PR:000011406 PR glucocorticoid receptor CHEBI:35366 CHEBI fatty acid CHEBI:17855 CHEBI triglyceride GO:0004883 GO glucocorticoid receptor activity GO:0006635 GO fatty acid beta-oxidation 1 WIKI increased 2 WIKI decreased PPARalpha antagonists 2017-06-02T14:46:13 2017-06-02T14:46:13 9606 NCBI Homo sapiens 10090 NCBI Mus musculus WikiUser_28 Vertebrates Activation, Glucocorticoid Receptor Molecular <p><strong>Site of action:</strong> The molecular site of action is the glucocorticoid receptor (GR). The GR is a steroid receptor belonging to the nuclear receptor (NR) family of ligand-dependent transcription factors. In the absence of a ligand, the GR is transcriptionally inactive in the cytoplasm. <strong>Responses at the macromolecular level:</strong> Binding of a hormonal ligand enables GR to translocate into the nucleas where it binds to genomic GC-response elements (GRE) and regulates trascription of associated genes.</p> <p>Glucocorticoid activation can be measured in a number of assays as stated by the EPA&rsquo;s comptox dashboard (<a href="https://comptox.epa.gov/dashboard/assay_endpoints?search=NR3C1">https://comptox.epa.gov/dashboard/assay_endpoints?search=NR3C1</a>).</p> <ul> <li><a href="https://comptox.epa.gov/dashboard/assay_endpoints/ATG_GRE_CIS_up">ATG_GRE_CIS_up</a></li> <li><a href="https://comptox.epa.gov/dashboard/assay_endpoints/ATG_GR_TRANS_up">ATG_GR_TRANS_up</a></li> <li><a href="https://comptox.epa.gov/dashboard/assay_endpoints/NVS_NR_hGR">NVS_NR_hGR</a></li> <li><a href="https://comptox.epa.gov/dashboard/assay_endpoints/TOX21_GR_BLA_Agonist_ratio">TOX21_GR_BLA_Agonist_ratio</a></li> </ul> <p>Receptor Transactivation Assays:</p> <ul> <li>Indigo Biosciences Human GR reporter assay system. Product Family IB0020 GR</li> <li>Androgen receptor assays using adenoviral transduction of MMTV-luc reporter and/or hAR for endocrine screening of surface water samples (Hartig et al, 2002).</li> </ul> <p>In addition to invitro assay, induction of glucocorticoid receptor-regulated genes such as annexin a1b, gilz, glula, and fkbp1 are also indicative of GR activation in vivo (Garland et al., 2019).</p> <p>Glucocorticoid receptor is fairly conserved across vertebrates. Fish however, have two copies of the gene resulting in two different receptors. Although conserved across species, the sensitivity of the glucocorticoid receptor varies based on species (Solte et al., 2006).</p> <p>&nbsp;</p> CL:0000255 CL eukaryotic cell Moderate Mixed Moderate All life stages <p style="margin-left:0.5in">Garland MA, Sengupta S, Mathew LK, Truong L, Jong ED, Piersma AH, Du JL, Tanguay RL. 2019. <em>Glucocorticoid receptor-dependent induction of </em>cripto-1<em> (one-eyed pinhead) inhibits zebrafish caudal fin regeneration. </em>Toxicology Reports 6:529-537. https://doi.org/10.1016/j.toxrep.2019.05.013</p> <p style="margin-left:0.5in">Solte EH, Lidy Verberg van Kemenade BM, Savelkoul FJ, Flik G. 2006. <em>Evolution of glucocorticoid receptors with different glucocorticoid sensitivity.</em> Journal of Endocrinology 190:17-28. DOI: 10.1677/joe.1.06703</p> <p style="margin-left:0.5in">Medlock Kakaley EK, Blackwell BR, Cardon MC, Conley JM, Evans N, Feifarek DJ, Furlong ET, Glassmeyer ST, Gray LE Jr, Hartig PC, Kolpin DW, Mills MA, Rosenblum L, Villeneuve DL, Wilson VS. <em>De Facto Water Reuse: Bioassay suite approach delivers depth and breadth in endocrine active compound detection</em>. Sci Total Environ. 2020 Jan 10;699:134297. doi: 10.1016/j.scitotenv.2019.134297. Epub 2019 Sep 4. PubMed PMID: 31683213.</p> <p>Conley JM, Lambright CS, Evans N, Strynar MJ, McCord J, McIntyre BS, Travlos GS, Cardon MC, Medlock-Kakaley E, Hartig PC, Wilson VS, Gray LE Jr. <em>Adverse Maternal, Fetal, and Postnatal Effects of Hexafluoropropylene Oxide Dimer Acid (GenX) from Oral Gestational Exposure in Sprague-Dawley Rats. Environ Health Perspect</em>. 2019 Mar;127(3):37008. doi: 10.1289/EHP4372. PubMed PMID: 30920876;PubMed Central PMCID: PMC6768323.</p> <p>Medlock Kakaley E, Cardon MC, Gray LE, Hartig PC, Wilson VS. <em>Generalized Concentration Addition Model Predicts Glucocorticoid Activity Bioassay Responses to Environmentally Detected Receptor-Ligand Mixtures</em>. Toxicol Sci. 2019 Mar 1;168(1):252-263. doi: 10.1093/toxsci/kfy290. PubMed PMID: 30535411; PubMed Central PMCID: PMC6709530.