Decrease, Coupling of oxidative phosphorylation

51-28-5

UFBJCMHMOXMLKC-UHFFFAOYSA-N

2,4-Dinitrophenol

DNP 1,3-Dinitro-4-hydroxybenzene 1-Hydroxy-2,4-dinitrobenzene 2,4-dinitrofenol Aldifen Dinitrophenol DINITROPHENOL, 2,4- Dinofan Fenoxyl Carbon N NSC 1532 Phenol, α-dinitro- UN 1320 UN 1599 α-Dinitrophenol Phenol, 2,4-dinitro-

DTXSID0020523

87-86-5

IZUPBVBPLAPZRR-UHFFFAOYSA-N

Pentachlorophenol

PCP Phenol, pentachloro- 1-Hydroxy-2,3,4,5,6-pentachlorobenzene 1-Hydroxypentachlorobenzene Chlorophenasic acid CHLOROPHENATE Dowicide EC 7 Dura Treet II Fungifen Grundier Arbezol Lauxtol Liroprem NSC 263497 Penchlorol Pentachlorphenol Perchlorophenol Permasan Phenol, 2,3,4,5,6-pentachloro- Pole topper Pole topper fluid Preventol P Santophen 20 Satophen UN 3155 Witophen P Woodtreat A 2,3,4,5,6-Pentachlorophenol

DTXSID7021106

3380-34-5

XEFQLINVKFYRCS-UHFFFAOYSA-N

Triclosan

5-Chloro-2-(2,4-dichlorophenoxy)phenol Phenol, 5-chloro-2-(2,4-dichlorophenoxy)- 2, 4, 4'-Trichloro-2'-hydroxydiphenylether 2,2'-Oxybis(1',5'-dichlorophenyl-5-chlorophenol) 2,4,4'-TRICHLORO-2'-HYDROXY DIPHENYLETHER 2',4',4-Trichloro-2-hydroxydiphenyl ether 2',4,4'-Trichloro-2-hydroxydiphenyl ether 2,4,4'-Trichloro-2'-hydroxydiphenyl ether 2'-Hydroxy-2,4,4'-trichlorodiphenyl ether 2-Hydroxy-2',4,4'-trichlorodiphenyl ether 3-Chloro-6-(2,4-dichlorophenoxy)phenol 4-Chloro-2-hydroxyphenyl 2,4-dichlorophenyl ether 5-Chloro-2-(2', 4'-dichlorophenoxy) phenol Aquasept Bacti-Stat soap Cansan TCH DIPHENYL ETHER, 2,4,4'-TRICHLORO-2'-HYDROXY- Irgacare MP Irgacide LP 10 Irgaguard B 1000 Irgaguard B 1325 Irgasan Irgasan CH 3565 Irgasan DP 30 Irgasan DP 300 Irgasan DP 3000 Irgasan DP 400 Irgasan PE 30 Irgasan PG 60 Microban Additive B Microban B Oletron Phenol, 5-chloro-2-(2,4-dichlorophenoxy) Phenol, 5-chloro-2-(2,4-dichlorophenoxy)-, dihydrogen phosphate Sanitized XTX Sapoderm SterZac Tinosan AM 100 Tinosan AM 110 TRICLOSAM Ultra Fresh NM 100 Ultrafresh NM-V 2 Vinyzene DP 7000 Yujiexin Zilesan UW

DTXSID5032498

518-82-1

RHMXXJGYXNZAPX-UHFFFAOYSA-N

Emodin

9,10-Anthracenedione, 1,3,8-trihydroxy-6-methyl- 1,3,8-trihidroxi-6-metilantraquinona 1,3,8-Trihydroxy-6-methyl-9,10-anthraquinone 1,3,8-Trihydroxy-6-methylanthrachinon 1,3,8-trihydroxy-6-methylanthraquinone 1,6,8-Trihydroxy-3-methylanthraquinone 3-Methyl-1,6,8-trihydroxyanthraquinone 4,5,7-Trihydroxy-2-methylanthraquinone Anthraquinone, 1,3,8-trihydroxy-6-methyl- Frangula emodin Frangulic acid NSC 408120 NSC 622947 Rheum emodin Schuttgelb

