CHEBI:26523 CHEBI reactive oxygen species GO:1903409 GO reactive oxygen species biosynthetic process 1 WIKI increased WikiUser_28 Vertebrates Increase, cytosolic fatty acid Cellular <p>Biological state: amount of fatty acid in the cytosol</p> <p>Biological compartment: cytosol</p> <p>General role in biology: fatty acids are a storage form for energy. Fatty acids are metabolized in hepatocytes into glucose.</p> <p>Cytosolic fatty acid content can be measured in many ways. These include lipidomics approaches and histological staining.</p> <p>Fatty acids are well known energy storage molecules used in many vertebrates.</p> High Unspecific High All life stages High AOPWiki 2017-04-12T14:40:37 2017-11-27T12:20:36 steatohepatitis Organ <p>Biological state: steatohepatisis is steatosis (fatty liver) presenting with inflammation.&nbsp;</p> <p>Biological compartment: liver.</p> <p>Role in biology: Steatohepatisis is a disease and adverse endpoint. If this state continues, it will eventually lead to fibrosis and cirrhosis of the liver.&nbsp;</p> <p>Steatohepatitis is typically measured histologically. Fatty liver is noticed by oil red O staining, although it also may be noted using lipidomics. Inflammatory cell infiltration is typically noted histologically.&nbsp;</p> <p>NASH (non-alcoholic steatohepatitis) can occur in any organism that contains a liver.</p> High Unspecific High All life stages High AOPWiki 2017-11-13T12:47:00 2017-11-27T13:41:43 Inhibition of fatty acid beta oxidation Molecular <p>Biological state being measured: fatty acid beta oxidation</p> <p>Biological compartment: mitochondria or peroxisome</p> <p>General role in biology: Fatty acid beta oxidation (FABO) is the process by which fatty acids are metabolized into glucose for energy utilization.&nbsp;</p> <p>Fatty acid beta oxidation (FABO) can be measured by:</p> <p>1) Activity of the enzymes that perform FABO</p> <p>2) Flourescence assays measuring extracellular oxygen consumption</p> <p>3) Radiolabel assays using labeled palmitate</p> <p>This is a well-known metabolic pathway.</p> AOPWiki 2017-11-13T12:50:02 2017-11-27T12:15:16 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 Increased, Reactive oxygen species Cellular <p>Biological State: increased reactive oxygen species (ROS)</p> <p>Biological compartment: an entire cell -- may be cytosolic, may also enter organelles.</p> <p>Reactive oxygen species (ROS) are O2- derived molecules that can be both free radicals (e.g. superoxide, hydroxyl, peroxyl, alcoxyl) and non-radicals (hypochlorous acid, ozone and singlet oxygen) (Bedard and Krause 2007; Ozcan and Ogun 2015). ROS production occurs naturally in all kinds of tissues inside various cellular compartments, such as mitochondria and peroxisomes (Drew and Leeuwenburgh 2002; Ozcan and Ogun 2015). Furthermore, these molecules have an important function in the regulation of several biological processes &ndash; they might act as antimicrobial agents or triggers of animal gamete activation and capacitation (Goud et al. 2008; Parrish 2010; Bisht et al. 2017).&nbsp;<br /> However, in environmental stress situations (exposure to radiation, chemicals, high temperatures) these molecules have its levels drastically increased, and overly interact with macromolecules, namely nucleic acids, proteins, carbohydrates and lipids, causing cell and tissue damage (Brieger et al. 2012; Ozcan and Ogun 2015).&nbsp;</p> <p>Photocolorimetric assays (Sharma et al. 2017; Griendling et al. 2016) or through commercial kits purchased from specialized companies.</p> <p>Yuan, Yan, et al., (2013) described ROS monitoring by using H₂-DCF-DA, a redox-sensitive fluorescent dye. Briefly, the harvested cells were incubated with H₂-DCF-DA (50 &micro;mol/L final concentration) for 30 min in the dark at 37&deg;C. After treatment, cells were immediately washed twice, re-suspended in PBS, and analyzed on a BD-FACS Aria flow cytometry. ROS generation was based on fluorescent intensity which was recorded by excitation at 504 nm and emission at 529 nm.</p> <p>Lipid peroxidation (LPO) can be measured as an indicator of oxidative stress damage Yen, Cheng Chien, et al., (2013).