. 2005. “Differential Effects of Phthalates on the Testis and the Liver.” Biology of Reproduction 72 (3) (March): 745–54. doi:10.1095/biolreprod.104.031583.

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.

Dufour, Jannette M, My-Nuong Vo, Nandini Bhattacharya, Janice Okita, Richard Okita, and Kwan Hee Kim. 2003. “Peroxisome Proliferators Disrupt Retinoic Acid Receptor Alpha Signaling in the Testis.” Biology of Reproduction 68 (4) (April): 1215–24. doi:10.1095/biolreprod.102.010488.

Feige, Jérôme N, Laurent Gelman, Daniel Rossi, Vincent Zoete, Raphaël Métivier, Cicerone Tudor, Silvia I Anghel, et al. 2007. “The Endocrine Disruptor Monoethyl-Hexyl-Phthalate Is a Selective Peroxisome Proliferator-Activated Receptor Gamma Modulator That Promotes Adipogenesis.” The Journal of Biological Chemistry 282 (26) (June 29): 19152–66. doi:10.1074/jbc.M702724200.

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.

Kaya, Taner, Scott C Mohr, David J Waxman, and Sandor Vajda. 2006. “Computational Screening of Phthalate Monoesters for Binding to PPARgamma.” Chemical Research in Toxicology 19 (8) (August): 999–1009. doi:10.1021/tx050301s.

Lampen, Alfonso, Susan Zimnik, and Heinz Nau. 2003. “Teratogenic Phthalate Esters and Metabolites Activate the Nuclear Receptors PPARs and Induce Differentiation of F9 Cells.” Toxicology and Applied Pharmacology 188 (1) (April): 14–23. doi:10.1016/S0041-008X(03)00014-0.

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.

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