DTXSID5025231

10537-47-0

MZOPWQKISXCCTP-UHFFFAOYSA-N

Malonoben

DTXSID1042106

GO:0005739

GO mitochondrion

UBERON:0000468

UBERON multicellular organism

GO:1901691

GO proton binding

GO:0017077

GO oxidative phosphorylation uncoupler activity

GO:0051881

GO regulation of mitochondrial membrane potential

GO:0008219

GO cell death

GO:0040007

GO growth

WIKI increased

WIKI decreased

2,4-Dinitrophenol

2016-11-29T18:42:27

Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone

2020-11-12T17:59:28

Carbonyl cyanide m-chlorophenyl hydrazone

2020-11-12T17:59:47

Pentachlorophenol

2020-11-12T17:59:12

Triclosan

2020-11-12T18:00:07

Emodin

2020-11-20T13:48:58

Malonoben

2020-11-27T14:43:47

WCS_7955

common ecological species zebrafish

WCS_9606

common toxicological species human

10090

NCBI mouse

10116

NCBI rat

WCS_4472

common ecological species Lemna minor

WikiUser_25

Wikiuser: Cyauk human and other cells in culture

10116

NCBI Rattus norvegicus

WCS_90988

common ecological species fathead minnow

WCS_35525

common ecological species Daphnia magna

Decrease, Coupling of oxidative phosphorylation

Decrease, Coupling of OXPHOS

Molecular

Decreased coupling of oxidative phosphorylation (OXPHOS), or uncoupling of OXPHOS, describes dissipation of protonmotive force (PMF) across the inner mitochondrial membrane (IMM) by environmental stressors. In eukaryotes, the mitochondrial electron transport chain mediates a series of redox reactions to create a PMF across the IMM. The PMF is used as energy to drive adenosine triphosphate (ATP) synthesis through phosphorylation of adenosine diphosphate (ADP). These processes are coupled and referred to as OXPHOS. A number of chemicals can dissipate the PMF, leading to uncoupling of OXPHOS. This key event describes the main outcome of the interactions between an uncoupler and the transmembrane PMF. An uncoupler can bind to a proton in the mitochondrial inter membrane space, transport the proton to the matrix side of the IMM, release the proton and move back to the inter membrane space. These processes are repeated until the transmembrane PMF is dissipated. This KE is therefore a lumped term of these processes and represents the final consequence of the interactions.

Uncoupling of oxidative phosphorylation can be indicated by reduced mitochondrial membrane potential, increased proton leak and/or increased oxygen consumption rate. <ul> <li>Mitochondrial membrane potential can be determined using ToxCast high-throughput screening bioassays such as “APR_HepG2_MitoMembPot”, “APR_Hepat_MitoFxnI”, and “APR_Mitochondrial_membrane_potential”, and the Tox21 high-throughput screening assay “tox21-mitotox-p1”.</li> <li>Mitochondrial membrane potential can also be measured using commercially available fluorescent probes such as TMRM (tetramethylrhodamine, methyl ester, perchlorate), TMRE (tetramethylrhodamine, ethyl ester, perchlorate) and JC-1 (Perry 2011).</li> <li>Proton leak and oxygen consumption rate can be measured using a high-resolution respirometry (Affourtit 2018) or a Seahorse XF analyzer (Divakaruni 2014).</li> </ul>

Taxonomic applicability domain This key event is in general considered applicable to most eukaryotes, as the mitochondrion and oxidative phosphorylation are highly conserved (Roger 2017).     Life stage applicability domain This key event is considered applicable to all life stages, as ATP synthesis by oxidative phosphorylation is an essential biological process for most living organisms.   Sex applicability domain This key event is considered sex-unspecific, as both males and females use oxidative phosphorylation as a main process to generate ATP.