&nbsp;</p> <p>Conley JM, Evans N, Cardon MC, Rosenblum L, Iwanowicz LR, Hartig PC, Schenck KM, Bradley PM, Wilson VS. <em>Occurrence and In Vitro Bioactivity of Estrogen, Androgen, and Glucocorticoid Compounds in a Nationwide Screen of United States Stream Waters</em>. Environ Sci Technol. 2017 May 2;51(9):4781-4791. doi:10.1021/acs.est.6b06515. Epub 2017 Apr 12. PubMed PMID: 28401766.&nbsp;</p> <p>Hartig PC, Bobseine KL, Britt BH, Cardon MC, Lambright CR, Wilson VS, Gray LE Jr. <em>Development of two androgen receptor assays using adenoviral transduction of MMTV-luc reporter and/or hAR for endocrine screening</em>. Toxicol Sci. 2002 Mar;66(1):82-90. PubMed PMID: 11861975.</p> <p>&nbsp;</p> AOPWiki 2016-11-29T18:41:22 2020-07-07T12:19:59 Decreased, Mitochondrial Fatty Acid Beta Oxidation Molecular <p>PPAR&alpha; acts as a positive transcriptional regulator for many of the genes involved in mitochondrial fatty acid beta oxidation as well as genes involved in the pre- and post-processing of fatty acids in peroxisomal pathways (Desvergne and Wahili 1999, Kersten 2014).&nbsp; Thus, decreased PPAR&alpha; nuclear signaling results in decreased transcriptional expression of genes that are regulated by PPAR&alpha;, and subsequently, decreased expression of the coded proteins and enzymes that ultimately decrease fatty acid metabolism within the mitochondria.</p> <p><strong><em>Genes Involved:</em></strong>&nbsp; As reviewed in Kersten (2014), the genes (and associated functions) regulated by PPAR&alpha; in the mitochondrial processing of fatty acids include the following:&nbsp; (1) Import of acyl-CoAs into the mitochondria is facilitated by PPARalpha-induced increases in expression of carnitine palmitoyl-transferases 1a, 1b, and 1 (Cpt1a, Cpt1b, Cpt2) and acyl-carnitine translocase (Slc25a20, Brandt et al 1998; Mascaro et al 1998).&nbsp; (2) The first step of mitochondrial beta-oxidation is catalyzed by length-specific acyl-CoA hydrogenases (Acadvl, Acadl, Acadm, Acads; Aoyama et al 1998, Gulick et al 1994).&nbsp; (3) The three subsequent steps in mitochondrial beta-oxidation that successively release acetyl-CoAs from the hydrocarbon chain are catalyzed by the mitochondrial trifunctional enzyme (Hadha and Hadhb).&nbsp; These enzymes are replaced upon progressive chain shortening by Hadh and Acaa2.&nbsp; (4) the final PPARalpha targets include Eci1, Eci2, Decr1, and Hsd17b10 which convert unsaturated and 2-methlylated aclyl-CoAs into intermediates of beta-oxidation (Sanderson et al 2008, Aoyama et al 1998).</p> <p><strong><em>Metabolism Affected:</em></strong> Mitochondrial processing of fatty acids involves:&nbsp; (1) Import of short, medium and long chain fatty acids (&lt;C20) acyl-CoAs into the mitochondria by carnitine palmitoyl-transferases 1a, 1b, and 1 (Cpt1a, Cpt1b, Cpt2) and acyl-carnitine translocase (Slc25a20, Brandt et al 1998; Mascaro et al 1998, Kersten et al 2014).&nbsp; (2) The first step of beta-oxidation catalyzed by the length-specific acyl-CoA hydrogenases (Acadvl, Acadl, Acadm, Acads; Aoyama et al 1998, Gulick et al 1994, Kersten et al 2014).&nbsp; (3) The three subsequent steps in mitochondrial beta-oxidation that successively release acetyl-CoAs from the hydrocarbon chain are catalyzed by the mitochondrial trifunctional enzyme (Hadha and Hadhb, Kersten et al 2014).&nbsp; These enzymes are replaced upon progressive chain shortening by Hadh and Acaa2 (Kersten et al 2014).&nbsp; (4) The conversion of unsaturated and 2-methylated acetyl-CoAs into intermediates of beta-oxidation are catalyzed by Eci1, Eci2, Decr1, and Hsd17b10 (Sanderson et al 2008, Aoyama et al 1998, Kersten et al 2014).</p> <p>Beta oxidation of fatty acids in mitochondria has been measured using mouse liver homogenates where a radio-labeled fatty acid substrate was reacted for 30 minutes and then centrifuged to separate reaction products for fractional radioactivity measurements (Aoyama et al 1998). Comparative measures of reaction products were also measured where potassium cyanide was added to the reaction mixture to inhibit mitochondrial beta oxidation activity to normalize the contribution of mitochondrial enzymatic reactions to the overall reaction product (Aoyama et al 1998).