117-81-7BJQHLKABXJIVAM-UHFFFAOYNA-NBJQHLKABXJIVAM-UHFFFAOYSA-N
Di(2-ethylhexyl) phthalate1,2-Benzenedicarboxylic acid, bis(2-ethylhexyl) ester
DEHP
1,2-Benzedicarboxylic acid, bis(2-ethyl-hexyl) ester
1,2-Benzenedicarboxylic acid bis(2-ethylhexyl) ester
1,2-Benzenedicarboxylic acid, 1,2-bis(2-ethylhexyl) ester
1,2-Benzenedicarboxylic acid,bis(2-ethylhexylester)
Bis(2-ethylhexyl) 1,2-benzenedicarboxylate
Bis(2-ethylhexyl) o-phthalate
bis(2-ethylhexyl) phthalate
Bis(2-ethylhexyl)phthalat
Bis(2-ethylhexyl)phthalate
Bisoflex 81
Bisoflex DOP
Corflex 400
Di(2-ethylhexyl)phthalate
Di(isooctyl) phthalate
Di-2-ethylhexlphthalate
Di-2-ethylhexyl phthalate
DI-2-ETHYLHEXYL-PHTHALATE
Diacizer DOP
Diethylhexyl phthalate
Dioctylphthalate
DOF
Ergoplast FDO
Ergoplast FDO-S
ETHYLHEXYL PHTHALATE
Eviplast 80
Eviplast 81
Fleximel
Flexol DOD
Flexol DOP
ftlalato de bis(2-etilhexilo)
Garbeflex DOP-D 40
Good-rite GP 264
Hatco DOP
Jayflex DOP
Kodaflex DEHP
Kodaflex DOP
Monocizer DOP
NSC 17069
Palatinol AH
Palatinol AH-L
Phtalate de Bis (Ethyle-2-Hexyle)
Phtalate de bis(2-ethylhexyle)
PHTHALATE, BIS(2-ETHYLHEXYL)
Phthalic acid di(2-ethylhexyl) ester
Phthalic acid, bis(2-ethylhexyl) ester
PHTHALIC ACID, BIS(2-ETHYLHEXYL)ESTER
PHTHALSAEURE-BIS-(2-AETHYLHEXYL)-ESTER
Pittsburgh PX 138
Plasthall DOP
Reomol D 79P
Sansocizer DOP
Sansocizer R 8000
Sconamoll DOP
Staflex DOP
Truflex DOP
Vestinol AH
Vinycizer 80
Vinycizer 80K
Witcizer 312
DTXSID502060797322-87-7GXPHKUHSUJUWKP-UHFFFAOYNA-NGXPHKUHSUJUWKP-UHFFFAOYSA-N
TroglitazoneDTXSID8023719688-73-3DBGVGMSCBYYSLD-UHFFFAOYSA-NDBGVGMSCBYYSLD-UHFFFAOYSA-N
Tributyltinhidruro de tri-n-butilestano
Hydridotris(butyl)tin
Hydrure de tributylstannane
hydrure de tri-n-butyletain
Tributylstannane
Tributylstannic hydride
Tributylstannyl hydride
TRIBUTYLTIN HYDRIDE
Tri-n-butylstannane
tri-n-butyltin hydride
Tri-n-butylzinnhydrid
DTXSID0040709PR:000011398nuclear receptor subfamily 1 group I member 3PR:000015611sterol regulatory element-binding protein 1PR:000010460carbohydrate-responsive element-binding proteinCHEBI:35366fatty acidCHEBI:17855triglyceridePR:000001905platelet glycoprotein 4PR:000014497acyl-CoA desaturasePR:000007348fatty acid synthasePR:000013056peroxisome proliferator-activated receptor alphaPR:000011394oxysterols receptor LXR-betaPR:000011395oxysterols receptor LXR-alphaPR:000013058peroxisome proliferator-activated receptor gammaPR:000003596acetyl-CoA carboxylase 1GO:0023052signalingGO:0032933SREBP signaling pathwayGO:0006633fatty acid biosynthetic processHP:0001397Hepatic steatosisGO:0019432triglyceride biosynthetic processGO:0009058biosynthetic processGO:0010467gene expressionGO:0035357peroxisome proliferator activated receptor signaling pathwayGO:0006635fatty acid beta-oxidationGO:0003989acetyl-CoA carboxylase activityGO:0015908fatty acid transport2decreased1increasedMono(2-ethylhexyl) phthalate2016-11-29T18:42:262016-11-29T18:42:26Di(2-ethylhexyl) phthalate2016-11-29T18:42:262016-11-29T18:42:26Troglitazone2016-11-29T18:42:262016-11-29T18:42:26Tributyltin2017-07-24T16:32:022017-07-24T16:32:02WikiUser_28Vertebrates10095miceWCS_9606human10116ratWikiUser_1human, mouse, ratSuppression, Constitutive androstane receptor, NR1l3Suppression, Constitutive androstane receptor, NR1l3MolecularCL:0000182hepatocyte2016-11-29T18:41:242017-09-16T10:15:14Activation, SREBF1Activation, SREBF1MolecularCL:0000182hepatocyte2016-11-29T18:41:242017-09-16T10:15:16Activation, ChREBPActivation, ChREBPMolecular<p>ChREBP is an LXR target that independently enhances the up-regulation of select lipogenic genes. The up-regulation of the ChREBP target gene is through liver-type pyruvate kinase (L-PK). Therefore, activation of LXR not only increases ChREBP mRNA via enhanced transcription but also modulates its activity <sup id="cite_ref-1" class="reference"><a href="#cite_note-1">[1]</a></sup>. In the liver, ChREBP mediates activation of several regulatory enzymes of glycolysis and lipogenesis including L-PK, acetyl CoA carboxylase (ACC), and fatty acid synthase (FAS). However, according to the study of Denechaud increase in the glucose flux in the cell is a prerequisite for ChREBP activation from T0901317 in mice <sup id="cite_ref-2" class="reference"><a href="#cite_note-2">[2]</a></sup>.
