Deposition of Energy

60-35-5

DLFVBJFMPXGRIB-UHFFFAOYSA-N

Acetamide

Acetamid acetamida Acetic acid amide Acetimidic acid Ethanamide Ethanimidic acid Methanecarboxamide NSC 25945

DTXSID7020005

103-90-2

RZVAJINKPMORJF-UHFFFAOYSA-N

Acetaminophen

4-Acetamidophenol APAP Paracetamol 4-hydroxyacetanilide Acetamide, N-(4-hydroxyphenyl)- 4-(Acetylamino)phenol 4-(N-Acetylamino)phenol 4-Acetaminophenol 4'-Hydroxyacetanilide Abensanil Acetagesic Acetalgin ACETAMIDE, N-(4-HYDROXYPHENYL) Acetaminofen Acetanilide, 4'-hydroxy- ACETANILIDE, 4-HYDROXY- Algotropyl Alvedon Anaflon Apamide Banesin Ben-u-ron Bickie-mol Biocetamol Cetadol Citramon P Claratal Clixodyne Dafalgan Daphalgan Dial-a-gesic Disprol Doliprane Dolprone Dymadon Efferalgan Endophy Febrilex Febrilix Febro-Gesic Febrolin Fepanil Finimal Gattaphen T Gelocatil Gutte Enteric Homoolan Jin Gang Lestemp Liquagesic Lonarid Lyteca Syrup Minoset Momentum N-(4-Hydroxyphenyl)acetamide N-Acetyl-4-aminophenol N-Acetyl-4-hydroxyaniline N-Acetyl-p-aminophenol Napafen Naprinol Nobedon NSC 109028 NSC 3991 Ortensan p-(Acetylamino)phenol p-Aceaminophenol Pacemol p-Acetamidophenol p-Acetoaminophen P-ACETYLAMINOPHENOL Paldesic panadeine Panadol Panadol Actifast Panadol Extend Panaleve Panasorb Panodil Paracetamol DC Paracetamole Parageniol Paramol Paraspen Parelan Pasolind N Perfalgan Phenaphen Phendon p-Hydroxyacetanilide Prodafalgan Puerxitong Pyrinazine Resfenol Resprin Rhodapop NCR Salzone Tabalgin Tachipirina Tempanal Tralgon Tylenol TylolHot Valadol Valgesic Vermidon Vick Pyrena

DTXSID2020006

968-81-0

VGZSUPCWNCWDAN-UHFFFAOYSA-N

Acetohexamide

Benzenesulfonamide, 4-acetyl-N-[(cyclohexylamino)carbonyl]- 1-(p-Acetylbenzenesulfonyl)-3-cyclohexylurea 1-[(p-Acetylphenyl)sulfonyl]-3-cyclohexylurea Acetohexamid acetohexamida Dimelin Dimelor Dymelor Gamadiabet Hypoglicil Metaglucina Minoral N-(p-Acetylphenylsulfonyl)-N'-cyclohexylurea Ordimel Tsiklamid Urea, 1-[(p-acetylphenyl)sulfonyl]-3-cyclohexyl-

DTXSID7020007

67-66-3

HEDRZPFGACZZDS-UHFFFAOYSA-N

Chloroform

Trichloromethane Methane, trichloro- CARBON TRICHLORIDE Chloroforme cloroformo Formyl trichloride Methane trichloride Methane,trichloro- NSC 77361 Trichloroform UN 1888

