51-28-5UFBJCMHMOXMLKC-UHFFFAOYSA-NUFBJCMHMOXMLKC-UHFFFAOYSA-N
2,4-DinitrophenolDNP
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-
DTXSID002052387-86-5IZUPBVBPLAPZRR-UHFFFAOYSA-NIZUPBVBPLAPZRR-UHFFFAOYSA-N
PentachlorophenolPCP
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
DTXSID70211063380-34-5XEFQLINVKFYRCS-UHFFFAOYSA-NXEFQLINVKFYRCS-UHFFFAOYSA-N
Triclosan5-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
DTXSID5032498518-82-1RHMXXJGYXNZAPX-UHFFFAOYSA-NRHMXXJGYXNZAPX-UHFFFAOYSA-N
Emodin9,10-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
DTXSID502523110537-47-0MZOPWQKISXCCTP-UHFFFAOYSA-NMZOPWQKISXCCTP-UHFFFAOYSA-N
MalonobenDTXSID1042106GO:0005739mitochondrionGO:0005623cellUBERON:0000468multicellular organismGO:1901691proton bindingGO:0017077oxidative phosphorylation uncoupler activityGO:0051881regulation of mitochondrial membrane potentialGO:0008283cell proliferationGO:0040007growth1increased2decreased2,4-Dinitrophenol2016-11-29T18:42:272016-11-29T18:42:27Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone2020-11-12T17:59:282020-11-12T17:59:28Carbonyl cyanide m-chlorophenyl hydrazone2020-11-12T17:59:472020-11-12T17:59:47Pentachlorophenol2020-11-12T17:59:122020-11-12T17:59:12Triclosan2020-11-12T18:00:072020-11-12T18:00:07Emodin2020-11-20T13:48:582020-11-20T13:48:58Malonoben2020-11-27T14:43:472020-11-27T14:43:47WCS_7955zebrafishWCS_9606human10090mouse10116ratWCS_4472Lemna minorWCS_90988fathead minnowWCS_35525Daphnia magnaDecrease, Coupling of oxidative phosphorylationDecrease, Coupling of OXPHOSMolecular<p style="text-align:justify">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.</p>
<p style="text-align:justify">Uncoupling of oxidative phosphorylation can be indicated by reduced mitochondrial membrane potential, increased proton leak and/or increased oxygen consumption rate.</p>
<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>
<p style="text-align:justify"><strong><em>Taxonomic applicability domain</em></strong></p>
<p style="text-align:justify">This key event is in general considered applicable to most eukaryotes, as the mitochondrion and oxidative phosphorylation are highly conserved (Roger 2017). <!--![endif]----></p>
<p style="text-align:justify"> </p>
<p style="text-align:justify"><!--[endif]----></p>
<p style="text-align:justify"><strong><em>Life stage applicability domain</em></strong></p>
<p style="text-align:justify">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.</p>
<p style="text-align:justify"> </p>
<p style="text-align:justify"><strong><em>Sex applicability domain</em></strong></p>
<p style="text-align:justify">This key event is considered sex-unspecific, as both males and females use oxidative phosphorylation as a main process to generate ATP.</p>
<p><!--![endif]----></p>
CL:0000000cellHighUnspecificHighEmbryoHighJuvenileModerateAdult, reproductively matureHighHighHighHighHigh<p style="text-align:justify"><!--[if supportFields]><span
style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.REFLIST <span style='mso-element:
field-separator'></span><![endif]-->Affourtit C, Wong H-S, Brand MD. 2018. Measurement of proton leak in isolated mitochondria. In Palmeira CM, Moreno AJ, eds, <em>Mitochondrial Bioenergetics: Methods and Protocols</em>. Springer New York, New York, NY, pp 157-170.</p>
<p style="text-align:justify">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. <em>Chemical Research in Toxicology</em> 26:1323-1332. DOI: 10.1021/tx4001754.</p>
<p style="text-align:justify">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. <em>Environ Health Persp</em> 123:49-56. DOI: 10.1289/ehp.1408642.</p>
<p style="text-align:justify">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, <em>Methods in Enzymology</em>. Vol 547. Academic Press, pp 309-354.</p>