</p>CL:0000182hepatocyte<ol class="references">
<li id="cite_note-1"><span class="mw-cite-backlink"><a href="#cite_ref-1">↑</a></span> <span class="reference-text">Cha & Repa 2007</span>
</li>
<li id="cite_note-2"><span class="mw-cite-backlink"><a href="#cite_ref-2">↑</a></span> <span class="reference-text">Denechaud et al. 2008</span>
</li>
</ol>2016-11-29T18:41:222017-09-16T10:14:53Increased, De Novo FA synthesisIncreased, De Novo FA synthesisCellularCL:0000182hepatocyte2016-11-29T18:41:242017-09-16T10:15:16Increased, Liver SteatosisIncreased, Liver SteatosisOrgan<p>Biological state: liver steatosis is the inappropriate storage of fat in hepatocytes. <em>Four major pathways for triglyceride accumulation are: 1. Increased fatty acid uptake; 2. Increased De Novo FA and Lipid Synthesis; 3. Decreased FA Oxidation; 4. Decreased Lipid Efflux (Angrish et al. 2016). Chemical stressors can increase gene expression of key genes involving these pathways, leading to increased accumulation of triglycerides (Aguayo-Orozco et al. 2018). In addition, excessive dietary compounds of fatty compounds can also increase likelihood of accumulation of triglycerides (Nguyen et al. 2008). </em></p>
<p>Biological compartment: steatosis is generally an organ-level diagnosis; however, the pathology occurs within the hepatocytes.</p>
<p>Role in biology: steatosis is an adverse endpoint. </p>
<p> </p>
<p>Description from EU-ToxRisk:</p>
<p>Activation of stellate cells results in collagen accumulation and change in extracellular matrix composition in the liver causing fibrosis. (Landesmann, 2016)(Koo et al 2016)</p>
<p>Steatosis is measured by lipidomics approaches<em> (Yang and Han 2016)</em> that measure lipid levels, or by histology. <em>Concentrations of triglycerides, cholesterols, fatty acids, and related compounds are measured biochemically include high throughput enzymatic analyses, analytical ultracentrifuging, gradient gel electrophoresis, Nuclear Magnetic Resonance, and other direct assessment techniques (Schaefer et al. 2016).</em></p>
<p>Steatosis is the result of perturbations in well-known metabolic pathways that are well-studied and well-known in many taxa.</p>
<p><em>Life Stage: The life stage applicable to this key event is all life stages with a liver. Older individuals are more likely to manifest this adverse outcome pathway (adults > juveniles) due to accumulation of triglycerides.</em></p>
<p><em>Sex: This key event applies to both males and females.</em></p>
<p><em>Taxonomic: This key event appears to be present broadly in vertebrates, with most representative studies in mammals (humans, lab mice, lab rats).</em></p>
UBERON:0002107liverHighUnspecificHighAll life stagesHigh<p><em>Aguayo-Orozco, A.A., Bois, F.Y., Brunak, S., and Taboureau, O. 2018. Analysis of Time-Series Gene Expression Data to Explore Mechanisms of Chemical-Induced Hepatic Steatosis Toxicity. Frontiers in Genetics 9(Article 396): 1-15.</em></p>
<p><em>Angrish, M.M., Kaiser, J.P., McQueen, C.A., and Chorley, B.N. 2016. Tipping the Balance: Hepatotoxicity and the 4 Apical Key Events of Hepatic Steatosis. Toxicological Sciences 150(2): 261–268.</em></p>
<p>Landesmann, B. (2016). Adverse Outcome Pathway on Protein Alkylation Leading to Liver Fibrosis, (2).</p>
<p>https://doi.org/10.1016/j.molcel.2005.08.010</p>
<p>Koo, J. H., Lee, H. J., Kim, W., & Kim, S. G. (2016). Endoplasmic Reticulum Stress in Hepatic Stellate Cells Promotes Liver Fibrosis via PERK-Mediated Degradation of HNRNPA1 and Up-regulation of SMAD2. <em>Gastroenterology</em>, <em>150</em>(1), 181–193.e8. https://doi.org/10.1053/j.gastro.2015.09.039</p>
<p><em>Nguyen, P., Leray, V., Diez, M., Serisier, S., Le Bloc’h, J., Siliart, B., and Dumon, H. 2008. Liver lipid metabolism. Journal of Animal Physiology and Animal Nutrition 92: 272–283. </em></p>
<p><em>Schaefer EJ, Tsunoda F, Diffenderfer M, Polisecki, E., Thai, N., and Astalos, B. The Measurement of Lipids, Lipoproteins, Apolipoproteins, Fatty Acids, and Sterols, and Next Generation Sequencing for the Diagnosis and Treatment of Lipid Disorders. [Updated 2016 Mar 29]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK355892/</em></p>
<p><em>Yang, K. and Han, X. 2016. Lipidomics: Techniques, applications, and outcomes related to biomedical sciences. Trends in Biochemical Sciences 2016 November ; 41(11): 954–969.</em></p>
<p><em>NOTE: Italics symbolize edits from John Frisch</em></p>
2016-11-29T18:41:242024-03-26T13:17:41Increased, Triglyceride formationIncreased, Triglyceride formationCellularCL:0000182hepatocyte2016-11-29T18:41:242017-09-16T10:15:16Up Regulation, CD36Up Regulation, CD36Molecular<p>Fatty acid translocase CD36 (FAT/CD36) is a scavenger protein mediating uptake and intracellular transport of long-chain fatty acids (FA) in diverse cell types <sup><a href="#cite_note-1">[1]</a></sup>, <sup><a href="#cite_note-2">[2]</a></sup>. In addition, CD36 can bind a variety of molecules including acetylated low density lipoproteins (LDL), collagen and phospholipids <sup><a href="#cite_note-3">[3]</a></sup>. CD36 has been shown to be expressed in liver tissue <sup><a href="#cite_note-4">[4]</a></sup>, <sup><a href="#cite_note-5">[5]</a></sup>. It is located in lipid rafts and non-raft domains of the cellular plasma membrane and most likely facilitates LCFA transport by accumulating LCFA on the outer surface <sup><a href="#cite_note-6">[6]</a></sup>, <sup><a href="#cite_note-7">[7]</a></sup>, <sup><a href="#cite_note-8">[8]</a></sup>.</p>