CL:0000000

CL cell

High Unspecific

High

Embryo

High

Juvenile

Moderate

Adult, reproductively mature

High High High High High

Affourtit C, Wong H-S, Brand MD. 2018. Measurement of proton leak in isolated mitochondria. In Palmeira CM, Moreno AJ, eds, Mitochondrial Bioenergetics: Methods and Protocols. Springer New York, New York, NY, pp 157-170. Attene-Ramos MS, Huang R, Sakamuru S, Witt KL, Beeson GC, Shou L, Schnellmann RG, Beeson CC, Tice RR, Austin CP, Xia M. 2013. Systematic study of mitochondrial toxicity of environmental chemicals using quantitative high throughput screening. Chemical Research in Toxicology 26:1323-1332. DOI: 10.1021/tx4001754. Attene-Ramos MS, Huang RL, Michael S, Witt KL, Richard A, Tice RR, Simeonov A, Austin CP, Xia MH. 2015. Profiling of the Tox21 chemical collection for mitochondrial function to identify compounds that acutely decrease mitochondrial membrane potential. Environ Health Persp 123:49-56. DOI: 10.1289/ehp.1408642. Divakaruni AS, Paradyse A, Ferrick DA, Murphy AN, Jastroch M. 2014. Chapter Sixteen - Analysis and Interpretation of Microplate-Based Oxygen Consumption and pH Data. In Murphy AN, Chan DC, eds, Methods in Enzymology. Vol 547. Academic Press, pp 309-354. Dreier DA, Denslow ND, Martyniuk CJ. 2019. Computational in vitro toxicology uncovers chemical structures impairing mitochondrial membrane potential. J Chem Inf Model 59:702-712. DOI: 10.1021/acs.jcim.8b00433. Escher BI, Schwarzenbach RP. 2002. Mechanistic studies on baseline toxicity and uncoupling of organic compounds as a basis for modeling effective membrane concentrations in aquatic organisms. Aquatic Sciences 64:20-35. DOI: 10.1007/s00027-002-8052-2. Legradi J, Dahlberg A-K, Cenijn P, Marsh G, Asplund L, Bergman Å, Legler J. 2014. Disruption of Oxidative Phosphorylation (OXPHOS) by Hydroxylated Polybrominated Diphenyl Ethers (OH-PBDEs) Present in the Marine Environment. Environmental Science & Technology 48:14703-14711. DOI: 10.1021/es5039744. Naven RT, Swiss R, Klug-Mcleod J, Will Y, Greene N. 2012. The development of structure-activity relationships for mitochondrial dysfunction: Uncoupling of oxidative phosphorylation. Toxicol Sci 131:271-278. DOI: 10.1093/toxsci/kfs279. Perry SW, Norman JP, Barbieri J, Brown EB, Gelbard HA. 2011. Mitochondrial membrane potential probes and the proton gradient: a practical usage guide. BioTechniques 50:98-115. DOI: 10.2144/000113610. Roger AJ, Munoz-Gomez SA, Kamikawa R. 2017. The origin and diversification of mitochondria. Curr