Increased, Reactive oxygen species

CHEBI:26523

CHEBI reactive oxygen species

PR:000013058

PR peroxisome proliferator-activated receptor gamma

D009369

MESH Neoplasms

GO:1903409

GO reactive oxygen species biosynthetic process

GO:0035357

GO peroxisome proliferator activated receptor signaling pathway

GO:0006629

GO lipid metabolic process

MP:0006042

MP increased apoptosis

WIKI increased

WIKI decreased

WIKI abnormal

WikiUser_28

Vertebrates

WCS_9606

common toxicological species human

WikiUser_25

Wikiuser: Cyauk human and other cells in culture

10090

NCBI mouse

WCS_35525

common ecological species crustaceans

WCS_4472

common ecological species Lemna minor

WCS_7955

common ecological species zebrafish

10116

NCBI rat

9606

NCBI Homo sapiens

10116

NCBI Rattus norvegicus

10090

NCBI Mus musculus

Increased, Reactive oxygen species

Cellular

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).  Balancing ROS levels at the cellular and tissue level is an important part of many biological processes. Disbalance, mainly an increase in ROS levels, can cause cell dysfunction and irreversible cell damage. ROS are produced from both exogenous stressors and normal endogenous cellular processes, such as the mitochondrial electron transport chain (ETC). Inhibition of the ETC can result in the accumulation of ROS. Exposure to chemicals, heavy metal ions, or ionizing radiation can also result in increased production of ROS. Chemicals and heavy metal ions can deplete cellular antioxidants reducing the cell’s ability to control cellular ROS and resulting in the accumulation of ROS. Cellular antioxidants include glutathione (GSH), protein sulfhydryl groups, superoxide dismutase (SOD). ROS are radicals, ions, or molecules that have a single unpaired electron in their outermost shell of electrons, which can be categorized into two groups: free oxygen radicals and non-radical ROS [Liou et al., 2010]. <Free oxygen radicals> <div> <table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none"> <tbody> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:290px"> uperoxide </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:290px"> O2·- </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> hydroxyl radical </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> ·OH </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> nitric oxide </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> NO· </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> organic radicals </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> R· </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> peroxyl radicals </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> ROO· </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> alkoxyl radicals </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> RO· </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> thiyl radicals </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> RS· </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> sulfonyl radicals </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> ROS· </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> thiyl peroxyl radicals </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> RSOO· </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> disulfides </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> RSSR </td> </tr> </tbody> </table> </div> <Non-radical ROS> <div> <table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none"> <tbody> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:290px"> hydrogen peroxide </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:290px"> H2O2 </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> singlet oxygen </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> 1O2 </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> ozone/trioxygen </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> O3 </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> organic hydroperoxides </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> ROOH </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> hypochlorite </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> ClO- </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> peroxynitrite </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> ONOO- </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> nitrosoperoxycarbonate anion </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> O=NOOCO2- </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> nitrocarbonate anion </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> O2NOCO2- </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> dinitrogen dioxide </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> N2O2 </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> nitronium </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> NO2+ </td> </tr> <tr> <td colspan="2" style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:580px"> highly reactive lipid- or carbohydrate-derived carbonyl compounds </td> </tr> </tbody> </table> </div> Potential sources of ROS include NADPH oxidase, xanthine oxidase, mitochondria, nitric oxide synthase, cytochrome P450, lipoxygenase/cyclooxygenase, and monoamine oxidase [Granger et al., 2015]. ROS are generated through NADPH oxidases consisting of p47phox and p67phox. ROS are generated through xanthine oxidase activation in sepsis [Ramos et al., 2018]. Arsenic produces ROS [Zhang et al., 2011]. Mitochondria-targeted paraquat and metformin mediate ROS production [Chowdhury et al., 2020]. ROS are generated by bleomycin [Lu et al., 2010]. Radiation induces dose-dependent ROS production [Ji et al., 2019]. ROS are generated in the course of cellular respiration, metabolism, cell signaling, and inflammation [Dickinson and Chang 2011; Egea et al. 2017]. Hydrogen peroxide is also made by the endoplasmic reticulum in the course of protein folding. Nitric oxide (NO) is produced at the highest levels by nitric oxide synthase in endothelial cells and phagocytes. NO production is one of the main mechanisms by which phagocytes kill bacteria [Wang et al., 2017]. The other species are produced by reactions with superoxide or peroxide, or by other free radicals or enzymes. ROS activity is principally local. Most ROS have short half-lives, ranging from nano- to milliseconds, so diffusion is limited, while reactive nitrogen species (RNS) nitric oxide or peroxynitrite can survive long enough to diffuse across membranes [Calcerrada et al. 2011]. Consequently, local concentrations of ROS are much higher than average cellular concentrations, and signaling is typically controlled by colocalization with redox buffers [Dickinson and Chang 2011; Egea et al. 2017]. Although their existence is limited temporally and spatially, ROS interact with other ROS or with other nearby molecules to produce more ROS and participate in a feedback loop to amplify the ROS signal, which can increase RNS. Both ROS and RNS also move into neighboring cells, and ROS can increase intracellular ROS signaling in neighboring cells [Egea et al. 2017].