<p>FAT/CD36 gene is a liver specific target of LXR activation <sup><a href="#cite_note-9">[9]</a></sup>. Studies have confirmed that the lipogenic effect of LXR and activation of FAT/CD36 was not a simple association, since the effect of LXR agonists on increasing hepatic and circulating levels of triglycerides and free fatty acids (FFAs) was largely abolished in FAT/CD36 knockout mice suggesting that intact expression and/or activation of FAT/CD36 is required for the steatotic effect of LXR agonists <sup><a href="#cite_note-10">[10]</a></sup>, <sup><a href="#cite_note-11">[11]</a></sup>. In addition to the well-defined pathogenic role of FAT/CD36 in hepatic steatosis in rodents the human up-regulation of the FAT/CD36 in NASH patients is confirmed <sup><a href="#cite_note-12">[12]</a></sup>. There are now findings that can accelerate the translation of FAT/CD36 metabolic functions determined in rodents to humans <sup><a href="#cite_note-13">[13]</a></sup> and suggest that the translocation of this fatty acid transporter to the plasma membrane of hepatocytes may contribute to liver fat accumulation in patients with NAFLD and HCV <sup><a href="#cite_note-14">[14]</a></sup>. In addition, hepatic FAT/CD36 up-regulation is significantly associated with insulin resistance, hyperinsulinaemia and increased steatosis in patients with NASH and HCV G1 (Hepatitis C Virus Genotype1) with fatty liver. Recent data show that CD36 is also increased in the liver of morbidly obese patients and correlated to free FA levels <sup><a href="#cite_note-15">[15]</a></sup>.</p>
<p><em>CD36 is measured by changes in gene expression and protein levels. </em></p>
<p><em>Life Stage: Older individuals are more likely to manifest this key event (adults > juveniles) due to increased opportunity to upregulate gene expression.</em></p>
<p><em>Sex: Applies to both males and females.</em></p>
<p><em>Taxonomic: Appears to be present broadly in vertebrates, with most representative studies in mammals (humans, lab mice, lab rats).</em></p>
<p> </p>
CL:0000182hepatocyteHighUnspecificHighAdultModerateJuvenileHigh<ol>
<li><a href="#cite_ref-1">↑</a> Su & Abumrad 2009 - Su X., Abumrad N.A., Cellular fatty acid uptake: a pathway under construction. Trends<br />
Endocrinol. Metab., 20 (No 2), 72-77, 2009</li>
<li><a href="#cite_ref-2">↑</a> He et al. 2011 - He J. et al, The emerging roles of fatty acid translocase/CD36 and the aryl hydrocarbon<br />
receptor in fatty liver disease, Exp. Med. And Biology, 236, 1116-1121, 2011</li>
<li><a href="#cite_ref-3">↑</a> Krammer 2011 - Krammer J. et al, Overexpression of CD36 and Acyl-CoA Synthetases FATP2, FATP4<br />
and ACSL1 Increases Fatty Acid Uptake in Human Hepatoma Cells, Int. J. Med. Sci.,<br />
8(7), 599-614, 2011</li>
<li><a href="#cite_ref-4">↑</a> Pohl et al. 2005 - Pohl J., et al, FAT/CD36-mediated long-chain fatty acid uptake in adipocytes requires<br />
plasma membrane rafts, Mol. Biol. Cell., 16 (No 1), 24-31, 2005</li>
<li><a href="#cite_ref-5">↑</a> Cheung et al. 2007 - Cheung L., et al, Hormonal and nutritional regulation of alternative CD36 transcripts<br />
in rat liver--a role for growth hormone in alternative exon usage, BMC Mol. Biol., 8, 60,<br />
2007</li>
<li><a href="#cite_ref-6">↑</a> Ehehalt et al. 2008 - Ehehalt R., et al, Uptake of long chain fatty acids is regulated by dynamic interaction<br />
of FAT/CD36 with cholesterol/sphingolipid enriched microdomains (lipid rafts). BMC<br />
Cell. Biol., 9, 45, 2008</li>
<li><a href="#cite_ref-7">↑</a> Pohl et al. 2005 - Pohl J., et al, FAT/CD36-mediated long-chain fatty acid uptake in adipocytes requires<br />
plasma membrane rafts, Mol. Biol. Cell., 16 (No 1), 24-31, 2005</li>
<li><a href="#cite_ref-8">↑</a> Krammer 2011 - Krammer J. et al, Overexpression of CD36 and Acyl-CoA Synthetases FATP2, FATP4<br />
and ACSL1 Increases Fatty Acid Uptake in Human Hepatoma Cells, Int. J. Med. Sci.,<br />
8(7), 599-614, 2011</li>
<li><a href="#cite_ref-9">↑</a> Zhou 2008 - Zhou J., Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and<br />
PPAR gamma in promoting steatosis, Gastroenterology, 134 (No 2),556-567, 2008</li>
<li><a href="#cite_ref-10">↑</a> Febbraio et al. 1999 - Febbraio M., et al, A null mutation in murine CD36 reveals an important role in fatty<br />
acid and lipoprotein metabolism, J Biol Chem, 274, 19055–19062, 1999</li>
<li><a href="#cite_ref-11">↑</a> Lee et al. 2008 - Lee J.H., et al, PRX and LXR in hepatic Steatosis: a new dog and an old dog with new<br />
tricks, Mol. Pharm., 5(No 1),60-66, 2008</li>
<li><a href="#cite_ref-12">↑</a> Zhu et al. 2011 - Zhu L., et al, Lipid in the livers of adolescents with non-alcoholic steatohepatitis:<br />
combined effects of pathways on steatosis, Metabolism Clinical and experimental, 30,<br />
1001-1011, 2011</li>
<li><a href="#cite_ref-13">↑</a> Love-Gregory et al. 2011 - Love-Gregory L., Abumrad N.A., CD36 genetics and the metabolic complications of<br />
obesity, Current Opinions in Clinical Nutition and Metabolic Care, 14 (No 6), 527-534,<br />
2011</li>
<li><a href="#cite_ref-14">↑</a> Miquilena-Colina et al. 2011 - Miquilena-Colina M.E., et al, Hepatic fatty acid translocase CD36 upregulation is<br />
associated with insulin resistance, hyperinsulinaemia and increased steatosis in nonalcoholic<br />
steatohepatitis and chronic hepatitis C, Gut., 60 (No 10), 1394-1402 , 2011</li>
<li><a href="#cite_ref-15">↑</a> Bechmann et al. 2010 - Bechmann L.P., et al, Apoptosis is associated with CD36/fatty acid translocase<br />
upregulation in non-alcoholic steatohepatitis, Liver Int., 30 (No 6), 850-859, 2010 </li>
</ol>