DTXSID1020306

110-00-9

YLQBMQCUIZJEEH-UHFFFAOYSA-N

Furan

Divinylene oxide furanne Furfuran Oxacyclopentadiene Tetrole UN 2389

DTXSID6020646

7429-90-5

XAGFODPZIPBFFR-UHFFFAOYSA-N

AZDRQVAHHNSJOQ-UHFFFAOYSA-N

Aluminum

Aisin Metal Fiber Al 050P-H24 ALC Fine Alcan XI 1391 Almi-Paste SSP 303AR Aloxal 3010 Alpaste 00-0506 Alpaste 0100M Alpaste 0100MA Alpaste 0100M-C Alpaste 0200M Alpaste 0200T Alpaste 0230M Alpaste 0230T Alpaste 0241M Alpaste 0300M Alpaste 0500M Alpaste 0539X Alpaste 0620MS Alpaste 0625TS Alpaste 0638-70C Alpaste 0700M Alpaste 0780M Alpaste 0900M Alpaste 100M Alpaste 100MS Alpaste 100MSR Alpaste 1100M Alpaste 1100MA Alpaste 1100N Alpaste 1100NA Alpaste 1109MA Alpaste 1109MC Alpaste 1200M Alpaste 1200T Alpaste 1260MS Alpaste 1500MA Alpaste 1700NL Alpaste 1810YL Alpaste 1830YL Alpaste 1900M Alpaste 1900XS Alpaste 1950M Alpaste 1950N Alpaste 210N Alpaste 2172EA Alpaste 2173 Alpaste 240T Alpaste 241M Alpaste 417 Alpaste 46-046 Alpaste 4-621 Alpaste 4919 Alpaste 50-63 Alpaste 50-635 Alpaste 51-148B Alpaste 51-231 Alpaste 5205N Alpaste 5207N Alpaste 52-509 Alpaste 52-568 Alpaste 5301N Alpaste 5302N Alpaste 53-119 Alpaste 5422NS Alpaste 54-452 Alpaste 54-497 Alpaste 54-542 Alpaste 55-516 Alpaste 55-519 Alpaste 55-574 Alpaste 5620NS Alpaste 5630NS Alpaste 5640NS Alpaste 56-501 Alpaste 5650NS Alpaste 5653NS Alpaste 5654NS Alpaste 5680N Alpaste 5680NS Alpaste 60-600 Alpaste 60-760 Alpaste 60-768 Alpaste 62-356 Alpaste 6340NS Alpaste 6370NS Alpaste 6390NS Alpaste 640NS Alpaste 65-388 Alpaste 66NLB Alpaste 710N Alpaste 7130N Alpaste 7160N Alpaste 7160NS Alpaste 725N Alpaste 740NS Alpaste 7430NS Alpaste 7580NS Alpaste 7620NS Alpaste 7640NS Alpaste 7670M Alpaste 7670NS Alpaste 7675NS Alpaste 7679NS Alpaste 7680N Alpaste 7680NS Alpaste 76840NS Alpaste 7730N Alpaste 7770N Alpaste 7830N Alpaste 8004 Alpaste 8080N Alpaste 8260NAR Alpaste 891K Alpaste 91-0562 Alpaste 92-0592 Alpaste 93-0595 Alpaste 93-0647 Alpaste 94-2315 Alpaste 95-0570 Alpaste 96-0635 Alpaste 96-2104 Alpaste 97-0510 Alpaste 97-0534 Alpaste AW 520B Alpaste AW 612 Alpaste AW 9800 Alpaste F 795 Alpaste FM 7680K Alpaste FX 440 Alpaste FX 910 Alpaste FZ 0534 Alpaste FZU 40C Alpaste G Alpaste HR 8801 Alpaste HS 2 Alpaste J Alpaste K 9800 Alpaste MC 666 Alpaste MC 707 Alpaste MF 20 Alpaste MG 01 Alpaste MG 1000 Alpaste MG 1300 Alpaste MG 500 Alpaste MG 600 Alpaste MH 6601 Alpaste MH 8801 Alpaste MH 9901 Alpaste MR 7000 Alpaste MR 9000 Alpaste MS 630 Alpaste N 1700NL Alpaste NS 7670 Alpaste O 100N Alpaste O 2130 Alpaste O 300M Alpaste P 0100 Alpaste P 1950 Alpaste S Alpaste SAP 110 Alpaste SAP 414P Alpaste SAP 550N Alpaste SCR 5070 Alpaste TCR 2020 Alpaste TCR 2060 Alpaste TCR 2070 Alpaste TCR 3010 Alpaste TCR 3030 Alpaste TCR 3040 Alpaste TCR 3130 Alpaste TD 200T Alpaste UF 500 Alpaste WB 0230 Alpaste WD 500 Alpaste WJP-U 75C Alpaste WX 0630 Alpaste WX 7830 Alpaste WXA 7640 Alpaste WXM 0630 Alpaste WXM 0650 Alpaste WXM 0660 Alpaste WXM 1415 Alpaste WXM 1440 Alpaste WXM 5422 Alpaste WXM 760b Alpaste WXM 7640 Alpaste WXM 7675 Alpaste WXM-T 60B Alpaste WXM-U 75 Alpaste WXM-U 75C Altop X Aluchrome Ultrafin Super Alumat 1600 Alumet H 30 aluminio Aluminium Aluminium Flake Aluminum 27 Aluminum atom Aluminum element Aluminum Flake PCF 7620 Aluminum granules ALUMINUM