</p> <p>Chattopadhyay, Sukumar, et al. (2002) assayed the generation of free radicals within the cells and their extracellular release in the medium by addition of yellow NBT salt solution (Park et al., 1968). Extracellular release of ROS converted NBT to a purple colored formazan. The cells were incubated with 100 ml of 1 mg/ml NBT solution for 1 h at 37&nbsp;&deg;C and the product formed was assayed at 550 nm in an Anthos 2001 plate reader. The observations of the &lsquo;cell-free system&rsquo; were confirmed by cytological examination of parallel set of explants stained with chromogenic reactions for NO and ROS.</p> <p>&nbsp;</p> <p>ROS is a normal constituent found in all organisms.</p> High Unspecific High All life stages High <p>B.H. Park, S.M. Fikrig, E.M. Smithwick Infection and nitroblue tetrazolium reduction by neutrophils: a diagnostic aid Lancet, 2 (1968), pp. 532-534</p> <p>Bedard, Karen, and Karl-Heinz Krause. 2007. &ldquo;The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology.&rdquo; Physiological Reviews 87 (1): 245&ndash;313.</p> <p>Bisht, Shilpa, Muneeb Faiq, Madhuri Tolahunase, and Rima Dada. 2017. &ldquo;Oxidative Stress and Male Infertility.&rdquo; Nature Reviews. Urology 14 (8): 470&ndash;85.</p> <p>Brieger, K., S. Schiavone, F. J. Miller Jr, and K-H Krause. 2012. &ldquo;Reactive Oxygen Species: From Health to Disease.&rdquo; Swiss Medical Weekly 142 (August): w13659.</p> <p>Chattopadhyay, Sukumar, et al. &quot;Apoptosis and necrosis in developing brain cells due to arsenic toxicity and protection with antioxidants.&quot; Toxicology letters 136.1 (2002): 65-76.</p> <p>Drew, Barry, and Christiaan Leeuwenburgh. 2002. &ldquo;Aging and the Role of Reactive Nitrogen Species.&rdquo; Annals of the New York Academy of Sciences 959 (April): 66&ndash;81.</p> <p>Goud, Anuradha P., Pravin T. Goud, Michael P. Diamond, Bernard Gonik, and Husam M. Abu-Soud. 2008. &ldquo;Reactive Oxygen Species and Oocyte Aging: Role of Superoxide, Hydrogen Peroxide, and Hypochlorous Acid.&rdquo; Free Radical Biology &amp; Medicine 44 (7): 1295&ndash;1304.</p> <p>Griendling, Kathy K., Rhian M. Touyz, Jay L. Zweier, Sergey Dikalov, William Chilian, Yeong-Renn Chen, David G. Harrison, Aruni Bhatnagar, and American Heart Association Council on Basic Cardiovascular Sciences. 2016. &ldquo;Measurement of Reactive Oxygen Species, Reactive Nitrogen Species, and Redox-Dependent Signaling in the Cardiovascular System: A Scientific Statement From the American Heart Association.&rdquo; Circulation Research 119 (5): e39&ndash;75.</p> <p>Ozcan, Ayla, and Metin Ogun. 2015. &ldquo;Biochemistry of Reactive Oxygen and Nitrogen Species.&rdquo; In Basic Principles and Clinical Significance of Oxidative Stress, edited by Sivakumar Joghi Thatha Gowder. Rijeka: IntechOpen.</p> <p>Parrish, A. R. 2010. &ldquo;2.27 - Hypoxia/Ischemia Signaling.&rdquo; In Comprehensive Toxicology (Second Edition), edited by Charlene A. McQueen, 529&ndash;42. Oxford: Elsevier.</p> <p>Sharma, Gunjan, Nishant Kumar Rana, Priya Singh, Pradeep Dubey, Daya Shankar Pandey, and Biplob Koch. 2017. &ldquo;p53 Dependent Apoptosis and Cell Cycle Delay Induced by Heteroleptic Complexes in Human Cervical Cancer Cells.&rdquo; Biomedicine &amp; Pharmacotherapy = Biomedecine &amp; Pharmacotherapie 88 (April): 218&ndash;31.</p> <p>Yen, Cheng Chien, et al. &quot;Inorganic arsenic causes cell apoptosis in mouse cerebrum through an oxidative stress-regulated signaling pathway.&quot; Archives of toxicology 85 (2011): 565-575.</p> <p>Yuan, Yan, et al. &quot;Cadmium-induced apoptosis in primary rat cerebral cortical neurons culture is mediated by a calcium signaling pathway.&quot; PloS one 8.5 (2013): e64330.</p> AOPWiki 2016-11-29T18:41:29 2023-07-26T14:34:09 increased, oncotic necrosis Tissue <p>Biological state: cell death resulting from cellular swelling, as opposed to apoptosis.</p> <p>Biological compartment: tissue level -- cellular swelling and death.</p> <p>General role in biology: oncotic necrosis is cell death that is not planned or programmed. Oncotic necrosis typically results in inflammation.</p> <p>Typically using plasma membrane permeability.</p> <p>Known to occur in most eukaryotes.