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Key Event Title
Increased, Reactive oxygen species
|Level of Biological Organization|
Key Event Components
|reactive oxygen species biosynthetic process||reactive oxygen species||increased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|unknown MIE renal failure||KeyEvent||Kellie Fay (send email)||Under Development: Contributions and Comments Welcome|
|Inhibition fatty acid beta oxidation leading to nonalcoholic steatohepatisis (NASH)||KeyEvent||Lyle Burgoon (send email)||Open for adoption|
|Frustrated phagocytosis-induced lung cancer||KeyEvent||Carole Seidel (send email)||Under development: Not open for comment. Do not cite||Under Development|
|ACE2 inhibition, liver fibrosis||KeyEvent||Young Jun Kim (send email)||Under development: Not open for comment. Do not cite||Under Development|
|AT1R, lung fibrosis||KeyEvent||Young Jun Kim (send email)||Under development: Not open for comment. Do not cite||Under Development|
|ACE/Ang-II/AT1R axis, chronic kidney disease (CKD)||KeyEvent||Young Jun Kim (send email)||Under development: Not open for comment. Do not cite|
|Deposition of ionizing energy leads to population decline via impaired meiosis||KeyEvent||Erica Maremonti (send email)||Under development: Not open for comment. Do not cite|
|Frustrated phagocytosis leads to malignant mesothelioma||KeyEvent||Penny Nymark (send email)||Under development: Not open for comment. Do not cite|
|Oxidation of Reduced Glutathione Leading to Mortality||KeyEvent||Zarin Hossain (send email)||Open for citation & comment|
|AHR activation leading to lung cancer via IL-6 tox path||KeyEvent||Dianke Yu (send email)||Under development: Not open for comment. Do not cite|
|AHR activation decreasing lung function via AHR-ARNT tox path||KeyEvent||Dianke Yu (send email)||Under development: Not open for comment. Do not cite|
|ROS production leading to population decline via photosynthesis inhibition||KeyEvent||Knut Erik Tollefsen (send email)||Under development: Not open for comment. Do not cite|
|ROS production leading to population decline via mitochondrial dysfunction||KeyEvent||Knut Erik Tollefsen (send email)||Under development: Not open for comment. Do not cite|
|Binding to ACE2 leads to lung fibrosis||KeyEvent||Young Jun Kim (send email)||Open for comment. Do not cite||Under Development|
|Interaction with lung cells leads to lung cancer||KeyEvent||Penny Nymark (send email)||Under development: Not open for comment. Do not cite|
|Adverse Outcome Pathways diagram related to PBDEs associated male reproductive toxicity||MolecularInitiatingEvent||Yue Zhang (send email)||Under development: Not open for comment. Do not cite|
|Glutathione conjugation leading to reproductive dysfunction||KeyEvent||Leonardo Vieira (send email)||Under Development: Contributions and Comments Welcome|
|ERa inactivation leads to insulin resistance in skeletal muscle and metabolic syndrome||KeyEvent||Min Ji Kim (send email)||Under development: Not open for comment. Do not cite|
|MEK-ERK1/2 activation leading to deficits in learning and cognition via ROS||KeyEvent||Travis Karschnik (send email)||Under development: Not open for comment. Do not cite|
|ROS formation leads to cancer via inflammation pathway||MolecularInitiatingEvent||John Frisch (send email)||Under development: Not open for comment. Do not cite|
|ROS formation leads to cancer via PPAR pathway||MolecularInitiatingEvent||John Frisch (send email)||Under development: Not open for comment. Do not cite|
|All life stages||High|
Key Event Description
Biological State: increased reactive oxygen species (ROS)
Biological compartment: an entire cell -- may be cytosolic, may also enter organelles.
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 – they might act as antimicrobial agents or triggers of animal gamete activation and capacitation (Goud et al. 2008; Parrish 2010; Bisht et al. 2017). 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).
How It Is Measured or Detected
Photocolorimetric assays (Sharma et al. 2017; Griendling et al. 2016) or through commercial kits purchased from specialized companies.
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 µmol/L final concentration) for 30 min in the dark at 37°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.
Lipid peroxidation (LPO) can be measured as an indicator of oxidative stress damage Yen, Cheng Chien, et al., (2013).
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 °C and the product formed was assayed at 550 nm in an Anthos 2001 plate reader. The observations of the ‘cell-free system’ were confirmed by cytological examination of parallel set of explants stained with chromogenic reactions for NO and ROS.
Domain of Applicability
ROS is a normal constituent found in all organisms.
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
Bedard, Karen, and Karl-Heinz Krause. 2007. “The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology.” Physiological Reviews 87 (1): 245–313.
Bisht, Shilpa, Muneeb Faiq, Madhuri Tolahunase, and Rima Dada. 2017. “Oxidative Stress and Male Infertility.” Nature Reviews. Urology 14 (8): 470–85.
Brieger, K., S. Schiavone, F. J. Miller Jr, and K-H Krause. 2012. “Reactive Oxygen Species: From Health to Disease.” Swiss Medical Weekly 142 (August): w13659.
Chattopadhyay, Sukumar, et al. "Apoptosis and necrosis in developing brain cells due to arsenic toxicity and protection with antioxidants." Toxicology letters 136.1 (2002): 65-76.
Drew, Barry, and Christiaan Leeuwenburgh. 2002. “Aging and the Role of Reactive Nitrogen Species.” Annals of the New York Academy of Sciences 959 (April): 66–81.
Goud, Anuradha P., Pravin T. Goud, Michael P. Diamond, Bernard Gonik, and Husam M. Abu-Soud. 2008. “Reactive Oxygen Species and Oocyte Aging: Role of Superoxide, Hydrogen Peroxide, and Hypochlorous Acid.” Free Radical Biology & Medicine 44 (7): 1295–1304.
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. “Measurement of Reactive Oxygen Species, Reactive Nitrogen Species, and Redox-Dependent Signaling in the Cardiovascular System: A Scientific Statement From the American Heart Association.” Circulation Research 119 (5): e39–75.
Ozcan, Ayla, and Metin Ogun. 2015. “Biochemistry of Reactive Oxygen and Nitrogen Species.” In Basic Principles and Clinical Significance of Oxidative Stress, edited by Sivakumar Joghi Thatha Gowder. Rijeka: IntechOpen.
Parrish, A. R. 2010. “2.27 - Hypoxia/Ischemia Signaling.” In Comprehensive Toxicology (Second Edition), edited by Charlene A. McQueen, 529–42. Oxford: Elsevier.
Sharma, Gunjan, Nishant Kumar Rana, Priya Singh, Pradeep Dubey, Daya Shankar Pandey, and Biplob Koch. 2017. “p53 Dependent Apoptosis and Cell Cycle Delay Induced by Heteroleptic Complexes in Human Cervical Cancer Cells.” Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 88 (April): 218–31.
Yen, Cheng Chien, et al. "Inorganic arsenic causes cell apoptosis in mouse cerebrum through an oxidative stress-regulated signaling pathway." Archives of toxicology 85 (2011): 565-575.
Yuan, Yan, et al. "Cadmium-induced apoptosis in primary rat cerebral cortical neurons culture is mediated by a calcium signaling pathway." PloS one 8.5 (2013): e64330.