</p> <p>Various methods were used for gene expression investigations. Brandt et al (1998) investigated concentration response effects of Oleate, Decanoate and Hexanoate fatty acid chains on mitochondrial carnitine palmitoyl-transferases I (M-CPT I) expression using promoter-reporter plasmid MCPT.Luc.1025 reporter transfected into rat neonate cardiac myocytes. Human M-CPT I was investigate using an analogous method (Brandt et al 1998). Expression of human medium chain acyl-CoA dehydrogenase (MCAD) was investigated using a MCAD.luc.1054 reporter transfected into HepG2 cells in response to fatty acids with various chain lengths (Gulick et al 1994). Investigation of various enzymes involved in hepatic fatty acid metabolism described in Aoyama et al (1998) were investigated using Western immunoblot quantitiation.</p> <p>Human (as reviewed in Brandt et al 1998, Evans et al 2004, Gulick et al 1994, Kersten 2014 and Desvergne and Wahli 1999). Mouse (as measured in Aoyama et al 1998, and as reviewed in Kersten 2014 and Desvergne and Wahli 1999).</p> CL:0000182 CL hepatocyte High Male High Female Not Specified Not Otherwise Specified High High <p><br /> Aoyama, T., Peters, J.M., Iritani, N., Nakajima, T., Furihata, K., Hashimoto, T., et al., 1998. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). Journal of Biological Chemistry 273:5678e5684.</p> <p>Brandt, J.M., Djouadi, F., Kelly, D.P., 1998. Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor alpha. Journal of Biological Chemistry 273:23786e23792.</p> <p>Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine Reviews 20(5): 649-688.</p> <p>Gulick, T., Cresci, S., Caira, T., Moore, D.D., Kelly, D.P., 1994. The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proceedings of the National Academy of Sciences of the United States of America 91:11012e11016.</p> <p>Kersten S. 2014. Integrated physiology and systems biology of PPARalpha. Molecular Metabolism 2014, 3(4):354-371.</p> <p>Mascaro, C., Acosta, E., Ortiz, J.A., Marrero, P.F., Hegardt, F.G., Haro, D., 1998. Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator-activated receptor. Journal of Biological Chemistry 273:8560e8563.</p> <p>Sanderson, L.M., de Groot, P.J., Hooiveld, G.J., Koppen, A., Kalkhoven, E., Muller, M., et al., 2008. Effect of synthetic dietary triglycerides: a novel research paradigm for nutrigenomics. PLoS One 3:e1681.</p> AOPWiki 2016-11-29T18:41:27 2017-09-16T10:14:20 Increased, Liver Steatosis Organ <p>Biological state: liver steatosis is the inappropriate storage of fat in hepatocytes.</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.&nbsp;</p> <p>&nbsp;</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 that measure lipid levels, or by histology.</p> <p>Steatosis is the result of perturbations in well-known metabolic pathways that are well-studied and well-known in many taxa.</p> UBERON:0002107 UBERON liver High Unspecific High All life stages High <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., &amp; 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&ndash;193.e8. https://doi.org/10.1053/j.gastro.2015.09.039</p> AOPWiki 2016-11-29T18:41:24 2019-03-07T09:49:48 Accumulation, Triglyceride Cellular <p>Leads to Fatty Liver Cells. </p> CL:0000182 CL hepatocyte AOPWiki 2016-11-29T18:41:23 2017-09-16T10:14:54 Decrease, ACAD Molecular AOPWiki 2021-01-15T11:39:50 2021-01-15T11:43:58 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9b6d328> AOPWiki 2021-01-15T11:43:37 2021-01-15T11:43:37 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9baf390> AOPWiki 2021-01-15T11:44:34 2021-01-15T11:44:34 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9b9ca10> AOPWiki 2021-01-15T11:14:31 2021-01-15T11:14:31 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9be67f0> AOPWiki 2021-01-15T11:16:04 2021-01-15T11:16:04 GR activation leading to hepatic steatosis Agnes Aggy BY-SA 2.0 <p>Steatosis is a regulatory endpoint and has been used as an endpoint in many US EPA assessments, including IRIS assessments.</p> adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified AOPWiki 2020-02-22T08:39:30 2023-09-25T16:27:01