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. <div> <Direct detection> Many fluorescent compounds can be used to detect ROS, some of which are specific, and others are less specific. ・ROS can be detected by fluorescent probes such as p-methoxy-phenol derivative [Ashoka et al., 2020]. ・Chemiluminescence analysis can detect the superoxide, where some probes have a wider range for detecting hydroxyl radical, hydrogen peroxide, and peroxynitrite [Fuloria et al., 2021]. ・ROS in the blood can be detected using superparamagnetic iron oxide nanoparticles (SPION)-based biosensor [Lee et al., 2020]. ・Hydrogen peroxide (H2O2) can be detected with a colorimetric probe, which reacts with H2O2 in a 1:1 stoichiometry to produce a bright pink colored product, followed by the detection with a standard colorimetric microplate reader with a filter in the 540-570 nm range. ・The levels of ROS can be quantified using multiple-step amperometry using a stainless steel counter electrode and non-leak Ag|AgCl reference node [Flaherty et al., 2017]. ・Singlet oxygen can be measured by monitoring the bleaching of p-nitrosodimethylaniline at 440 nm using a spectrophotometer with imidazole as a selective acceptor of singlet oxygen [Onoue et al., 2014]. <Indirect Detection> Alternative methods involve the detection of redox-dependent changes to cellular constituents such as proteins, DNA, lipids, or glutathione [Dickinson and Chang 2011; Wang et al. 2013; Griendling et al. 2016]. However, these methods cannot generally distinguish between the oxidative species behind the changes and cannot provide good resolution for the kinetics of oxidative activity. </div>

ROS is a normal constituent found in all organisms, lifestages, and sexes.

UBERON:0000062

UBERON organ

CL:0000000

CL cell

High Unspecific

High

All life stages

High Moderate Moderate Moderate High High High

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. AOPWiki 2016-11-29T18:41:29

2025-01-29T12:41:14

Decreased, PPAR-gamma activation

Molecular

The Peroxisome Proliferator-Activated Receptors (PPAR) family of genes involved in regulation of lipid metabolism and energy pathways (Desvergne and Wahli 1999, Hihi et al. 2002, Ahmed et al. 2007).  Fatty acids stimulate the expression of PPAR genes, which initiate a variety of cellular responses focused on lipid metabolism, but also inflammation and apoptosis pathways.  Decreases in PPAR-gamma expression are associated with disruption of adipocyte differentiation and glucose homeostasis.

Peroxisome proliferation-activated receptors are investigated by changes in gene expression and protein levels.  X-ray crystallography can be used to determine molecular structure.  Effects of PPAR gamma on expression of downstream genes can be investigating using metabolomics and RT-qPCR approaches.

Life Stage: All life stages.  Sex: Applies to both males and females. Taxonomic: Appears to be present broadly, with representative studies in mammals.

CL:0000182

CL hepatocyte

Not Specified Unspecific

Not Specified

All life stages

Not Specified Not Specified Not Specified

Ahmed, W., Ziouzenkova, O., Brown, J. Devchand, P. Francis, S., Kadakia, M., Kanda, T., Orasanu, G., Sharlach, M., Zandbergen, F., and Plutzky, J.  2007.  PPARs and their metabolic modulation: new mechanisms for transcriptional regulation?  Journal of Internal Medicine 262: 184-198. Desvergne, B. and Wahli, W. 1999.  Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine Reviews 20(5): 649-688. Hihi, A.K., Michalik, L., Wahli, W. 2002. PPARs: transcriptional effectors of fatty acids and their derivatives. Cellular and Molecular Life Sciences 59: 790-798. AOPWiki 2016-11-29T18:41:23

2023-10-30T09:07:07

Alteration, lipid metabolism

Cellular

Lipids are important molecules for efficient energy storage, in addition to roles as signaling molecules and basic building blocks in organisms.  In addition to energy release, lipid metabolism affects the amount of stored fat.  Alteration of lipid metabolism reflects a disruption of normal function, as evidenced by changes in gene expression, enzyme levels, break-down products, or fat content.  Peroxisome proliferation-activated receptors pathways (and associated genes and proteins) are commonly monitored for downstream effects on lipid metabolism (Luquet et al. 2005; Den Broeder et al. 2015; Chamorro-Garcia et al. 2018; Venezia et al. 2021).

Changes in lipid metabolism can be detected by examining organism fat content, or by examination of organs (ex. stomach, liver, intestines) for break-down products (ex. proteins) or changes in gene expression.

Life Stage: All life stages.  Sex: Applies to both males and females. Taxonomic: Appears to be present broadly, with representative studies in mammals.

CL:0000255

CL eukaryotic cell

Not Specified Unspecific

Not Specified

All life stages

Not Specified Not Specified Not Specified

Chamorro-Garcia, R., Shoucri, B.M., Willner, S., Kach, H., Janesick, A., and Blumberg, B.  2018.  Effect of perinatal exposure to dibutyltin chloride on fat and glucose metabolism in mice, and molecular mechanisms, in vitro.  Environmental Health Perspectives 126: 057006. Den Broeder, M.J., Kopylova, V.A., Kamminga, L.M. Legler, J.  2015.  Zebrafish as a model to study the role of peroxisome proliferating-activated receptors in adipogenesis and obesity.  PPAR Research 2015: 358029. Luquet, S., Gaudel, C., Holst, D., Lopez-Soriano, J., Jehl-Pietri, C., Fredenrich, A., and Grimaldi, P.A.  2005.  Roles of PPAR delta in lipid absorption and metabolism: A new target for the treatment of type 2 diabetes.  Biochimica and Biophysica Acta 1740: 313-317. Venezia, O., Islam, S., Cho, C., Timme-Laragy, A.R., and Sant, K.E.  2021.  Modulation of PPAR signaling disrupts pancreas development in the zebrafish, Danio rerio.  Toxicology and Applied Pharmacology 426: 115653. AOPWiki 2016-11-29T18:41:29

2023-10-30T09:11:26

General Apoptosis

Cellular

Apoptosis is the programmed cell death in general. This process is well regulated with a sequence of events before cell fragmentation occurs. Changes in the nucleus of a cell are the first step in apoptosis. Before that, other factors such as stress, inflammation, cell damage can induce expression or activation of signal proteins which will activate the pathway for apoptosis. Examples of proteins which are involved in apoptosis are the proteins p53, Bcl-2, JNK, and several caspases. When the first step is taken in the apoptosis process the cell will end in membrane-bounded apoptotic bodies. These bodies are cleared by macrophages or other cells where the degradation process starts within heteorphagosomes.