<p><em>NOTE: Italics symbolize edits from John Frisch</em></p>
2016-11-29T18:41:222024-03-26T10:35:31Up Regulation, SCD-1Up Regulation, SCD-1MolecularCL:0000182hepatocyte2016-11-29T18:41:242017-09-16T10:15:13Up Regulation, FASUp Regulation, FASMolecularCL:0000182hepatocyte2016-11-29T18:41:242017-09-16T10:15:17Inhibition, PPAR alphaInhibition, PPAR alphaMolecularCL:0000182hepatocyte2016-11-29T18:41:242017-09-16T10:15:15Activation, LXRActivation, LXRMolecular<h3>The LXR receptor</h3>
<p>Liver X receptors (LXR) are ligand-activated transcription factors of the nuclear receptor superfamily first identified in 1994 in rat liver (Apfel et al. 1994, Song 1994). There are two LXR isoforms termed a and ß (NR1H3 and NR1H2) which upon activation form heterodimers with retinoid X receptor (RXR) and bind to the LXR response element found in the promoter region of the target genes (Baranowski 2008). LXRs were shown to function as sterol sensors protecting the cells from cholesterol overload by stimulating reverse cholesterol transport and activating its conversion to bile acids in the liver (Baranowski 2008).</p>
<p>LXRa expression is restricted to liver, kidney, intestine, fat tissue, macrophages, lung, and spleen and is highest in liver, hence the name liver X receptor a (LXRa). LXRβ is expressed in almost all tissues and organs, hence the early name UR (ubiquitous receptor) (Ory 2004). The different pattern of expression suggests that LXRa and LXRβ have different roles in regulating physiological function. This is also supported from the observation that LXRa deficient mice do not develop hepatic steatosis when treated with LXR agonist that activates both types (Lund et al. 2006) and consequently the role of the two isoforms in relation to adverse effects could be different.</p>
<p> </p>
<h3>The molecular initiating event</h3>
<p>Generally speaking chemicals that are able to act through NRs are usually specific ligands. These chemicals are mainly lipophilic and they mimic the action of natural hormones. However, in some cases hydrophilic chemicals (like phthalates) are also capable to act as ligands in NRs due to the molecular structure of the proteins and the pocket sites of the receptors.</p>
<p>The molecular initiating event in the presented MoA is the binding to the LXR or the permissive RXR of the LXR-RXR dimer leading to activation. LXR activation can be achieved via a wide range of endogenous neutral and acidic ligands as shown by crystallographic analysis (Williams et al. 2003). There are known endogenous but also synthetic ligands that can act as agonists. Endogenous agonists for this receptor are the oxysterols (oxidized cholesterol derivatives like 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, 27-hydroxycholesterol, and cholestenoic acid) mainly with similar affinity for the two isoforms (Baranowski 2008). Oxysterols bind directly to the typical hydrophobic pocket in the C-terminal domain (Williams et al. 2003). Other endogenous ligands are the D-glucose and D-Glucose-6-phosphate (Mitro 2007). However, the hydrophilic nature of glucose and its low affinity for LXR present a challenge to the central dogma about the nature of the NR-ligand interaction (Lazar & Wilson 2007). Unsaturated fatty acids have also been shown to bind and regulate LXRa activity in cells. However, in contrast to the role of oxysterols, the biological relevance of this observation has not been established in vivo (Pawar et al. 2003). The function of LXRs is also modulated by many currently used drugs such as statins, fibrates, and thazolidinedione derivatives (Jamroz-Wiśniewska et al. 2007). Some synthetic LXR agonists have been developed like the non-steroidal agonists T0901317 and GW3965 (Schultz et al 2000, Collins et al. 2002). LXR forms a permissive dimer with the RXR which means that chemicals that can activate this receptor can trigger the same pathway as the LXR agonists. The endogenous RXR agonist is 9-cis-retinoic acid (Heyman et al. 1992) while synthetic agonists include LGD1069 and LG100268 (Boehm et al. 1994 and 1995).</p>
<p>In addition to the agonist binding in the LXR there are other mechanisms for its control. LXRa gene promoter contains also functional peroxisome proliferator response element (PPRE) and peroxisome proliferator-activated receptor (PPAR) a and γ agonists were shown to stimulate LXRa expression in human and rodent (Baranowski 2008). Control of the LXRa expression is also dependent on insulin and post-translationally by protein kinase A that phosphorylates receptor protein at two sites thereby impairing its dimerization and DNA-binding (Baranowski 2008).</p>
<p> </p>
<h3>Identification of the site of action</h3>
<p>As already mentioned above LXR isoforms are expressed in various tissues but in relation to the presented MoA we refer to LXRs that are expressed in the hepatocytes.</p>
<p>Nuclear receptors may be classified into two broad classes according to their sub-cellular distribution in the absence of ligand. Type I NRs (like ER and AhR) are located in the cytosol (and they are translocated into the nucleus after ligand binding) while type II NRs like LXRs (but also PXR, PPARa and PPARγ) are located in the nucleus of the cell.</p>
<p>The specific site of binding and the affinity of a ligand for the LXRs depend on the structure of the ligand.</p>
<p> </p>
<h3>Binding in the LXREs and target genes transcription</h3>