</p> High Unspecific High All life stages AOPWiki 2017-11-14T10:27:25 2017-11-27T13:31:45 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430ae56410> AOPWiki 2017-11-13T12:51:00 2017-11-13T12:51:00 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430ae89ef0> AOPWiki 2017-11-14T10:25:09 2017-11-14T10:25:09 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430aebe060> AOPWiki 2017-11-14T10:26:22 2017-11-14T10:26:22 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430aeea1b0> AOPWiki 2017-11-14T10:27:45 2017-11-14T10:27:45 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430af033b8> AOPWiki 2017-11-14T10:28:02 2017-11-14T10:28:02 Inhibition fatty acid beta oxidation leading to nonalcoholic steatohepatisis (NASH) Arthur Author <p>Lyle Burgoon, US Army Engineer Research and Development Center</p> <p>Edward Perkins, US Army Engineer Research and Development Center</p> Open for adoption 1.0 <p>Non-alcoholic steatohepatitis (NASH) is a significant disease of the liver. NASH presents as steatosis (fatty liver) and hepatitis (liver inflammation). NASH is on a spectrum of liver disease, starting at steatosis and ultimately leading to cirrhosis (liver fibrosis) if chemical exposure and injury continues. This AOP is focused on fatty acid beta oxidation and its contribution as a molecular initiating event in the formation of NASH. Steatosis is ultimately a net increase in fatty acids within hepatocytes. This can be from a net decrease in efflux (e.g., influx &gt;&gt; efflux), a net decrease in overall fatty acid oxidation/metabolism to glucose and intermediates, or a combination of these factors. In this AOP, our MIE is the inhibition of fatty acid beta oxidation (FABO). This leads to an overall increase in fatty acids. These fatty acids undergo lipid peroxidation resulting in fatty acid free radicals. When the reduction potential of the cell is overwhelmed, the free radicals lead to oncotic cell death, and the release of signals that stimulate inflammatory cell infiltration.</p> <p>Steatosis is the condition where an abnormal amount of fat is being stored within the liver. The liver is the site where sugars and fats are converted for the purposes of supplying energy to the rest of the body. The liver will convert glucose to fatty acids and package them as triglycerides for distribution throughout the body via the bloodstream and storage in adipose tissue. The liver also takes in fatty acids and triglycerides, and oxidizes them back to glucose for distribution throughout the body. When the influx/efflux and metabolism of fatty acids is altered, leading to a net increase in cellular fatty acids, the result is steatosis. As steatosis progresses, these fatty acids may lead to oxidative stress that ultimately leads to oncotic necrosis (cell death) and inflammatory cell infiltration (inflammation). This is termed steatohepatitis.&nbsp;&nbsp;</p> <p>The precursor state to NASH&nbsp;(non-alcoholic steatohepatitis), steatosis, has been used in US EPA IRIS assessments as an adverse outcome.&nbsp;</p> adjacent High High adjacent High High adjacent Low High adjacent Low High adjacent Low High High Unspecific High All life stages High <p>Overall, the confidence in this AOP is high. Most of the components of fatty acid metabolism are well known biochemical pathways that are well studied. Although components of this AOP occur within cells, the overall diagnosis of this condition is typically at the organ level. The adverse outcome is known to occur in vertebrates in the liver. Steatosis has been used as a regulatory endpoint or potential regulatory endpoint in many assessments from the US EPA.</p> <p>This AOP begins at inhibition of fatty acid beta-oxidation. This results in an increase in the overall amount of cytosolic fatty acids in the cytoplasm (under certain assumptions mentioned below). To lead to toxicity, the cytoplasm must become a net sink of fatty acids, with the rate of fatty acid deposition being greater than the rate of fatty acid efflux.&nbsp;This increase in cytosolic fatty acids increases the likelihood that reactive oxygen species will have lipids to undergo peroxidation, leading to a cascade of protein and membrane damage once the cellular reduction system is depleted. This damage leads to oncotic necrosis which results in the spillage of cytoplasmic contents, which triggers an inflammatory response. The result is steatohepatitis.