Biol 27:R1177-R1192. DOI: 10.1016/j.cub.2017.09.015. Russom CL, Bradbury SP, Broderius SJ, Hammermeister DE, Drummond RA. 1997. Predicting modes of toxic action from chemical structure: Acute toxicity in the fathead minnow (Pimephales promelas). Environ Toxicol Chem 16:948-967. DOI: <a href="https://doi.org/10.1002/etc.5620160514">https://doi.org/10.1002/etc.5620160514</a>. Schultz TW, Cronin MTD. 1997. Quantitative structure-activity relationships for weak acid respiratory uncouplers to Vibrio fisheri. Environ Toxicol Chem 16:357-360. DOI: <a href="https://doi.org/10.1002/etc.5620160235">https://doi.org/10.1002/etc.5620160235</a>. Shim J, Weatherly LM, Luc RH, Dorman MT, Neilson A, Ng R, Kim CH, Millard PJ, Gosse JA. 2016. Triclosan is a mitochondrial uncoupler in live zebrafish. J Appl Toxicol 36:1662-1667. DOI: 10.1002/jat.3311. Sugiyama Y, Shudo T, Hosokawa S, Watanabe A, Nakano M, Kakizuka A. 2019. Emodin, as a mitochondrial uncoupler, induces strong decreases in adenosine triphosphate (ATP) levels and proliferation of B16F10 cells, owing to their poor glycolytic reserve. Genes to Cells 24:569-584. DOI: <a href="https://doi.org/10.1111/gtc.12712">https://doi.org/10.1111/gtc.12712</a>. Terada H. 1990. Uncouplers of oxidative phosphorylation. Environ Health Perspect 87:213-218. DOI: 10.1289/ehp.9087213. Troger F, Delp J, Funke M, van der Stel W, Colas C, Leist M, van de Water B, Ecker GF. 2020. Identification of mitochondrial toxicants by combined in silico and in vitro studies – A structure-based view on the adverse outcome pathway. Computational Toxicology 14:100123. DOI: <a href="https://doi.org/10.1016/j.comtox.2020.100123">https://doi.org/10.1016/j.comtox.2020.100123</a>. Weatherly LM, Shim J, Hashmi HN, Kennedy RH, Hess ST, Gosse JA. 2016. Antimicrobial agent triclosan is a proton ionophore uncoupler of mitochondria in living rat and human mast cells and in primary human keratinocytes. Journal of Applied Toxicology 36:777-789. DOI: <a href="https://doi.org/10.1002/jat.3209">https://doi.org/10.1002/jat.3209</a>. Xia M, Huang R, Shi Q, Boyd WA, Zhao J, Sun N, Rice JR, Dunlap PE, Hackstadt AJ, Bridge MF, Smith MV, Dai S, Zheng W, Chu PH, Gerhold D, Witt KL, DeVito M, Freedman JH, Austin CP, Houck KA, Thomas RS, Paules RS, Tice RR, Simeonov A. 2018. Comprehensive analyses and prioritization of Tox21 10K chemicals affecting mitochondrial function by in-depth mechanistic studies. Environ Health Perspect 126:077010. DOI: 10.1289/EHP2589.  AOPWiki 2017-06-29T08:05:51