There are several possibilities to measure and detect apoptosis, some common techniques are: <ul> <li>The detection of Lactate dehydrogenase (LDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) substances which are released from cells which undergo apoptosis. </li> <li>An older but effective technique it the annexin V – affinity assay. The principle of this assay is the high affinity binding between annexin V and phosphatidylserine. In a vital cell there is a membrane lipid asymmetry where phosphatidylserine molecules are facing the cytosol. During apoptosis the membrane lipid asymmetry is lost, and the phosphatidylserine molecules are expressed in the outer membrane. When annexin-V is present in combination with Ca2+ it binds with high affinity to phosphatidylserine. With a hapten label at the annexin-V this process can be detected.</li> <li>Another technique is the detection of cleaved caspase-3, which could be done with western blot or enzyme-linked immunosorbent assays. </li> <li>Cytochrome c is also a protein which is released in an early stage of apoptosis. Detection of cytochrome c can be done with metal nanoclusters which have a fluorescent probe in addition to western blot assay.</li> </ul>

Taxonomic: appears to be present broadly among multicellular organisms.

High Unspecific

High

All life stages

High High High

Shtilbans, V., Wu, M. & Burstein, D. E. Evaluation of apoptosis in cytologic specimens. Diagnostic Cytopathology 38, 685–697 (2010). Wu, J., Sun, J. & Xue, Y. Involvement of JNK and P53 activation in G2/M cell cycle arrest and apoptosis induced by titanium dioxide nanoparticles in neuron cells. Toxicol. Lett. 199, 269–276 (2010). Redza-Dutordoir, M. & Averill-Bates, D. A. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim. Biophys. Acta - Mol. Cell Res. 1863, 2977–2992 (2016). Lossi, L., Castagna, C. & Merighi, A. Neuronal cell death: An overview of its different forms in central and peripheral neurons. in Neuronal Cell Death: Methods and Protocols 1–18 (2014). doi:10.1007/978-1-4939-2152-2_1 Van Engeland, M., Nieland, L. J. W., Ramaekers, F. C. S., Schutte, B. & Reutelingsperger, C. P. M. Annexin V-affinity assay: A review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry 31, 1–9 (1998). Shamsipur, M., Molaabasi, F., Hosseinkhani, S. & Rahmati, F. Detection of Early Stage Apoptotic Cells Based on Label-Free Cytochrome c Assay Using Bioconjugated Metal Nanoclusters as Fluorescent Probes. Anal. Chem. 88, 2188–2197 (2016). AOPWiki 2018-04-04T14:30:27

2023-10-18T12:20:28

Increase, Cancer

Tissue

Cancer is a general key event for related diseases each exhibiting uncontrolled proliferation of abnormal cells (for review see Hanahan and Weinberg 2011).  A cancer often is initially associated with a specific organ, with malignant tumors developing ability to metastasize, or travel to other areas of the body.  Most cancers develop from genetic mutations in normal cells, although a minority of cancers are hereditary.   Exposure to chemical stressors, radiation, tobacco smoke, or viruses can increase the likelihood that cancer will develop. Cancer cells proliferate due to capabilities summarized by Hanahan and Weinberg (2011): <ol> <li>Sustained proliferation signaling – by deregulating normal cell signals, cancer cells can sustain chronic proliferation.</li> <li>Evading growth suppressors – by evading activities of tumor suppressor genes, cancer cells continue to proliferate.</li> <li>Activating invasion and metastasis – by altering shape and attachment to cells in the extracellular matrix, cancer cells gain ability to move to other locations.</li> <li>Enabling replicative immortality – by disabling senescence pathways, cancer cells have extended lifespans.</li> <li>Inducing angiogenesis – by enabling neovasculature, cancer cells receive nutrients and oxygen and get rid of waste products.</li> <li>Resisting cell death – by evading apotosis and necrosis defense pathways, cancer cells avoid elimination.</li> </ol>

Most carcinogenicity studies are conducted with rodents (see OECD 2018; Zhou et al. 2023 for methods) or in-vitro with mammalian cell lines (see OECD 2023 for methods).  Cancer is usually detected by biopsy or histopathological examination of tissue.  Gene expression levels can also be assessed, as increased transcription of known genes have been associated with specific cancers (ex. Tumor Necrosis Factor (Pavet et al. 2014); Heat Shock Factors (Vihervaara and Sistonen 2014; Androgen Receptor (Heinlein and Chang 2004)).

Life Stage: All life stages.  Older individuals are more likely to manifest this key event (adults > juveniles > embryos). Sex: Applies to both males and females. Taxonomic: Appears to be present broadly, with representative studies including mammals (humans, lab mice, lab rats), teleost fish, and invertebrates (cladocerans, mussels).