<p>Upon ligand-induced activation both isoforms form obligate heterodimers with the retinoid X receptor (RXR) and regulate gene expression through binding to LXR response elements (LXREs) in the promoter regions of the target genes (Fig. 1). The LXRE consists of two idealized hexanucleotide sequences (AGGTCA) separated by four bases (DR-4 element).</p>
<p><br />
<a class="image" href="/wiki/index.php/File:Mechanism-of-transcriptional-regulation-mediated-by-LXRs.png"><img alt="Mechanism-of-transcriptional-regulation-mediated-by-LXRs.png" src="/wiki/images/b/b0/Mechanism-of-transcriptional-regulation-mediated-by-LXRs.png" style="height:350px; width:449px" /></a></p>
<p><br />
Figure 1. Mechanism of transcriptional regulation mediated by LXRs. RXR - retinoid X receptor, LXRE - LXR response element (Baranowski 2008)</p>
<p>Target genes of LXRs are involved in cholesterol and lipid metabolism regulation (<sup><a href="#cite_note-1">[1]</a></sup>, <sup><a href="#cite_note-2">[2]</a></sup>) including:</p>
<ul>
<li>ABC - ATP Binding Cassette transporter isoforms A1, G1, G5, and G8</li>
<li>ApoE - Apolipoprotein E</li>
<li>CETP - Cholesterylester Transfer Protein</li>
<li>CYP7A1 - Cytochrome P450 isoform 7A1 - cholesterol 7a-hydroxylase</li>
<li>FAS - Fatty Acid Synthase</li>
<li>LPL - Lipoprotein Lipase</li>
<li>LXR-a - Liver X Receptor-a</li>
<li>SREBP-1c - Sterol Response Element Binding Protein 1c</li>
<li>ChREBP - Carbohydrate Response Element Binding Protein</li>
<li>FAT/CD36 – Fatty acid uptake transporter (liver)</li>
</ul>
<p> </p>
<h3>Auto-regulation of the LXRa</h3>
<p>Human specific auto-regulated expression specifically of the LXRa has been demonstrated from several studies (Laffitte et al. 2001, Whitney et al. 2001, Li et al. 2002, Kase et al. 2007). Human LXRa gene promoter has a functional LXRE activated by both LXRa and β. In addition human liver LXRa expression is induced by both natural and synthetic LXR agonists.</p>
<p><em>Liver X receptor (LXR) is measured by changes in gene expression and protein levels. Effects of LXR on expression of downstream genes can be investigating using metabolomics and RT-qPCR approaches.</em></p>
<p><em>Life Stage: Older individuals are more likely to manifest this adverse outcome pathway (adults > juveniles) due to increased opportunity to upregulate gene expression.</em></p>
<p><em>Sex: Applies to both males and females.</em></p>
<p><em>Taxonomic: Appears to be present broadly in vertebrates, with most representative studies in mammals (humans, lab mice, lab rats).</em></p>
CL:0000182hepatocyteHighUnspecificHighAdultModerateJuvenileHigh<ol>
<li><a href="#cite_ref-1">↑</a> Peet 1998 - Peet D.J., Cholesterol and Bile Acid Metabolism Are Impaired in Mice Lacking the<br />
Nuclear Oxysterol Receptor LXRa in mammals, Cell, 93, 693–704, 1998</li>
<li><a href="#cite_ref-2">↑</a> Edwardsa et al. 2002 - Edwardsa P.A., et al, LXRs; Oxysterol-activated nuclear receptors that regulate genes<br />
controlling lipid homeostasis, (Oxidized Lipids as Potential Mediators of<br />
Atherosclerosis), Vascular Pharmacology, 38 (No 4), 249–256, 2002</li>
</ol>
<p><em>NOTE: Italics symbolize edits from John Frisch</em></p>
2016-11-29T18:41:232024-03-27T11:29:19peroxisome proliferator activated receptor promoter demethylationdemethylation, PPARg promoterMolecular<p><strong>Biological state</strong></p>
<p>The Peroxisome Proliferator Activated receptor γ (PPARγ) belongs to <a href="/wiki/index.php/Peroxisome_Proliferator_Activated_receptors_(PPARs;_NR1C)" title="Peroxisome Proliferator Activated receptors (PPARs; NR1C)">Peroxisome Proliferator Activated receptors (PPARs; NR1C)</a> steroid/thyroid/retinoid receptor superfamily of transcription factors, which respond to specific ligands by altering gene expression in a cell-specific manner. The PPARγ gene contains three promoters that yield three isoforms, namely, PPAR-γ1, 2 and 3. PPAR-γ1 and γ3 RNA transcripts translate into the identical PPAR-γ1 protein.</p>
<p><strong>Biological compartments</strong></p>
<p>PPARγ is abundantly expressed in adipose tissue, promoting adipocyte differentiation, but is also present in various cells and tissues, for review see (Braissant et al. 1996). PPARγ expression is tissue dependent (L Fajas et al. 1997), (Lluis Fajas, Fruchart, and Auwerx 1998). PPARγ is most highly expressed in white adipose tissue and brown adipose tissue, where it is a master regulator of adipogenesis as well as a potent modulator of whole-body lipid metabolism and insulin sensitivity (Evans, Barish, and Wang 2004), (Tontonoz and Spiegelman 2008). Whereas PPARγ1 is expressed in many tissues, the expression of PPARγ2 is restricted to adipose tissue under physiological conditions but can be induced in other tissues by a high-fat diet (Saraf et al. 2012).</p>
<p><strong>General role in biology</strong></p>
<p>PPARγ is activated after the binding of natural ligands such as polyunsaturated fatty acids and prostaglandin metabolites. It can also be activated by synthetic ligands such as thiazolidinediones (TZDs) (rosiglitazone, pioglitazone or troglitazone) (Lehmann et al., 1995). PPARγ controls many vital processes such as glucose metabolism and inflammation as well as variety of developmental programs(Wahli & Desvergne, 1999), (Rotman et al., 2008), (Wahli & Michalik, 2012). This receptor itself is essential for developmental processes since targeted disruption of this gene results in embryo lethality, due in part to defective placental development, therefore modulation of PPARγ activity may impact endocrine regulated processes during development as well as later in life.</p>
<p><em>Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible? </em></p>