<p style="text-align:justify">Dreier DA, Denslow ND, Martyniuk CJ. 2019. Computational <em>in vitro</em> toxicology uncovers chemical structures impairing mitochondrial membrane potential. <em>J Chem Inf Model</em> 59:702-712. DOI: 10.1021/acs.jcim.8b00433.</p>
<p style="text-align:justify">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. <em>Aquatic Sciences</em> 64:20-35. DOI: 10.1007/s00027-002-8052-2.</p>
<p style="text-align:justify">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. <em>Environmental Science & Technology</em> 48:14703-14711. DOI: 10.1021/es5039744.</p>
<p style="text-align:justify">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. <em>Toxicol Sci</em> 131:271-278. DOI: 10.1093/toxsci/kfs279.</p>
<p style="text-align:justify">Perry SW, Norman JP, Barbieri J, Brown EB, Gelbard HA. 2011. Mitochondrial membrane potential probes and the proton gradient: a practical usage guide. <em>BioTechniques</em> 50:98-115. DOI: 10.2144/000113610.</p>
<p style="text-align:justify">Roger AJ, Munoz-Gomez SA, Kamikawa R. 2017. The origin and diversification of mitochondria. <em>Curr Biol</em> 27:R1177-R1192. DOI: 10.1016/j.cub.2017.09.015.</p>
<p style="text-align:justify">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). <em>Environ Toxicol Chem</em> 16:948-967. DOI: <a href="https://doi.org/10.1002/etc.5620160514">https://doi.org/10.1002/etc.5620160514</a>.</p>
<p style="text-align:justify">Schultz TW, Cronin MTD. 1997. Quantitative structure-activity relationships for weak acid respiratory uncouplers to Vibrio fisheri. <em>Environ Toxicol Chem</em> 16:357-360. DOI: <a href="https://doi.org/10.1002/etc.5620160235">https://doi.org/10.1002/etc.5620160235</a>.</p>
<p style="text-align:justify">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. <em>J Appl Toxicol</em> 36:1662-1667. DOI: 10.1002/jat.3311.</p>
<p style="text-align:justify">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. <em>Genes to Cells</em> 24:569-584. DOI: <a href="https://doi.org/10.1111/gtc.12712">https://doi.org/10.1111/gtc.12712</a>.</p>
<p style="text-align:justify">Terada H. 1990. Uncouplers of oxidative phosphorylation. <em>Environ Health Perspect</em> 87:213-218. DOI: 10.1289/ehp.9087213.</p>
<p style="text-align:justify">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. <em>Computational Toxicology</em> 14:100123. DOI: <a href="https://doi.org/10.1016/j.comtox.2020.100123">https://doi.org/10.1016/j.comtox.2020.100123</a>.</p>
<p style="text-align:justify">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. <em>Journal of Applied Toxicology</em> 36:777-789. DOI: <a href="https://doi.org/10.1002/jat.3209">https://doi.org/10.1002/jat.3209</a>.</p>
<p style="text-align:justify">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. <em>Environ Health Perspect</em> 126:077010. DOI: 10.1289/EHP2589.</p>
<p><!--[if supportFields]><span style='font-size:11.0pt;font-family:"Calibri",sans-serif;
mso-fareast-font-family:等线;mso-fareast-theme-font:minor-fareast;mso-ansi-language:
EN-US;mso-fareast-language:ZH-CN;mso-bidi-language:AR-SA'><span
style='mso-element:field-end'></span></span><![endif]--></p>
2017-06-29T08:05:512021-05-28T07:59:24Increase, GlycolysisIncrease, GlycolysisCellular2022-11-01T16:25:382022-11-01T16:25:38Decrease, Glucose poolDecrease, Glucose poolCellular2022-11-01T16:26:282022-11-01T16:27:41Decrease, Cell proliferationDecrease, Cell proliferationCellular<p style="text-align:justify">Decreased cell proliferation describes the outcome of reduced cell division and cell growth. Cell proliferation is considered the main mechanism of tissue and organismal growth (Conlon 1999). Decreased cell proliferation has been associated with abnormal growth-factor signaling and cellular energy depletion (DeBerardinis 2008).</p>