High Unspecific

High

All life stages

High High High

Abraha, A.M. and Ketema, E.B.  2016.  Apoptotic pathways as a therapeutic target for colorectal cancer treatment.  World Journal of Gastrointestinal Oncology 8 (8): 583-491 European Parliament.  2022.  Directive 2004/37/EC of the European Parliament on the protection of workers from the risks related to exposure to carcinogens, mutagens or reprotoxic substances at work.  Retrieved 3 August 2023 from http://data.europa.eu/eli/dir/2004/37/2022-04-05 Hanahan, D. and Weinberg, R.A.  2011.  Hallmarks of cancer: the next generation.  Cell 144(5): 646-674. Heinlein, C.A. and Chang, C.  2004.  Androgen receptor in prostate cancer.  Endocrine Reviews 25: 276-308. OECD.  2018.  Test no. 451: OECD Guideline for the Testing of Chemicals: Carcinogenicity Studies.  OECD Publishing, Paris.  Retrieved 3 August 2023 from <a href="https://www.oecd.org/env/test-no-451-carcinogenicity-studies-9789264071186-en.htm" style="color:#0563c1; text-decoration:underline">https://www.oecd.org/env/test-no-451-carcinogenicity-studies-9789264071186-en.htm</a> OECD.  2023. Test No. 487: In Vitro Mammalian Cell Micronucleus Test, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris.  Retrieved 3 August 2023 from  <a href="https://doi.org/10.1787/9789264264861-en.htm" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1787/9789264264861-en.htm</a> OSHA. 2023.  Carcinogens.  Retrieved 3 August 2023 from <a href="https://www.osha.gov/carcinogens/standards" style="color:#0563c1; text-decoration:underline">https://www.osha.gov/carcinogens/standards</a> Pavet, V., Shlyakhtina, Y., He, T., Ceschin, D.G., Kohonen, P., Perala, M., Kallioniemi, O., and Gronemeyer, H.  2014.  Plasminogen activator urokinase expression reveals TRAIL responsiveness and support fractional survival of cancer cells.  Cell Death and Disease 5: e1043. Vihervaara, A. and Sistonen, L.  2014.  HSF1 at a glance.  Journal of Cell Scientce 127: 261-266. Zhou, Y., Xia, J., Xu, S., She, T., Zhang, Y., Sun, Y., Wen, M., Jiang, T., Xiong, Y., and Lei, J.  2023.  Experimental mouse models for translational human cancer research.  Frontiers in Immunology 14: 1095388. AOPWiki 2016-11-29T18:41:27

2023-08-22T14:32:34

<upstream-id>b97ae408-8cff-4a54-8e34-9a2e1594d034</upstream-id> <downstream-id>036e536b-291d-4df8-874e-0f1fe87c5476</downstream-id> Oxidative stress occurs due to the accumulation of reactive oxygen species (ROS).    ROS can damage DNA, lipids, and proteins (Shields et al. 2021).  Superoxide dismutase is an enzyme in a common cellular defense pathway, in which superoxide dismutase converts superoxide radicals to hydrogen peroxide.  When cellular defense mechanisms are unable to mitigate ROS formation from mitochondrial respiration and stressors (biological, chemical, radiation), one established pathway that is disrupted involves Peroxisome proliferation-activated receptors.

This KER was identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. Support for this KER is referenced in publications cited in the originating work of Jeong and Choi (2020).

The biological plausibility linking decreases in Peroxisome proliferation-activated receptors to reactive oxygen species (ROS) is strong.  Reactive oxygen species (ROS) are produced by many normal cellular processes (ex. cellular respiration, mitochondrial electron transport, specialized enzyme reactions) and occur in multiple chemical forms (ex. superoxide anion, hydroxyl radical, hydrogen peroxide).  Antioxidant enzymes play a major role in reducing reactive oxygen species (ROS) levels in cells (Ray et al. 2012) to prevent cellular damage to lipids, proteins, and DNA (Juan et al. 2021).   This Key Event Relationship focuses on the disruption of Peroxisome proliferation-activated receptors gene expression due to increases in Reactive oxygen species (ROS) level.

<table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none"> <tbody> <tr> <td style="background-color:#f2f2f2; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:89px"> Species </td> <td style="background-color:#f2f2f2; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:89px"> Duration </td> <td style="background-color:#f2f2f2; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:89px"> Dose </td> <td style="background-color:#f2f2f2; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:89px"> Increased ROS? </td> <td style="background-color:#f2f2f2; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:89px"> Decreased PPAR? </td> <td style="background-color:#f2f2f2; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:89px"> Summary </td> <td style="background-color:#f2f2f2; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:89px"> Citation </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Lab rats (Rattus norvegicus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> 4 weeks </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Diet exposure of 10% D-glucose, with 1000 mg/kg feed alpha-lipoic acid supplement evaluated to mitigate D-glucose effects </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Yes   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Male rats showed increased superoxide levels in glucose treatment but not glucose plus alpha-lipoic acid treatment, and corresponding patterns in PPAR-gamma gene expression in the treatments. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> El Midaoui et al. (2006) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Human (Homo sapiens) and cow (Bos taurus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> 72 hours </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> In vitro exposure of 1-1000 uM hydrogen peroxide </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Assumed </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Human umbilical vein endothelial cells and bovine aortic endothelial cells showed increased dose-dependent cytotoxicity when was assumed to correlated with higher reactive oxygen species (ROS) levels, PPARgamma gene expression levels showed corresponding decreases. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Blanquicett et al. (2010) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Lab mice (Mus musculus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> 5 weeks </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Diet exposure of 100, 1000 ug/L of 0.5, 50 um polystyrene microplastics </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Assumed </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Study selected stressor(s) known to elevate reactive oxygen species (ROS) levels.  Male mice showed decreased gene expression of Peroxisome proliferation-activated receptor (PPAR-gamma) in blood. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Lu et al. (2018) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> 4 weeks </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Diet exposure of rosiglitazone, mitigation with N-acetylcysteine, L-carnitine, cold and heat stress, fish with PPAR-gamma mutations </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Male and female fish had increased ROS levels and corresponding decreases in PPAR-gamma expression levels </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:89px"> Wang et al. (2022) </td> </tr> </tbody> </table> 1 Assumed: study selected stressor(s) known to elevate reactive oxygen species (ROS) levels, endpoints verified increased oxidative stress and disrupted pathway.

High Unspecific

High

All life stages

High High High

Life Stage: The life stage applicable to this key event relationship is all life stages. Sex: This key event relationship applies to both males and females. Taxonomic: This key event relationship appears to be present broadly, with representative studies including mammals (humans, lab mice, lab rats) and teleost fish.