<p>Binding of ligands to PPARγ is measured using binding assays in vitro and in silico, whereas the information about functional activation is derived from the transactivation using e.g. reporter assay with a 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 & Reddy, 2007) (Viswakarma et al., 2010. Transactivation assays are performed using the transient or stably transfected cells with the PPARγ expression plasmid and a reporter plasmid, correspondingly. There are also other methods that have been used to measure PPARγ activity, such as the Electrophoretic Mobility Shift Assay (EMSA) or commercially available PPARγ transcription factor assay kits, see Table 1. The transactivation (stable transfection) assay provides the most applicable OECD Level 2 assay aimed at identifying the initiating event leading to adverse outcome (LeBlanc, Norris, & Kloas, 2011). Currently no internationally validated assays are available.</p>
<p> </p>
<p> </p>
<table class="wikitable" id="Event228">
<tbody>
<tr>
<th>Key event</th>
<th colspan="7">PPARγ activation</th>
</tr>
<tr>
<td> </td>
<td>What is measured?</td>
<td>Ligand Binding</td>
<td> </td>
<td>Transcriptional activity</td>
<td> </td>
<td> </td>
<td> </td>
<td> </td>
</tr>
<tr>
<td>Method/test category</td>
<td>molecular modelling</td>
<td>binding assay</td>
<td>transactivation reporter gene assay</td>
<td> </td>
<td> </td>
<td>transcription factor assay</td>
<td> </td>
</tr>
<tr>
<td>Method/test name</td>
<td>molecular modelling; docking</td>
<td>Scintillation proximity binding assay</td>
<td>luciferase reporter gene assay</td>
<td> </td>
<td> </td>
<td>PPARγ (mouse/rat) Reporter Assay Kit</td>
<td>Electrophoretic Mobility Shift Assay (EMSA)</td>
</tr>
<tr>
<td>Test environment</td>
<td>In silico</td>
<td>In vitro</td>
<td>In vitro</td>
<td> </td>
<td> </td>
<td>In vitro, ex vivo</td>
<td> </td>
</tr>
<tr>
<td>Test principle</td>
<td>Computational simulation of a candidate ligand binding to a receptor, Predicts the strength of association or binding affinity.</td>
<td>direct binding indicating the mode of action for PPARα/γ</td>
<td>Quantifying changes in luciferase expression in the treated reporter cells provides a sensitive surrogate measure of the changes in PPAR functional activity.</td>
<td> </td>
<td> </td>
<td>PPARγ 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.</td>
<td> </td>
</tr>
<tr>
<td>Test outcome</td>
<td>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</td>
<td>Assess the ability of compounds to bind to PPARγ. Identifies the modulators of PPARγ.</td>
<td>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.</td>
<td> </td>
<td> </td>
<td>Protein: DNA binding, DNA binding activity</td>
<td> </td>
</tr>
<tr>
<td>Test background</td>
<td>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.</td>
<td>This assay determines whether compounds interact directly with PPARγ.</td>
<td>PPARγ COS-1cell transactivation assay (transient transfection with human or mouse PPARγ expression plasmid and pHD(x3)-Luc reporter plasmid</td>
<td>(PPRE)3- luciferase reporter construct C2C12</td>
<td>Proprietary rodent cell line expressing the mouse/rat PPARγ</td>
<td>Transcriptional activity of PPARγ can be assessed using commercially available kits like e.g. PPARγ transcription factor assay kit (Abcam, Cambridge, USA or Cayman Chemical, USA).</td>
<td>Gene regulation and determining protein: DNA interactions are the 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 genes upstream regulatory region. EMSA can also be utilized quantitatively to measure thermodynamic and kinetic parameters.</td>
</tr>
<tr>
<td>Assay type</td>
<td>Quantitative</td>
<td>Qualitative</td>
<td>Quantitative</td>
<td>Quantitative</td>
<td>Quantitative</td>
<td>Quantitative</td>
<td>Quantitative</td>
</tr>
<tr>
<td>Application domain</td>
<td>Virtual screening</td>
<td>In vitro screening</td>
<td>In vitro Screening, functional studies activity (reported use: agonist)</td>
<td> </td>
<td>In vitro Screening functional activity (antagonist/agonist)</td>
<td>Functional studies</td>
<td>Functional studies</td>
</tr>
<tr>
<td>Source</td>
<td>Research/commercial</td>
<td>Research</td>
<td>Research</td>
<td>Research</td>
<td>commercial</td>
<td>commercial</td>
<td>Research/commercial</td>
</tr>
<tr>
<td>Ref</td>
<td>(Feige et al., 2007), (Kaya, Mohr, Waxman, & Vajda, 2006)</td>
<td>(Lapinskas et al., 2005), (Wu, Gao, & Wang, 2005)</td>
<td>(Maloney & Waxman, 1999)</td>
<td>(Feige et al., 2007)</td>
<td>Cayman, (Gijsbers et al. 2013)</td>
<td>Abcam<a class="external autonumber" href="http://www.abcam.com/ppar-gamma-transcription-factor-assay-kit-ab133101.html" rel="nofollow" target="_blank">[1]</a></td>
<td> </td>
</tr>
</tbody>
</table>
<p>Table 1 Summary of the chosen methods to measure the PPARγ activation.</p>
<p>PPARγ have been identified in frog (Xenopus laevis), mouse, human, rat, fish, hamster and chicken (Wahli & Desvergne, 1999).</p>
CL:0000182hepatocyteHighModerateModerate<p>Barak, Y., Nelson, M. C., Ong, E. S., Jones, Y. Z., Ruiz-Lozano, P., Chien, K. R., … Evans, R. M. (1999). PPAR gamma is required for placental, cardiac, and adipose tissue development. Molecular Cell, 4(4), 585–95.</p>
<p>Braissant, O., Foufelle, F., Scotto, C., Dauça, M., & Wahli, W. (1996). Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology, 137(1), 354–66.</p>
<p>Burns, K. A., & Vanden Heuvel, J. P. (2007). Modulation of PPAR activity via phosphorylation. Biochimica et Biophysica Acta, 1771(8), 952–60. doi:10.1016/j.bbalip.2007.04.018</p>