2021-05-28T07:59:24

Increase, Mitochondrial swelling

Cellular

AOPWiki 2022-11-01T16:50:26

2022-11-01T16:50:26

Cell injury/death

Cellular

Two types of cell death can be distinguished by morphological features, although it is likely that these are two ends of a spectrum with possible intermediate forms. Apoptosis involves shrinkage, nuclear disassembly, and fragmentation of the cell into discrete bodies with intact plasma membranes. These are rapidly phagocytosed by neighbouring cells. An important feature of apoptosis is the requirement for adenosine triphosphate (ATP) to initiate the execution phase. In contrast, necrotic cell death is characterized by cell swelling and lysis. This is usually a consequence of profound loss of mitochondrial function and resultant ATP depletion, leading to loss of ion homeostasis, including volume regulation, and increased intracellular Ca2+. The latter activates a number of nonspecific hydrolases (i.e., proteases, nucleases, and phospholipases) as well as calcium dependent kinases. Activation of calpain I, the Ca2+-dependent cysteine protease cleaves the death-promoting Bcl-2 family members Bid and Bax which translocate to mitochondrial membranes, resulting in release of truncated apoptosis-inducing factor (tAIF), cytochrome c and endonuclease in the case of Bid and cytocrome c in the case of Bax. tAIF translocates to cell nuclei, and together with cyclophilin A and phosphorylated histone H2AX (γH2AX) is responsible for DNA cleavage, a feature of programmed necrosis. Activated calpain I has also been shown to cleave the plasma membrane Na+–Ca2+ exchanger, which leads to build-up of intracellular Ca2+, which is the source of additional increased intracellular Ca2+. Cytochrome c in cellular apoptosis is a component of the apoptosome. DNA damage activates nuclear poly(ADP-ribose) polymerase-1(PARP-1), a DNA repair enzyme. PARP-1 forms poly(ADP-ribose) polymers, to repair DNA, but when DNA damage is extensive, PAR accumulates, exits cell nuclei and travels to mitochondrial membranes, where it, like calpain I, is involved in AIF release from mitochondria. A fundamental distinction between necrosis and apoptosis is the loss of plasma membrane integrity; this is integral to the former but not the latter. As a consequence, lytic release of cellular constituents promotes a local inflammatory reaction, whereas the rapid removal of apoptotic bodies minimizes such a reaction. The distinction between the two modes of death is easily accomplished in vitro but not in vivo. Thus, although claims that certain drugs induce apoptosis have been made, these are relatively unconvincing. DNA fragmentation can occur in necrosis, leading to positive TUNEL staining (see explanation below). Conversely, when apoptosis is massive, it can exceed the capacity for rapid phagocytosis, resulting in the eventual appearance of secondary necrosis. Two alternative pathways - either extrinsic (receptor-mediated) or intrinsic (mitochondria-mediated) - lead to apoptotic cell death. The initiation of cell death begins either at the plasma membrane with the binding of TNF or FasL to their cognate receptors or within the cell. The latter is due to the occurrence of intracellular stress in the form of biochemical events such as oxidative stress, redox changes, covalent binding, lipid peroxidation, and consequent functional effects on mitochondria, endoplasmic reticulum, microtubules, cytoskeleton, or DNA. The intrinsic mitochondrial pathway involves the initiator, caspase-9, which, when activated, forms an “apoptosome” in the cytosol, together with cytochrome c, which translocates from mitochondria, Apaf-1 and dATP. The apoptosome activates caspase-3, the central effector caspase, which in turn activates downstream factors that are responsible for the apoptotic death of a cell (Fujikawa, 2015). Intracellular stress either directly affects mitochondria or can lead to effects on other organelles, which then send signals to the mitochondria to recruit participation in the death process (Fujikawa, 2015; Malhi et al., 2010). Constitutively expressed nitric oxide synthase (nNOS) is a Ca2+-dependent cytosolic enzyme that forms nitric oxide (NO) from L-arginine, and NO reacts with the free radical such as superoxide (O2−) to form the very toxic free radical peroxynitrite (ONOO−). Free radicals such as ONOO−, O2 − and hydroxyl radical (OH−) damage cellular membranes and intracellular proteins, enzymes and DNA (Fujikawa, 2015; Malhi et al., 2010; Kaplowitz, 2002; Kroemer et al., 2009).