Blanquicett, C., Kang, B-Y., Ritzenthaler, J.D. Jones, D.P., and Hart, C.M.  2010.  Oxidative stress modulates PPARγ in vascular endothelial cells.  Free Radical Biology and Medicine 48: 1618-1625. El Midaoui, A., Wu, L., Wang, R., and de Champlain, J.  2006.  Modulation of cardiac and aortic peroxisome proliferator-activated receptor-gamma expression by oxidative stress in chronically glucose-fed rats.  American Journal of Hypertension 19: 407-412. Juan, C.A., de la Lastra, J.M.P., Plou, F.J., and Lebena, E.P.  2021.  The chemistry of reactive oxygen species (ROS) revisited: Outlining their role in biological macromolecules (DNA, lipids and proteins) and induced pathologies.  International Journal of Molecular Sciences  22: 4642. Lu, L., Wan, Z., Luo, T., Fu, Z., and Jin, Y.  2018.  Polystyrene microplastics induce microbiota dysbiosis and hepatic lipid metabolism disorder in mice. Science of the Total Environment 631-632: 449-458. Ray, P.D., Huang, B.-W., and Tsuji, Y.  2012.  Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signalling.  Cellular Signalling 24:981-990.   AOPWiki 2023-10-18T09:02:55

2023-10-19T10:55:36

<upstream-id>036e536b-291d-4df8-874e-0f1fe87c5476</upstream-id> <downstream-id>b5d5ea06-a62e-4f62-bc92-b6770cbdc0f0</downstream-id> Expression of Peroxisome proliferator-activated receptors (PPAR) family genes are closely related to different aspects of lipid metabolism, and resulting organism fat content.  PPAR-alpha, PPAR-gamma, and PPAR-delta families of genes are most often discussed when considering lipid metabolism.  PPAR-alpha family genes are linked to regulation of lipid metabolism, lipoprotein synthesis, and metabolism processes, while PPAR-gamma family genes are linked to the proliferation of adipose cells, and PPAR-delta family genes are linked to changes in metabolic response due to environmental change.  In this Key Event Relationship, we focus on the effects of decreased expression of PPAR-gamma family genes, with altered lipid metabolism.

The biological plausibility linking decreases in Peroxisome proliferation-activated receptors to lipid metabolism is strong.  Disruption of cellular processors via stressors have been shown to decrease PPAR-gamma gene expression, with corresponding decreases in lipid metabolism and/or increases in fat content of organisms.

For review see Berger et al. (2002), Luquet et al. (2005), Den Broder et al. (2015).  Experiments cited here have been conducted with lab mammals and with fish. <table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none"> <tbody> <tr> <td style="background-color:#f2f2f2; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:83px"> Species </td> <td style="background-color:#f2f2f2; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:76px"> Duration </td> <td style="background-color:#f2f2f2; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:103px"> Dose </td> <td style="background-color:#f2f2f2; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:81px"> Decreased PPAR? </td> <td style="background-color:#f2f2f2; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:92px"> Alteration lipid metabolism? </td> <td style="background-color:#f2f2f2; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:105px"> Summary </td> <td style="background-color:#f2f2f2; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:84px"> Citation </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:83px"> Human (Homo sapiens) and lab mice (Mus musculus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> 2 hours – 16 weeks </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:103px"> In vitro exposure of 10e-10M to 10e-5M dibutyltin and tributyltin and 500 nm rosiglitazone and diet exposure of 50, 500 nM dibutyltin and 50 nM tributyltin. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:92px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:105px"> In human and mouse cells, as well as lab mice, increased activation of PPAR-gamma gene expression was correlated with increases in glucose levels and increased weight gain. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:84px"> Chamorro-Garcia et al. (2018) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:83px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> 3 days </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:103px"> Aquatic exposure of  10 μM Rosiglitazone, T0070907, GW6471, GW590735, GSK3787, or GW501516. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:92px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:105px"> Embryos exposed to PPAR antagonist compounds had decreased PPAR-gamma gene expression correlated with decreased lipid accumulations, embryos exposed to PPAR agonist compounds had increased PPAR-gamma gene expression correlated with increased lipid accumulations. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:84px"> Venezia et al. (2021) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:83px"> Lab mice (Mus musculus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"> 5 weeks </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:103px"> Diet exposure of 100, 1000 ug/L of 0.5, 50 um polystyrene microplastics </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:92px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:105px"> Male mice showed decreased gene expression of Peroxisome proliferation-activated receptor (PPAR-gamma) correlated with decreased glucose levels and fat content. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:84px"> Lu et al. (2018) </td> </tr> </tbody> </table>

High Unspecific

High

All life stages

High High

Berger, J. and Moller, D.  2002.  The mechanisms of action of PPARS.  Annual Review of Medicine 53: 409-435. Chamorro-Garcia, R., Shoucri, B.M., Willner, S., Kach, H., Janesick, A., and Blumberg, B.  2018.  Effect of perinatal exposure to dibutyltin chloride on fat and glucose metabolism in mice, and molecular mechanisms, in vitro.  Environmental Health Perspectives 126(5): 057006. Den Broeder, M.J., Kopylova, V.A., Kamminga, L.M. Legler, J.  2015.  Zebrafish as a model to study the role of peroxisome proliferating-activated receptors in adipogenesis and obesity.  PPAR Research 2015: 358029. Lu, L., Wan, Z., Luo, T., Fu, Z., and Jin, Y.  2018.  Polystyrene microplastics induce microbiota dysbiosis and hepatic lipid metabolism disorder in mice. Science of the Total Environment 631-632: 449-458. Luquet, S., Gaudel, C., Holst, D., Lopez-Soriano, J., Jehl-Pietri, C., Fredenrich, A., and Grimaldi, P.A.  2005.  Roles of PPAR delta in lipid absorption and metabolism: A new target for the treatment of type 2 diabetes.  Biochimica and Biophysica Acta 1740: 313-317. Venezia, O., Islam, S., Cho, C., Timme-Laragy, A.R., and Sant, K.E.  2021.  Modulation of PPAR signaling disrupts pancreas development in the zebrafish, Danio rerio.  Toxicology and Applied Pharmacology 426: 115653. AOPWiki 2023-10-18T09:03:17