<p>Fajas, L., Auboeuf, D., Raspé, E., Schoonjans, K., Lefebvre, A. M., Saladin, R., … Auwerx, J. (1997). The organization, promoter analysis, and expression of the human PPARgamma gene. The Journal of Biological Chemistry, 272(30), 18779–89.</p>
<p>Fajas, L., Fruchart, J.-C., & Auwerx, J. (1998). PPARγ3 mRNA: a distinct PPARγ mRNA subtype transcribed from an independent promoter. FEBS Letters, 438(1-2), 55–60. doi:10.1016/S0014-5793(98)01273-3</p>
<p>Feige, J. N., Gelman, L., Michalik, L., Desvergne, B., & Wahli, W. (2006). From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Progress in Lipid Research, 45(2), 120–59. doi:10.1016/j.plipres.2005.12.002</p>
<p>Feige, J. N., Gelman, L., Rossi, D., Zoete, V., Métivier, R., Tudor, C., … Desvergne, B. (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), 19152–66. doi:10.1074/jbc.M702724200</p>
<p>Gijsbers, Linda, Henriëtte D L M van Eekelen, Laura H J de Haan, Jorik M Swier, Nienke L Heijink, Samantha K Kloet, Hai-Yen Man, et al. 2013. “Induction of Peroxisome Proliferator-Activated Receptor Γ (PPARγ)-Mediated Gene Expression by Tomato (Solanum Lycopersicum L.) Extracts.” Journal of Agricultural and Food Chemistry 61 (14) (April 10): 3419–27. doi:10.1021/jf304790a.</p>
<p>Issemann, I., & Green, S. (1990). Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature, 347(6294), 645–650.</p>
<p>Kaya, T., Mohr, S. C., Waxman, D. J., & Vajda, S. (2006). Computational screening of phthalate monoesters for binding to PPARgamma. Chemical Research in Toxicology, 19(8), 999–1009. doi:10.1021/tx050301s</p>
<p>Lapinskas, P. J., Brown, S., Leesnitzer, L. M., Blanchard, S., Swanson, C., Cattley, R. C., & Corton, J. C. (2005). Role of PPARα in mediating the effects of phthalates and metabolites in the liver. Toxicology, 207(1), 149–163.</p>
<p>Le Maire, A., Grimaldi, M., Roecklin, D., Dagnino, S., Vivat-Hannah, V., Balaguer, P., & Bourguet, W. (2009). Activation of RXR-PPAR heterodimers by organotin environmental endocrine disruptors. EMBO Reports, 10(4), 367–73. doi:10.1038/embor.2009.8</p>
<p>LeBlanc, G., Norris, D., & Kloas, W. (2011). Detailed Review Paper State of the Science on Novel In Vitro and In Vivo Screening and Testing Methods and Endpoints for Evaluating Endocrine Disruptors, (178).</p>
<p>Lehmann, J. M., Moore, L. B., Smith-Oliver, T. A., Wilkison, W. O., Willson, T. M., & Kliewer, S. A. (1995). An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-activated Receptor (PPAR ). Journal of Biological Chemistry, 270(22), 12953–12956. doi:10.1074/jbc.270.22.12953</p>
<p>Maloney, E. K., & Waxman, D. J. (1999). trans-Activation of PPARα and PPARγ by Structurally Diverse Environmental Chemicals. Toxicology and Applied Pharmacology, 161(2), 209–218.</p>
<p>Michalik, L., Zoete, V., Krey, G., Grosdidier, A., Gelman, L., Chodanowski, P., … Michielin, O. (2007). Combined simulation and mutagenesis analyses reveal the involvement of key residues for peroxisome proliferator-activated receptor alpha helix 12 dynamic behavior. The Journal of Biological Chemistry, 282(13), 9666–77. doi:10.1074/jbc.M610523200</p>
<p>Morán-Salvador, E., López-Parra, M., García-Alonso, V., Titos, E., Martínez-Clemente, M., González-Périz, A., … Clària, J. (2011). Role for PPARγ in obesity-induced hepatic steatosis as determined by hepatocyte- and macrophage-specific conditional knockouts. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 25(8), 2538–50. doi:10.1096/fj.10-173716</p>
<p>Pereira-Fernandes, A., Demaegdt, H., Vandermeiren, K., Hectors, T. L. M., Jorens, P. G., Blust, R., & Vanparys, C. (2013). Evaluation of a screening system for obesogenic compounds: screening of endocrine disrupting compounds and evaluation of the PPAR dependency of the effect. PloS One, 8(10), e77481. doi:10.1371/journal.pone.0077481</p>
<p>ToxCastTM Data, US Environmental Protection Agency. <a class="external free" href="http://www.epa.gov/ncct/toxcast/data.html" rel="nofollow" target="_blank">http://www.epa.gov/ncct/toxcast/data.html</a>.</p>
<p><br />
Vanden Heuvel, J. P. (1999). Peroxisome proliferator-activated receptors (PPARS) and carcinogenesis. Toxicological Sciences : An Official Journal of the Society of Toxicology, 47(1), 1–8.</p>
<p>Viswakarma, N., Jia, Y., Bai, L., Vluggens, A., Borensztajn, J., Xu, J., & Reddy, J. K. (2010). Coactivators in PPAR-Regulated Gene Expression. PPAR Research, 2010. doi:10.1155/2010/250126</p>
<p>Wahli, W., & Desvergne, B. (1999). Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine Reviews, 20(5), 649–88.</p>
<p>Wu, B., Gao, J., & Wang, M. (2005). Development of a complex scintillation proximity assay for high-throughput screening of PPARgamma modulators. Acta Pharmacologica Sinica, 26(3), 339–44. doi:10.1111/j.1745-7254.2005.00040.x</p>
<p>Yu, S., & Reddy, J. K. (2007). Transcription coactivators for peroxisome proliferator-activated receptors. Biochimica et Biophysica Acta, 1771(8), 936–51. doi:10.1016/j.bbalip.2007.01.008</p>