Necrosis: Lactate dehydrogenase (LDH) is a soluble cytoplasmic enzyme that is present in almost all cells and is released into extracellular space when the plasma membrane is damaged. To detect the leakage of LDH into cell culture medium, a tetrazolium salt is used in this assay. In the first step, LDH produces reduced nicotinamide adenine dinucleotide (NADH) when it catalyzes the oxidation of lactate to pyruvate. In the second step, a tetrazolium salt is converted to a colored formazan product using newly synthesized NADH in the presence of an electron acceptor. The amount of formazan product can be colorimetrically quantified by standard spectroscopy. Because of the linearity of the assay, it can be used to enumerate the percentage of necrotic cells in a sample (Chan et al., 2013).  The MTT assay is a colorimetric assay for assessing cell viability. NAD(P)H-dependent cellular oxidoreductase enzymes may reflect the number of viable cells present. These enzymes are capable of reducing the tetrazolium dye MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide to its insoluble formazan, which has a purple color. Other closely related tetrazolium dyes include XTT, MTS and the WSTs. Tetrazolium dye assays can also be used to measure cytotoxicity (loss of viable cells) or cytostatic activity (shift from proliferation to quiescence) of potential medicinal agents and toxic materials. MTT assays are usually done in the dark since the MTT reagent is sensitive to light (Berridgeet al.,2005). Propidium iodide (PI) is an intercalating agent and a fluorescent molecule used to stain necrotic cells. It is cell membrane impermeant so it stains only those cells where the cell membrane is destroyed. When PI is bound to nucleic acids, the fluorescence excitation maximum is 535 nm and the emission maximum is 617 nm (Moore et al.,1998) Alamar Blue (resazurin) is a fluorescent dye. The oxidized blue non fluorescent Alamar blue is reduced to a pink fluorescent dye in the medium by cell activity (O'Brien et al., 2000) (12). Neutral red uptake, which is based on the ability of viable cells to incorporate and bind the supravital dye neutral red in lysosomes (Repetto et al., 2008)(13). Moreover, quantification of ATP, signaling the presence of metabolically active cells, can be performed (CellTiter-Glo; Promega). ATP assay: Quantification of ATP, signaling the presence of metabolically active cells (CellTiter-Glo; Promega). Apoptosis: TUNEL is a common method for detecting DNA fragmentation that results from apoptotic signalling cascades. The assay relies on the presence of nicks in the DNA which can be identified by terminal deoxynucleotidyl transferase or TdT, an enzyme that will catalyze the addition of dUTPs that are secondarily labeled with a marker. It may also label cells that have suffered severe DNA damage. Caspase activity assays measured by fluorescence. During apoptosis, mainly caspase-3 and -7 cleave PARP to yield an 85 kDa and a 25 kDa fragment. PARP cleavage is considered to be one of the classical characteristics of apoptosis. Antibodies to the 85 kDa fragment of cleaved PARP or to caspase-3 both serve as markers for apoptotic cells that can be monitored using immunofluorescence (Li, Peng et al., 2004). Hoechst 33342 staining: Hoechst dyes are cell-permeable and bind to DNA in live or fixed cells. Therefore, these stains are often called supravital, which means that cells survive a treatment with these compounds. The stained, condensed or fragmented DNA is a marker of apoptosis (Loo, 2002; Kubbies and Rabinovitch, 1983).  Acridine Orange/Ethidium Bromide staining is used to visualize nuclear changes and apoptotic body formation that are characteristic of apoptosis. Cells are viewed under a fluorescence microscope and counted to quantify apoptosis.

Cell death is an universal event occurring in cells of any species (Fink and Cookson,2005).