2023-10-19T11:10:51

<upstream-id>b5d5ea06-a62e-4f62-bc92-b6770cbdc0f0</upstream-id> <downstream-id>d19011c9-41f2-42fe-b65a-e7f2214dba7a</downstream-id> Alteration of lipid metabolism leads to changes in cell lipid levels, structural changes in membranes (lipids are key components), and changes in signaling pathways affecting gene and protein expression (Huang and Freter, 2015).  Loss of plasma membrane integrity due to disruptions to lipid metabolism results in cellular processes identifying cells as damaged, triggering apoptosis pathways.  Oxidation of fatty acids can lead to increases of reactive oxygen species (ROS), creating an additional stress disrupting the cellular environment.  As lipids represent a diverse class of molecules, and the basic building blocks for many biologically important compounds, disruption of lipid function will eventually lead to damaged cells and cell death via apoptosis.

The biological plausibility linking alterations in lipid metabolism to apoptosis is moderate.  Disruption of lipid metabolism via stressors has been shown to lead to apoptosis, particularly through resulting loss of plasma membrane integrity.

See Huang and Freter (2015) for review of the relationship between lipid metabolism and apoptosis. <table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none"> <tbody> <tr> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:80px"> Species </td> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:65px"> Duration </td> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:128px"> Dose </td> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:88px"> Alteration lipid metabolism? </td> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:70px"> General Apoptosis? </td> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:132px"> Summary </td> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:59px"> Citation </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:80px"> Lab rats (Rattus norvegicus) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:65px"> 4 hours </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:128px"> Injection exposure of methamphetamine. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:88px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:70px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> In rats, methamphetamine exposure induced expression genes that control lipid metabolism and apoptosis. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:59px"> Cadet et al. (2010) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:80px"> Human (Homo sapiens) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:65px"> 48 hours </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:128px"> In vitro exposure of  50-300 uM CPI-613. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:88px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:70px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Human pancreatic cells exposed to PPAR antagonist compounds repressed lipid metabolism and triggered apoptosis. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:59px"> Gao et al. (2020) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:80px"> Mussel (Mytilus galloprovincialis) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:65px"> 7 days </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:128px"> Aquatic exposure of 0.5, 5, 50 ug/L of <100, 100-1000 um polyethylene and polystyrene microplastics </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:88px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:70px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Mussels showed altered gene expression of genes associated with lipid metabolism and apoptosis. </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:59px"> Avio et al. (2015) </td> </tr> </tbody> </table>

High Unspecific

High

All life stages

High High

Life Stage: The life stage applicable to this key event relationship is all life stages. Sex: This key event relationship applies to both males and females. Taxonomic: This key event relationship appears to be present broadly, with representative studies on mammals (humans, lab mice, lab rats).

2023-10-19T11:25:15

<upstream-id>d19011c9-41f2-42fe-b65a-e7f2214dba7a</upstream-id> <downstream-id>e812d8a4-eadb-4114-8062-75f91dd244d1</downstream-id> Cancer is a general key event for related diseases each exhibiting uncontrolled proliferation of abnormal cells (for review see Hanahan and Weinberg 2011).  A cancer often is initially associated with a specific organ, with malignant tumors developing ability to metastasize, or travel to other areas of the body.  Most cancers develop from genetic mutations in normal cells; in this key event relationship we are focusing on disruption of apoptosis and necrosis pathways, leading to cancer.   Exposure to chemical stressors, radiation, tobacco smoke, or viruses can increase the likelihood that cancer will develop.  Pathways leading to apoptosis, or single cell death, have traditionally been studied as both independent and simultaneous from pathways leading to necrosis, or tissue-wide cell death, with both overlap and distinct mechanisms (Elmore 2007). For the purposes of this key event relationship, we are characterizing cancer due to widespread cell-death. Cancer cells proliferate due to capabilities summarized by Hanahan and Weinberg (2011): <ol> <li>Sustained proliferation signaling – by deregulating normal cell signals, cancer cells can sustain chronic proliferation.</li> <li>Evading growth suppressors – by evading activities of tumor suppressor genes, cancer cells continue to proliferate.</li> <li>Activating invasion and metastasis – by altering shape and attachment to cells in the extracellular matrix, cancer cells gain ability to move to other locations.</li> <li>Enabling replicative immortality – by disabling senescence pathways, cancer cells have extended lifespans.</li> <li>Inducing angiogenesis – by enabling neovasculature, cancer cells receive nutrients and oxygen and get rid of waste products.</li> <li>Resisting cell death – by evading apotosis and necrosis defense pathways, cancer cells avoid elimination.</li> </ol>

This KER was identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki.  Support for this KER is referenced in publications cited in the originating work of Jeong and Choi (2020).

The biological plausibility linking cancer to avoidance of apoptosis is strong.  Apoptosis is a series of related pathways that eliminate abnormal cells.  Cancer cells proliferate due to evasion of cellular defenses (apoptosis pathways) and tissue-level defenses (necrosis pathways).   Specific modifications to cancer cells that enable proliferation rather than elimination are listed under the Key Event Relationship Description. For review see: 1. Heinlein and Chang (2004): Role of androgen receptor in apoptosis, loss of androgen pathway function resulting in increases in mammalian prostate cancer. 2. Hanahan and Weinberg (2011): Biological capabilities gained by cancer cell to enable proliferation of tumor cells and evasion of normal regulating mechanisms of apoptosis and necrosis pathways in mammals. 3. Pavet et al. (2014): Role of tumor necrosis factor-related apoptosis-inducing ligandin to induce apoptosis in mammalian cells and reduce incidence of cancer. 4. Vihervaara and Sistonen (2014): Role of increased rate of transcription of heat shock factor 1 in mammalian cancer cells enhancing survival and metastasis, as well as evasion of cellular defenses.