2016-11-29T18:41:232017-09-16T10:14:53Inhibition, Mitochondrial fatty acid beta-oxidationInhibition, Mitochondrial fatty acid beta-oxidationMolecularCL:0000182hepatocyte2016-11-29T18:41:242017-09-16T10:15:13Accumulation, Fatty acidAccumulation, Fatty acidOrganUBERON:0002107liver2016-11-29T18:41:242017-09-16T10:14:56Up Regulation, Acetyl-CoA carboxylase-1 (ACC-1)Up Regulation, Acetyl-CoA carboxylase-1 (ACC-1)MolecularCL:0000255eukaryotic cell2016-11-29T18:41:242017-09-16T10:15:17Increased, FA InfluxIncreased, FA InfluxCellularCL:0000182hepatocyte2016-11-29T18:41:242017-09-16T10:15:14b1f5edf3-d6ba-4445-a6fb-15d62780f0fb74efead5-ef73-4b6c-8edd-a439ca1e501b2016-11-29T18:41:342016-12-03T16:37:57b1f5edf3-d6ba-4445-a6fb-15d62780f0fb0e05e0a8-4ee1-45cf-b01e-5b0e9ee1e9202016-11-29T18:41:342016-12-03T16:37:5774efead5-ef73-4b6c-8edd-a439ca1e501bf512dcb2-ff84-4de5-8d44-45fa9ee3b7772016-11-29T18:41:342016-12-03T16:37:5774efead5-ef73-4b6c-8edd-a439ca1e501bb820637f-597c-45eb-8090-fa39613193792016-11-29T18:41:332016-12-03T16:37:55b820637f-597c-45eb-8090-fa396131937972b09dde-f16d-4fae-9fb0-1ad7d354b4772016-11-29T18:41:342016-12-03T16:37:57ff180673-dcb0-40b9-9694-b9fdca9062e8efb18c30-24ff-4136-b0a0-9f439535ffc62016-11-29T18:41:342016-12-03T16:37:570e05e0a8-4ee1-45cf-b01e-5b0e9ee1e920f512dcb2-ff84-4de5-8d44-45fa9ee3b7772016-11-29T18:41:342016-12-03T16:37:57f512dcb2-ff84-4de5-8d44-45fa9ee3b7770d75973b-f259-4dce-88ad-59c2e83abda32016-11-29T18:41:342016-12-03T16:37:5774efead5-ef73-4b6c-8edd-a439ca1e501bd2506614-eeb3-4708-b1c8-65c3ac8b24122016-11-29T18:41:332016-12-03T16:37:5574efead5-ef73-4b6c-8edd-a439ca1e501bd69aff7f-f672-4fdf-94df-e1dd1a5d46592016-11-29T18:41:342016-12-03T16:37:5774efead5-ef73-4b6c-8edd-a439ca1e501b0d75973b-f259-4dce-88ad-59c2e83abda32016-11-29T18:41:342016-12-03T16:37:57d69aff7f-f672-4fdf-94df-e1dd1a5d465972b09dde-f16d-4fae-9fb0-1ad7d354b4772016-11-29T18:41:342016-12-03T16:37:570d75973b-f259-4dce-88ad-59c2e83abda3ff180673-dcb0-40b9-9694-b9fdca9062e82016-11-29T18:41:342016-12-03T16:37:5774efead5-ef73-4b6c-8edd-a439ca1e501b13117848-7bc4-48cc-9054-2726fcb4f47e2016-11-29T18:41:342016-12-03T16:37:5713117848-7bc4-48cc-9054-2726fcb4f47ed6fd3c21-b204-4886-8700-55fde31f15a42016-11-29T18:41:342016-12-03T16:37:5772b09dde-f16d-4fae-9fb0-1ad7d354b477a90efca6-6a6e-4350-8ff0-184625e275e12016-11-29T18:41:342016-12-03T16:37:57a90efca6-6a6e-4350-8ff0-184625e275e1ff180673-dcb0-40b9-9694-b9fdca9062e82016-11-29T18:41:342016-12-03T16:37:57a90efca6-6a6e-4350-8ff0-184625e275e1efb18c30-24ff-4136-b0a0-9f439535ffc62016-11-29T18:41:342016-12-03T16:37:57d6fd3c21-b204-4886-8700-55fde31f15a4a90efca6-6a6e-4350-8ff0-184625e275e12016-11-29T18:41:342016-12-03T16:37:5674efead5-ef73-4b6c-8edd-a439ca1e501bee78f856-0852-4d3f-be19-50981050c1c92016-11-29T18:41:342016-12-03T16:37:57ee78f856-0852-4d3f-be19-50981050c1c972b09dde-f16d-4fae-9fb0-1ad7d354b4772016-11-29T18:41:342016-12-03T16:37:570e05e0a8-4ee1-45cf-b01e-5b0e9ee1e9202953d30d-a7a1-4266-9743-d2a85edf1a522017-08-31T10:26:542017-08-31T10:26:54d2506614-eeb3-4708-b1c8-65c3ac8b24122953d30d-a7a1-4266-9743-d2a85edf1a522016-11-29T18:41:342016-12-03T16:37:572953d30d-a7a1-4266-9743-d2a85edf1a52a90efca6-6a6e-4350-8ff0-184625e275e12016-11-29T18:41:342016-12-03T16:37:57NR1I3 (CAR) suppression leading to hepatic steatosisNR1I3 suppression to steatosis<p>Michelle Angrish, Brian Chorley</p>
Under Development: Contributions and Comments WelcomeUnder Development1.29<p><em>1.1 Binding and activation of receptor</em></p>
<p>PPARγ ligands thiazolidinediones (Rosiglitazone, Pioglitazone, Troglitazone) (Lehmann et al. 1995), (Forman et al. 1995), (Willson et al. 2000).</p>
<p><strong>Phthalates</strong></p>
<p>MEHP (CAS 4376-20-9) directly binds to PPARγ (Lapinskas et al. 2005), (ToxCastTM Data)in vitro and in silico (Feige et al. 2007), (Rotman et al. 2008), (Kaya et al. 2006) and activates this receptor in transactivation assays (Maloney & Waxman 1999), (Hurst & Waxman 2003b), (Venkata et al. 2006), (ToxCastTM Data). In summary, there is experimental in vitro evidence for binding and transcriptional activation of PPARγ. DEHP (CAS 117-81-7) was not found to bind and activate PPARγ (Lapinskas et al. 2005), (Maloney & Waxman 1999). However recent studies show activation of PPARγ by DEHP(ToxCastTM Data), (Pereira-Fernandes et al. 2013). DEHP was also found to increase the levels of PPARγ in vitro (Lin et al. 2011). Notably, PPARγ is responsive to DEHP in vitro and is translocated to the nucleus (in primary Sertoli cells) (Dufour et al. 2003), (Bhattacharya et al. 2005).</p>
<p><strong>Parabens</strong></p>
<p>Butylparaben was not found to bind to the PPARγ (ToxCastTM Data), but activated the human PPARγ (ToxCastTM Data), (Pereira-Fernandes et al. 2013) and mPPARγ in reporter gene assay (Taxvig et al., 2012).</p>
<p><strong>Phenols</strong></p>
<p>Bisphenol A was not found to bind to the PPARγ (ToxCastTM Data), but activated the human PPARγ (ToxCastTM Data), (Pereira-Fernandes et al. 2013) but not mouse PPARγ (Taxvig et al., 2012) in reporter gene assay. BPA was also reported to increase PPARγ (mRNA) in ovarian granulosa cell line and human luteinized granulosa cells (Kwintkiewicz, Nishi, Yanase, & Giudice, 2010).</p>
<p><strong>Organotin</strong></p>
<p>Tributyltin (TBT) activates all three heterodimers of PPAR with RXR, primarily through its interaction with RXR (le Maire et al. 2009).</p>
<p><br />
<em>1.2 Activation of target genes</em></p>
<p>MEHP activation of endogenous PPARγ target genes was evidenced by the stimulation of PPARγ-dependent adipogenesis in the 3T3-L1 cell differentiation model (Hurst & Waxman, 2003).</p>
<p>Steatosis is a regulatory endpoint and has been used as an endpoint in many US EPA assessments, including IRIS assessments.</p>
adjacentHighHighadjacentHighHighadjacentHighHighadjacentHighHighadjacentHighHighadjacentHighHighadjacentModerateModerateadjacentHighHighadjacentHighHighadjacentHighHighadjacentHighHighadjacentHighHighadjacentHighHighadjacentNot SpecifiedHighadjacentNot SpecifiedHighadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedHighadjacentModerateModerateadjacentHighHighadjacentNot SpecifiedHighnon-adjacentNot SpecifiedNot Specifiednon-adjacentNot SpecifiedHighModerate2016-11-29T18:41:162023-04-29T16:02:56