CL:0000255

CL eukaryotic cell

Not Specified Unspecific

Not Specified

All life stages

High High High High

<ul> <li>Fujikawa, D.G. (2015), The role of excitotoxic programmed necrosis in acute brain injury, Comput Struct Biotechnol J, vol. 13, pp. 212-221.</li> <li>Malhi, H. et al. (2010), Hepatocyte death: a clear and present danger, Physiol Rev, vol. 90, no. 3, pp. 1165-1194.</li> <li>Kaplowitz, N. (2002), Biochemical and Cellular Mechanisms of Toxic Liver Injury, Semin Liver Dis, vol. 22, no. 2, <a class="external free" href="http://www.medscape.com/viewarticle/433631" rel="nofollow" target="_blank">http://www.medscape.com/viewarticle/433631</a> (accessed on 20 January 2016).</li> <li>Kroemer, G. et al., (2009), Classification of cell death: recommendations of the Nomenclature Committee on Cell Death, Cell Death Differ, vol. 16, no. 1, pp. 3-11.</li> <li>Chan, F.K., K. Moriwaki and M.J. De Rosa (2013), Detection of necrosis by release of lactate dehydrogenase (LDH) activity, Methods Mol Biol, vol. 979, pp. 65–70.</li> <li>Berridge, M.V., P.M. Herst and A.S. Tan (2005), Tetrazolium dyes as tools in cell biology: new insights into their cellular reduction. Biotechnology Annual Review, vol. 11, pp 127-152.</li> <li>Moore, A, et al.(1998), Simultaneous measurement of cell cycle and apoptotic cell death,Methods Cell Biol, vol. 57, pp. 265–278.</li> <li>Li, Peng et al. (2004), Mitochondrial activation of apoptosis, Cell, vol. 116, no. 2 Suppl,pp. S57-59, 2 p following S59.</li> <li>Loo, D.T. (2002), TUNEL Assay an overview of techniques, Methods in Molecular Biology, vol. 203: In Situ Detection of DNA Damage, chapter 2, Didenko VV (ed.), Humana Press Inc.</li> <li>Kubbies, M. and P.S. Rabinovitch (1983), Flow cytometric analysis of factors which influence the BrdUrd-Hoechst quenching effect in cultivated human fibroblasts and lymphocytes, Cytometry, vol. 3, no. 4, pp. 276–281.</li> <li>Fink, S.L. and B.T. Cookson (2005), Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells, Infect Immun, vol. 73, no. 4, pp.1907-1916.</li> <li>O'Brien J, Wilson I, Orton T, Pognan F. 2000. Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity. European journal of biochemistry / FEBS 267(17): 5421-5426.</li> <li>Repetto G, del Peso A, Zurita JL. 2008. Neutral red uptake assay for the estimation of cell viability/cytotoxicity. Nature protocols 3(7): 1125-1131.</li> </ul> AOPWiki 2016-11-29T18:41:22

2022-07-15T09:46:25

Decrease, Growth

Individual

Decreased growth refers to a reduction in size and/or weight of a tissue, organ or individual organism. Growth is normally controlled by growth factors and mainly achieved through cell proliferation (Conlon 1999).

Growth can be indicated by measuring weight, length, total volume, and/or total area of a tissue, organ or individual organism.

Taxonomic applicability domain This key event is in general applicable to all eukaryotes.   Life stage applicability domain This key event is applicable to early life stages such as embryo and juvenile.   Sex applicability domain This key event is sex-unspecific.

High Unspecific

High

Embryo

High

Juvenile

Moderate Moderate Moderate High High High Moderate

Conlon I, Raff M. 1999. Size control in animal development. Cell 96:235-244. DOI: 10.1016/s0092-8674(00)80563-2.  AOPWiki 2018-05-24T15:24:11

2022-07-06T07:36:50

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430b123058> AOPWiki 2022-11-01T16:51:05

2022-11-01T16:51:05

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430b13fb40> AOPWiki 2022-11-01T16:51:13

2022-11-01T16:51:13

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430b14ca48> AOPWiki 2022-09-27T13:22:59

2022-09-27T13:22:59

Uncoupling of oxidative phosphorylation leading to growth inhibition via mitochondrial swelling

Uncoupling of OXPHOS leading to growth inhibition 6

Agnes Aggy

You Song Norwegian Institute for Water Research (NIVA), Økernveien 94, NO-0579 Oslo, Norway   Acknowledgement This project was funded by the Research Council of Norway (RCN), grant no. 301397 “RiskAOP - Quantitative Adverse Outcome Pathway assisted risk assessment of mitochondrial toxicants” (<a href="https://www.niva.no/en/projectweb/riskaop">https://www.niva.no/en/projectweb/riskaop</a>), and supported by the NIVA Computational Toxicology Program, NCTP (<a href="http://www.niva.no/nctp">www.niva.no/nctp</a>).