References cited by Jeong and Choi (2020) are review articles and gene expression studies.  Empirical studies linking apoptosis to cancer were not provided.

High Unspecific

High

All life stages

High High High

Life Stage: The life stage applicable to this key event relationship is all life stages.  Sex: This key event relationship applies to both males and females. Taxonomic: This key event relationship appears to be present broadly, with representative studies focused in mammals (humans, lab mice, lab rats).

Elmore, S.  2007.  Apoptosis: A Review of Programmed Cell Death.  Toxicologic pathology 35 (4): 495-516. Hanahan, D. and Weinberg, R.A.  2011.  Hallmarks of cancer: the next generation.  Cell 144(5): 646-674. Heinlein, C.A. and Chang, C.  2004.  Androgen receptor in prostate cancer.  Endocrine Reviews 25: 276-308. Pavet, V., Shlyakhtina, Y., He, T., Ceschin, D.G., Kohonen, P., Perala, M., Kallioniemi, O., and Gronemeyer, H.  2014.  Plasminogen activator urokinase expression reveals TRAIL responsiveness and support fractional survival of cancer cells.  Cell Death and Disease 5: e1043. Vihervaara, A. and Sistonen, L.  2014.  HSF1 at a glance.  Journal of Cell Scientce 127: 261-266.   AOPWiki 2023-07-31T09:36:36

2023-10-19T09:46:47

Reactive Oxygen (ROS) formation leads to cancer via Peroxisome proliferation-activated receptor (PPAR) pathway

ROS formation leads to cancer via PPAR pathway

Brendan Ferreri-Hanberry

Of the originating work: Jaesong Jeong and Jinhee Choi, School of Environmental Engineering, University of Seoul, Seoul, Republic of Korea Of the content populated in the AOP-Wiki: Daniel L. Villeneuve, US Environmental Protection Agency, Great Lakes Toxicology and Ecology Division, Duluth, MN Travis Karschnik and John R. Frisch, General Dynamics Information Technology, Duluth, Minnesota

BY-SA

2.6

Reactive oxygen species (ROS) are derived from oxygen molecules and can occur as free radicals (ex. superoxide, hydroxyl, peroxyl) or non-radicals (ex. ozone, singlet oxygen).  ROS production occurs via a variety of normal cellular process; however, in stress situations (ex. exposure to radiation, chemical or biological stressors) reactive oxygen species levels dramatically increase and cause damage to cellular components.  In this Adverse Outcome Pathway (AOP) we focus on the Peroxisome proliferation-activated receptor (PPAR) response to increases in oxidative stress.  Changes in activation rate of Peroxisome proliferation-activated receptors alter lipid metabolism, and decrease suppression of apoptosis.  In this AOP we focus on the apoptosis response to cellular damage.  Pathways leading to apoptosis, or single cell death, have traditionally been studied as both independent and simultaneous from pathways leading to necrosis, or tissue-wide cell death, with both overlap and distinct mechanisms (Elmore 2007). For the purposes of this AOP, we are characterizing cancer due to widespread cell-death, and recognize the complications in separating the related apoptosis and necrosis pathways. This Adverse Outcome Pathway focuses on the key pathways in which an established molecular disruption, increased levels of reactive oxygen species (ROS), leads to increased cancer.

This AOP was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki.  Jeong and Choi (2020) and Jeong and Choi (2019) provided initial network analysis from microplastic stressors, guided by weight of evidence from ToxCast assays.  These publications, and the work cited within, were used create and support this AOP and its respective KE and KER pages. The AOP-wiki authors did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the AOP.  A companion adverse outcome pathways is planned for an additional pathway initiated by reactive oxygen species (ROS), leading to increased cancer: Increased, Reactive oxygen species leads to Increase, Inflammation.

Cancer is a critical endpoint in human health risk assessment.   It is embedded in regulatory frameworks for human health protection in many countries (see OSHA 2023 for examples of US regulations and European Parliament 2022 for examples of regulations in Europe).

adjacent

Not Specified

High adjacent

Not Specified

High adjacent

Not Specified

High adjacent

Not Specified

High

High Unspecific

High

All life stages

High High High

<table cellspacing="0" class="Table" style="background:white; border-collapse:collapse; width:775px"> <tbody> <tr> <td colspan="2" style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:623px"> 1. Support for Biological Plausibility of Key Event Relationships: Is there a mechanistic relationship  between KEup and KEdown consistent with established biological knowledge? </td> </tr> <tr> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Key Event Relationship (KER) </td> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Evidence Strong = Extensive understanding of the KER based on extensive previous documentation and broad acceptance. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Relationship 3092: Increased, Reactive oxygen species leads to Decreased, PPAR-gamma activation </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Strong support.  Increases in reactive oxygen species (ROS) have been shown to cause a variety of cellular responses including decreased PPARgamma gene expression.   </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Relationship 3093: Decreased, PPAR-gamma activation leads to Alteration, lipid metabolism </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Strong support. Decreased PPAR gene expression have been shown to cause an alteration of lipid metabolism.  PPAR-gamma acts as a nuclear signaling element that controls the transcription of a variety of genes involved in lipid catabolism and energy production pathways. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Relationship 3094: Alteration, lipid metabolism leads to General Apoptosis </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Strong support. Alteration of lipid metabolism have been shown to results in abnormal cell function and activity, leading to apoptosis.  Alteration of lipid metabolism leads to changes in cell lipid levels, structural changes in membranes as lipids are key components, and changes in signaling pathways affecting gene and protein expression.  Loss of plasma membrane integrity due to disruptions to lipid metabolism results in cellular processes identifying cells as damaged, which acts as a signal for apoptosis. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Relationship 2977: General Apoptosis leads to Increase, Cancer </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Strong support.  The relationship between failure of apoptosis pathways to initiate cell death pathways and increases in cancer is broadly accepted and consistently supported across taxa. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Overall </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Strong support.  Extensive understanding of the relationships between events from empirical studies from a variety of taxa. </td> </tr> </tbody> </table> Life Stage: The life stage applicable is all life stages.  Sex: Applies to both males and females. Taxonomic: Appears to be present broadly, with representative studies including mammals (humans, lab mice, lab rats), telost fish, and invertebrates (cladocerans, mussels). .