<p style="text-align:justify">Multiple types of <em>in vitro</em> bioassays can be used to measure this key event:</p>
<ul>
<li>ToxCast high-throughput screening bioassays such as “BSK_3C_Proliferation”, “BSK_CASM3C_Proliferation” and “BSK_SAg_Proliferation” can be used to measure cell proliferation status.</li>
<li>Commercially available methods such as the well-established 5-bromo-2’-deoxyuridine (BrdU) (Raza 1985; Muir 1990) or 5-ethynyl-2’-deoxyuridine (EdU) assay. Both assays measure DNA synthesis in dividing cells to indicate proliferation status.<!--![endif]----></li>
</ul>
<p style="text-align:justify"><strong>Taxonomic applicability domain</strong></p>
<p>This key event is in general applicable to all eukaryotes, as most organisms are known to use cell proliferation to achieve growth.</p>
<p> </p>
<p><strong>Life stage applicability domain</strong></p>
<p>This key event is in general applicable to all life stages. As cell proliferation not only occurs in developing organisms, but also in adults.</p>
<p> </p>
<p><strong>Sex applicability domain</strong></p>
<p>This key event is sex-unspecific, as both genders use the same cell proliferation mechanisms.</p>
CL:0000000cellHighUnspecificHighEmbryoHighJuvenileHighHighHighHigh<p style="text-align:justify">Conlon I, Raff M. 1999. Size control in animal development. <em>Cell</em> 96:235-244. DOI: 10.1016/s0092-8674(00)80563-2.</p>
<p style="text-align:justify">DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. 2008. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. <em>Cell Metabolism</em> 7:11-20. DOI: <a href="https://doi.org/10.1016/j.cmet.2007.10.002">https://doi.org/10.1016/j.cmet.2007.10.002</a>.</p>
<p style="text-align:justify">Muir D, Varon S, Manthorpe M. 1990. An enzyme-linked immunosorbent assay for bromodeoxyuridine incorporation using fixed microcultures. <em>Analytical Biochemistry</em> 185:377-382. DOI: <a href="https://doi.org/10.1016/0003-2697(90)90310-6">https://doi.org/10.1016/0003-2697(90)90310-6</a>.</p>
<p style="text-align:justify">Raza A, Spiridonidis C, Ucar K, Mayers G, Bankert R, Preisler HD. 1985. Double labeling of S-phase murine cells with bromodeoxyuridine and a second DNA-specific probe. <em>Cancer Research</em> 45:2283-2287.</p>
2020-11-12T17:57:082020-12-07T06:55:47Decrease, GrowthDecrease, GrowthIndividual<p style="text-align:justify">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).</p>
<p style="text-align:justify">Growth can be indicated by measuring weight, length, total volume, and/or total area of a tissue, organ or individual organism. </p>
<p style="text-align:justify"><strong><em>Taxonomic applicability domain</em></strong></p>
<p style="text-align:justify">This key event is in general applicable to all eukaryotes.</p>
<p style="text-align:justify"> </p>
<p style="text-align:justify"><strong><em>Life stage applicability domain</em></strong></p>
<p style="text-align:justify">This key event is applicable to early life stages such as embryo and juvenile.</p>
<p style="text-align:justify"> </p>
<p style="text-align:justify"><strong><em>Sex applicability domain</em></strong></p>
<p style="text-align:justify">This key event is sex-unspecific.</p>
HighUnspecificHighEmbryoHighJuvenileModerateModerateModerateHighHighHighModerate<p style="text-align:justify"><!--[if supportFields]><span style='mso-element:
field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.REFLIST <span
style='mso-element:field-separator'></span><![endif]-->Conlon I, Raff M. 1999. Size control in animal development. <em>Cell</em> 96:235-244. DOI: 10.1016/s0092-8674(00)80563-2.</p>
<p><!--[if supportFields]><span style='font-size:11.0pt;font-family:等线;mso-ascii-theme-font:
minor-latin;mso-fareast-theme-font:minor-fareast;mso-hansi-theme-font:minor-latin;