BY-SA

Under Development

1.92

2.0

The proposed project aims to develop a network of AOPs for mitochondrial uncoupler mediated adverse effects on aquatic organisms. The mitochondrion is central for diverse types of physiological processes, such as energy production, cell cycle regulation, lipid metabolism and ion homeostasis. Mitochondrial dysfunction has frequently been reported as a common (eco)toxicological effect induced by a wide range of environmental stressors through direct or indirect modes of action (Meyer et al., 2013). Chemical mediated mitochondrial dysfunctions are tightly associated with various diseases in human, such as neurodegeneration, cardiovascular malfunction, diabetes and cancer, and multiple types of effects in wildlife, such as metabolic disorders, growth arrest, developmental abnormalities, reproduction failure, mortality and population decline (Meyer et al., 2013). Several mitochondrial dysfunction related MIEs have been well characterized, such as uncoupling of oxidative phosphorylation (OXPHOS) and inhibition of specific protein complexes in the mitochondrial electron transport chain. These MIEs commonly affect the mitochondrial membrane potential and ATP synthetic processes, induce reactive oxygen species (ROS) and oxidative damage to DNA, protein and lipid, modulate plasma membrane ion transporter activities and trigger programmed cell death.

Decreased coupling of oxidative phosphorylation can be directly triggered by “uncouplers” as a molecular initiating event. <ul> <li style="text-align:justify">Most of the chemical uncouplers are protonophores, a type of proton binders that can translocate protons across membranes. These protonophores share several common structural characteristics, such as bulky hydrophobic moiety, an acid dissociable group and a strong electron-withdrawing group (Terada 1990). Weak acids such as phenols, benzimidazoles and salicylic acids are considered potential protonophores.</li> <li style="text-align:justify">Classical uncouplers, such as carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), carbonyl cyanide m-chlorophenyl hydrazone (CCCP), 2,4-dinitrophenol (DNP), pentachlorophenol (PCP) and SF-6847 (Terada 1990).</li> <li style="text-align:justify">Newer uncouplers, such as triclosan (Shim 2016; Weatherly 2016), emodin (Sugiyama 2019), and hydroxylated polybrominated diphenyl ethers (PBDEs) (Legradi 2014) have been widely investigated in vertebrates.</li> <li style="text-align:justify">Computational predictions based on quantitative structure-activity relationships (Russom 1997; Schultz 1997; Naven 2012; Dreier 2019; Troger 2020) and in vitro high-throughput screening (Escher 2002; Attene-Ramos 2013; Attene-Ramos 2015; Xia 2018) have facilitated the identification and classification of potential uncouplers from a large list of chemicals.   </li> </ul>

Growth is a regulatory relevant chronic toxicity endpoint for almost all organisms. Multiple OECD test guidelines have included growth either as a main endpoint of concern, or as an additional endpoint to be considered in the toxicity assessments. Relevant test guidelines include, but not only limited to:   -Test No. 201: Freshwater Alga and Cyanobacteria, Growth Inhibition Test -Test No. 208: Terrestrial Plant Test: Seedling Emergence and Seedling Growth Test -Test No. 211: Daphnia magna Reproduction Test -Test No. 212: Fish, Short-term Toxicity Test on Embryo and Sac-Fry Stages -Test No. 215: Fish, Juvenile Growth Test -Test No. 221: Lemna sp. Growth Inhibition Test -Test No. 228: Determination of Developmental Toxicity to Dipteran Dung Flies (Scathophaga stercoraria L. (Scathophagidae), Musca autumnalis De Geer (Muscidae)) -Test No. 241: The Larval Amphibian Growth and Development Assay (LAGDA) -Test No. 407: Repeated Dose 28-day Oral Toxicity Study in Rodents -Test No. 408: Repeated Dose 90-Day Oral Toxicity Study in Rodents -Test No. 416: Two-Generation Reproduction Toxicity -Test No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test -Test No. 443: Extended One-Generation Reproductive Toxicity Study -Test No. 453: Combined Chronic Toxicity/Carcinogenicity Studies

adjacent

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<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>

AOPWiki 2018-06-12T04:33:44

2023-09-25T16:26:58