&nbsp;</p> <p>&nbsp;</p> <p>The domain of applicability for this AOP is all sexes in vertebrates at all life stages with a functional liver.&nbsp;</p> <p>It has been demonstrated that pharmacological inhibition of fatty acid beta-oxidation is sufficient to cause steatosis (1-4).&nbsp;</p> <p>Steatosis leading to inflammation (termed non-alcoholic steatohepatitis; NASH) is well known. Some hypotheses of how this may occur are discussed in (5). As steatosis is necessary for a diagnosis of NASH, it is essential by definition.</p> <p>NASH is a well-known adverse event that has been well-studied in the toxicology literature, especially in support of pharmaceutical development. The key events involved in NASH are relatively well-studied. There are many forking paths that lead to NASH, with inhibition of fatty acid beta-oxidation being just one. The progression from pre-steatosis to steatohepatitis is reviewed in (6). The key events are generally well-known; however, what is less well-known are the exact molecular key event components that lead from steatosis to activation of the hepatic Kuppfer cells (liver macrophages) which activate hepatitis. However, for the purposes of the AOP, this level of granular knowledge is not required.</p> <p>&nbsp;</p> <p>Based on information available in (2-3) it is possible to estimate the amount of fatty acid beta-oxidation inhibition that is required to lead to steatosis. The quantitative evidence for the steps leading from steatosis to hepatitis are relatively weak. This process is not entirely well-known at the granular, molecular level, and there is a derth of quantitative studies at this time.</p> <p>This AOP was developed to support the development of probabilistic AOPs, specifically the AOP Bayesian Network (AOPBN) for Steatosis featured in the BISCT tool (BISCT: Bayesian Inference for Substance and Chemical Toxicity <a href="https://doi.org/10.5281/zenodo.834767"><img alt="DOI" src="https://zenodo.org/badge/DOI/10.5281/zenodo.834767.svg" /></a>). The Steatosis AOPBN is intended for use in:</p> <ul> <li><strong>Chemical Screening</strong>, when coupled with HTS assays,&nbsp;</li> <li><strong>Hazard Identification</strong>, for risk screening and risk assessment</li> </ul> <p>The AOPBN in BISCT is compatible with data from HTS assays, high content assays (e.g., toxicogenomics), molecular assays, and more traditional assays.</p> <p>BISCT is open source software, available at <a href="https://github.com/DataSciBurgoon/bisct/releases">GitHub</a></p> <ol> <li>Begriche K, Igoudjil A, Pessayre D, Fromenty B. Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it.&nbsp;Mitochondrion.&nbsp;2006 Feb;6(1):1-28. Epub 2006 Jan 5.&nbsp;</li> <li>E Freneaux,&nbsp;B Fromenty,&nbsp;A Berson,&nbsp;G Labbe,&nbsp;C Degott,&nbsp;P Letteron,&nbsp;D Larrey&nbsp;and&nbsp;D Pessayre.&nbsp;Stereoselective and nonstereoselective effects of ibuprofen enantiomers on mitochondrial beta-oxidation of fatty acids.&nbsp;Journal of Pharmacology and Experimental Therapeutics&nbsp;November 1990,&nbsp;255&nbsp;(2)&nbsp;529-535.</li> <li>J Geneve,&nbsp;B Hayat-Bonan,&nbsp;G Labbe,&nbsp;C Degott,&nbsp;P Letteron,&nbsp;E Freneaux,&nbsp;T L Dinh,&nbsp;D Larrey&nbsp;and&nbsp;D Pessayre.&nbsp;Inhibition of mitochondrial beta-oxidation of fatty acids by pirprofen. Role in microvesicular steatosis due to this nonsteroidal anti-inflammatory drug.&nbsp;Journal of Pharmacology and Experimental Therapeutics&nbsp;September 1987,&nbsp;242&nbsp;(3)&nbsp;1133-1137.</li> <li>Seung-Hoi Koo.&nbsp;Nonalcoholic fatty liver disease: molecular mechanisms for the hepatic steatosis.&nbsp;Clin Mol Hepatol. 2013 Sep; 19(3): 210&ndash;215.</li> <li>Herbert Tilg, Alexander R. Moschen.&nbsp;Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis.&nbsp;Hepatology 2010;52:1836-1846.</li> <li>Satapathy SK,&nbsp;Kuwajima V,&nbsp;Nadelson J,&nbsp;Atiq O,&nbsp;Sanyal AJ.&nbsp;Drug-induced fatty liver disease: An overview of pathogenesis and management.&nbsp;Ann Hepatol.&nbsp;2015 Nov-Dec;14(6):789-806. doi: 10.5604/16652681.1171749.</li> </ol> AOPWiki 2017-04-12T13:28:27 2023-09-25T16:26:55