mso-bidi-font-family:Arial;mso-bidi-theme-font:minor-bidi;mso-ansi-language:
EN-US;mso-fareast-language:ZH-CN;mso-bidi-language:AR-SA'><span
style='mso-element:field-end'></span></span><![endif]--></p>
2018-05-24T15:24:112022-07-06T07:36:50954c5b51-e631-4058-8289-90593feacc842157f47e-14ac-476e-9875-882e2961376b2022-11-01T16:28:352022-11-01T16:28:352157f47e-14ac-476e-9875-882e2961376bead3f5ed-14ad-48cc-88d0-724b50e63a2d2022-11-01T16:28:472022-11-01T16:28:47ead3f5ed-14ad-48cc-88d0-724b50e63a2d36521265-2fd9-4aad-9946-6b5a20ff7ce72022-11-01T16:28:572022-11-01T16:28:5736521265-2fd9-4aad-9946-6b5a20ff7ce79f9d3162-9e2b-435b-bbab-90092254e307<p style="text-align:justify">This key event relationship describes reduced cell proliferation (cell growth, division or a combination of these) leading to reduced tissue, organ or individual growth.</p>
<p style="text-align:justify"><strong>The overall evidence supporting Relationship 2205 is considered</strong> moderate.</p>
<p style="text-align:justify"><strong>The biological plausibility of Relationship 2205 is considered</strong> high.</p>
<p><strong>Rationale</strong>: The biological structural and functional relationship between cell proliferation and growth is well established. It is commonly accepted that the size of an organism, organ or tissue is dependent on the total number and volume of the cells it contains, and the amount of extracellular matrix and fluids (Conlon 1999). Impairment to cell proliferation can logically affect tissue and organismal growth.</p>
<p style="text-align:justify"><strong>The empirical support of Relationship 2205 is considered</strong> low.</p>
<p><strong>Rationale</strong>: Because cell proliferation is typically measured in vitro, while growth of an organism is measured in vivo, few studies have measured both in the same experiment. There is one zebrafish study reporting concordant relationship between reduced cell proliferation and embryo growth with some inconsistencies (Bestman 2015). <!--![endif]----></p>
<ul>
<li style="text-align:justify">In zebrafish embryos exposed to 2,4-DNP, significant growth inhibition (AO), as indicated by whole embryo length, caudal primary (CaP) motor neuron axons and otic vesicle length (OVL) ratio after 21h, somite width and eye diameter after 45h exposure was identified, after 21h, whereas a non- significant reduction in cell proliferation was observed (Bestman 2015).</li>
</ul>
<p style="text-align:justify"><strong>The quantitative understanding of Relationship 2205 is</strong> moderate.</p>
<p><strong>Rationale:</strong> Multiple mathematical models describing the quantitative relationships between cell proliferation and tissue growth exist for both animals (Binder 2008) and plants (Mosca 2018). There are also numerous models that are specifically developed for predicting tumor growth based on the proliferation rate (Jarrett 2018).</p>
HighUnspecificHighEmbryoHigh<p style="text-align:justify"><em><strong>Taxonomic applicability</strong></em></p>
<p>Relationship 2205 is considered applicable to all eukaryotes (both unicellular and multicellular), as growth (or population growth of alga) is well known to be achieved through cell proliferation in animals, plants and some microorganisms.</p>
<p> </p>
<p><em><strong>Sex applicability</strong></em></p>
<p>Relationship 2205 is considered applicable to both all sexes, as cell proliferation leading to growth is a fundamental process and not sex-specific.</p>
<p> </p>
<p><em><strong>Life-stage applicability</strong></em></p>
<p>Relationship 2205 is considered applicable to all life stages, as cell proliferation leading to growth is essential for maintaining basic biological processes throughout an organism’s life.</p>