Support for the essentiality of the key events can be obtained from a wide diversity of taxonomic groups, with mammals (lab ice, lab rats, human cell lines), telost fish, and invertebrates (cladocerans and mussels) particularly well-studied. <table cellspacing="0" class="Table" style="background:white; border-collapse:collapse; width:775px"> <tbody> <tr> <td colspan="2" style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:623px"> 2. Essentiality of Key Events: Are downstream KEs and/or the AO prevented if an upstream KE is blocked? </td> </tr> <tr> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Key Event (KE) </td> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Evidence Strong = Direct evidence from specifically designed experimental studies illustrating essentiality and direct relationship between key events.   Moderate = Indirect evidence from experimental studies inferring essentiality of relationship between key events due to difficulty in directly measuring at least one of key events. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> MIE 1115: Increased, Reactive oxygen species </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Strong support. Increased Reactive oxygen species (ROS) levels are a primary cause of decreases in PPARgamma gene expression.  Evidence is available from studies of stressor exposure and resulting changes in gene expression and protein/enzyme levels. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> KE 233: Decreased, PPAR-gamma activation </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Strong support. The PPARgamma gene family is important in controlling rate of lipid metabolism.  Evidence is available from studies of stressor exposure and resulting changes in gene expression and protein/enzyme levels. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> KE 1060: Alteration, lipid metabolism </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Strong support.  Altered lipid metabolism, particularly resulting loss of plasma membrane integrity is a cause of apoptosis.  Evidence is available from studies of stressor exposure and resulting changes in gene expression and protein/enzyme levels. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> KE 1513: General Apoptosis </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Moderate support. Failure of apoptosis allows cancer cells to proliferate.  Evidence is available from studies of stressor exposure and resulting changes in gene expression, protein/enzyme levels, and histology. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> AO 885: Increase, Cancer </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Strong support. Cancer proliferates due to a variety of stressors and breakdown of multiple celluar processes.  Evidence is available from studies of stressor exposure and resulting changes in gene expression, protein/enzyme levels, and histology. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Overall </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Moderate to strong support.  Direct evidence from empirical studies for most key events, with more inferential evidence rather than direct evidence for apoptosis. </td> </tr> </tbody> </table>

<table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none"> <tbody> <tr> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:312px"> Path </td> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:312px"> Support </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Increased, Reactive oxygen species leads to Decreased, PPAR-gamma activation </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Biological plausibility is high.  Representative studies have been done with mammals (El Midaoui et al. 2006; Blanquicett et al. 2010; Lu et al. 2018; Jeong and Choi 2020) fish (Wang et al. 2022).  </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Decreased, Decreased, PPAR-gamma activation leads to Alteration, lipid metabolism </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Biological plausibility is high.  Representative studies have been done with mammals (Chamorro-Garcia et al. 2018; Jeong and Choi 2020); fish (Venezia et al. 2021).  For review (Tickner et al. 2001; Berger and Moller 2002; Luquet et al. 2005; Den Broeder et al. 2015). </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Alteration, lipid metabolism leads to General Apoptosis </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Biological plausibility is high.  Representative studies have been done with mammals (Cadet et al. 2010, Gao et al. 2020); invertebrates (Avio et al. 2015). For review (Huang and Freter 2015). </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> General Apoptosis leads to Increase, Cancer </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:312px"> Biological plausibility is high.  Representative studies have been done with mammals (Pavet et al. 2014; Jeong and Choi 2020).  For review (Heinlein and Chang 2004; Vihervaara and Sistonen 2014). </td> </tr> </tbody> </table> <table cellspacing="0" class="Table" style="background:white; border-collapse:collapse; width:775px"> <tbody> <tr> <td colspan="2" style="background-color:#cccccc; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:775px"> 3. Empirical Support for Key Event Relationship: Does empirical evidence support that a  change in KEup leads to an appropriate change in KEdown? </td> </tr> <tr> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:388px"> Key Event Relationship (KER) </td> <td style="background-color:#d0cece; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:388px"> Evidence Strong =  Experimental evidence from exposure to toxicant shows consistent change in both events across taxa and study conditions. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:388px"> Relationship 3092: Increased, Reactive oxygen species leads to Decreased, PPAR-gamma activation </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:388px"> Strong support. Increases in ROS leads to decreases in PPAR gamma gene expression, primarily by examining gene expression levels. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:388px"> Relationship 3093: Decreased, PPAR-gamma activation leads to Alteration, lipid metabolism </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:388px"> Strong support. Decreases in PPAR gamma expression leads to alteration of lipid metabolism, primarily by assessing lipid content and levels of energy metabolites. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:388px"> Relationship 3094: Alteration, lipid metabolism leads to General Apoptosis </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:388px"> Strong support. Altered lipid metabolism leads to apoptosis; problems with lipid metabolism lead to abnormal cells, triggering apoptosis pathways. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:388px"> Relationship 2977: General Apoptosis leads to Increase, Cancer </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:388px"> Strong support. Mechanistic studies show that failure for apoptosis to eliminate cancer cells allows increases in cancer proliferation. </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:388px"> Overall </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:388px"> Strong support. Exposure from empirical studies shows consistent change in both events from a variety of taxa. </td> </tr> </tbody> </table> For overview of the biological mechanisms involved in this AOP, see Liu et al. (2015) and Jeong and Choi (2020); their studies analyzed ToxCast in vitro assays of mammalian acute toxicity data to identify correlations between toxicity pathways and chemical stressors, providing support for the key event relationships represented here.

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

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