<p style="text-align:justify"><!--[if supportFields]><span
style='mso-element:field-begin'></span><span
style='mso-spacerun:yes'> </span>ADDIN EN.REFLIST <span style='mso-element:
field-separator'></span><![endif]--></p>
<p style="text-align:justify">Bestman JE, Stackley KD, Rahn JJ, Williamson TJ, Chan SS. 2015. The cellular and molecular progression of mitochondrial dysfunction induced by 2,4-dinitrophenol in developing zebrafish embryos. Differentiation 89:51-69. DOI: 10.1016/j.diff.2015.01.001.</p>
<p>Binder BJ, Landman KA, Simpson MJ, Mariani M, Newgreen DF. 2008. Modeling proliferative tissue growth: a general approach and an avian case study. Phys Rev E Stat Nonlin Soft Matter Phys 78:031912. DOI: 10.1103/PhysRevE.78.031912.</p>
<p>Conlon I, Raff M. 1999. Size control in animal development. Cell 96:235-244. DOI: 10.1016/s0092-8674(00)80563-2.</p>
<p>Jarrett AM, Lima EABF, Hormuth DA, McKenna MT, Feng X, Ekrut DA, Resende ACM, Brock A, Yankeelov TE. 2018. Mathematical models of tumor cell proliferation: A review of the literature. Expert Review of Anticancer Therapy 18:1271-1286. DOI: 10.1080/14737140.2018.1527689.</p>
<p>Mosca G, Adibi, M., Strauss, S., Runions, A., Sapala, A., Smith, R.S. 2018. Modeling Plant Tissue Growth and Cell Division. In Morris R., ed, Mathematical Modelling in Plant Biology. Springer, Cham.</p>
<p><!--[if supportFields]><span style='font-size:11.0pt;font-family:等线;mso-ascii-theme-font:
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style='mso-element:field-end'></span></span><![endif]--></p>
2020-11-12T17:58:062022-07-06T07:43:26Uncoupling of oxidative phosphorylation leading to growth inhibition via glucose depletionUncoupling of OXPHOS leading to growth inhibition 5<p>You Song</p>
<p>Norwegian Institute for Water Research (NIVA), Økernveien 94, NO-0579 Oslo, Norway</p>
<p> </p>
<p><strong><em>Acknowledgement</em></strong></p>
<p>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>).</p>
Under development: Not open for comment. Do not citeUnder DevelopmentIncluded in OECD Work Plan1.92<p>The proposed project aims to develop a network of AOPs for mitochondrial uncoupler mediated adverse effects on aquatic organisms.</p>
<p>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.</p>
<p style="text-align:justify">Decreased coupling of oxidative phosphorylation can be directly triggered by “uncouplers” as a molecular initiating event.</p>
<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. <!--![endif]----><!--![endif]----><!--![endif]----></li>
</ul>
<p style="text-align:justify">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:</p>
<p style="text-align:justify"> </p>
<p>-Test No. 201: Freshwater Alga and Cyanobacteria, Growth Inhibition Test</p>
<p>-Test No. 208: Terrestrial Plant Test: Seedling Emergence and Seedling Growth Test</p>
<p>-Test No. 211: Daphnia magna Reproduction Test</p>
<p>-Test No. 212: Fish, Short-term Toxicity Test on Embryo and Sac-Fry Stages</p>
<p>-Test No. 215: Fish, Juvenile Growth Test</p>
<p>-Test No. 221: Lemna sp. Growth Inhibition Test</p>
<p>-Test No. 228: Determination of Developmental Toxicity to Dipteran Dung Flies (Scathophaga stercoraria L. (Scathophagidae), Musca autumnalis De Geer (Muscidae))</p>
<p>-Test No. 241: The Larval Amphibian Growth and Development Assay (LAGDA)</p>
<p>-Test No. 407: Repeated Dose 28-day Oral Toxicity Study in Rodents</p>
<p>-Test No. 408: Repeated Dose 90-Day Oral Toxicity Study in Rodents</p>
<p>-Test No. 416: Two-Generation Reproduction Toxicity</p>
<p>-Test No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test</p>
<p>-Test No. 443: Extended One-Generation Reproductive Toxicity Study</p>
<p>-Test No. 453: Combined Chronic Toxicity/Carcinogenicity Studies</p>
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