METAL/GRANULE ALUMINUM PASTE ALUMINUM PIGMENT ALUMINUM TURNINGS Alumi-paste 640NS Alumipaste 91-0562 Alumipaste 98-1822T Alumipaste AW 620 Alumipaste CR 300 Alumipaste GX 180A Alumipaste GX 201A Alumipaste HR 7000 Alumipaste HR 850 Alumipaste MG 11 Alumipaste MH 8801 Aquamet NPW 2900 Aquapaste 205-5 Aquasilver LPW Astroflake 40 Astroflake Black N 020 Astroflake Black N 070 Astroflake LG 40 Astroflake LG 70 Astroflake Silver N 040 Astroshine NJ 1600 Astroshine T 8990 Atomizalumi VA 200 C.I. PIGMENT METAL 1 Chromal IV Chromal X Decomet 1001/10 Decomet 2018/10 Decomet High Gloss Al 1002/10 Ecka AS 081 Eckart 9155 Eterna Brite 301-1 Eterna Brite 601-1 Eterna Brite 651-1 Eterna Brite EBP 251PA Eterna Brite Primier 251PA Ferro FX 53-038 Friend Color F 500GR-W Friend Color F 500WT Friend Color F 700RE-W Friend Color F 701RE-W Hi Print 60T High Print 60T Hisparkle HS 2 Hydro Paste 8726 Hydrolac WHH 2153 Hydrolan 3560 Hydrolux Reflexal 100 Hydroshine WS 1001 JISA 51010P Kryal Z Lansford 243 LE Sheet 800 Leafing Alpaste LG-H Silver 25 Lunar Al-V 95 Metallux 161 Metallux 2154 Metallux 2192 Metalure Metalure 55350 Metalure L 55350 Metalure L 59510 Metalure W 2001 Metapor Metasheen 1800 Metasheen HR 0800 Metasheen KM 100 Metasheen KM 1000 Metasheen Slurry 1807 Metasheen Slurry 1811 Metasheen Slurry KM 100 Metax G Metax S Mirror Glow 1000 Mirror Glow 600 Mirrorsheen Noral Aluminium Noral Ink Grade Aluminium Obron 10890 Offset FM 4500 Puratronic Reflexal 145 Reynolds 400 Reynolds 4-301 Reynolds 4-591 Reynolds 667 SAP 260PW-HS SAP-FM 4010 SBC 516-20Z Scotchcal 7755SE Serumekku Setanium 50MIS-H8 Siberline ET 2025 Siberline ST 21030E1 Silvar A Silver VT 522 Silverline SSP 353 Silvex 793-20C Sparkle Silver 3141ST Sparkle Silver 3500 Sparkle Silver 3641 Sparkle Silver 5000AR Sparkle Silver 516AR Sparkle Silver 5242AR Sparkle Silver 5245AR Sparkle Silver 5271AR Sparkle Silver 5500 Sparkle Silver 5745 Sparkle Silver 7000AR Sparkle Silver 7005AR Sparkle Silver 7500 Sparkle Silver 960-25E1 Sparkle Silver E 1745AR Sparkle Silver L 1526AR Sparkle Silver Premier 751 Sparkle Silver SS 3130 Sparkle Silver SS 5242AR Sparkle Silver SS 5588 Sparkle Silver SSP 132AR Special PCR 507 Splendal 6001BG Spota Mobil 801 SSP 760-20C Stapa Aloxal PM 2010 Stapa Aloxal PM 3010 Stapa Aloxal PM 4010 Stapa Hydrolac BG 8n.1 Stapa Hydrolac BGH Chromal X Stapa Hydrolac PM Chromal VIII Stapa Hydrolac W 60NL Stapa Hydrolac WH 16 Stapa Hydrolac WH 66NL Stapa Hydrolux 2192 Stapa Hydrolux 8154 Stapa IL Hydrolan 2192-55900G Stapa Metallic R 607 Stapa Metallux 1050 Stapa Metallux 211 Stapa Metallux 212 Stapa Metallux 2196 Stapa Metallux 274 Stapa Mobilux 181 Stapa Offset 3000 Stapa PV 10 Stapa VP 46432G Starbrite 2100 Super Fine 18000 Super Fine 22000 Supramex 2022 Toyo Aluminum 02-0005 Toyo Aluminum 93-3040 Transmet K 102HE Tufflake 3645 Tufflake 5843 UN 1396 US Aluminum 809 Valimet H 2 Valimet H 3 White Silver 7080N White Silver 7130N

DTXSID3040273

7440-43-9

BDOSMKKIYDKNTQ-UHFFFAOYSA-N

Cadmium

Cadimium CADMIUM BLUE CADMIUM, IN PLATTEN, STANGEN, BROCKEN,KOERNER

DTXSID1023940

7439-97-6

QSHDDOUJBYECFT-UHFFFAOYSA-N

Mercury

Liquid silver Mercure MERCURIC METAL TRIPLE DISTILLED mercurio Mercury element Quecksilber Quicksilver UN 2024 UN 2809

DTXSID1024172

7440-61-1

JFALSRSLKYAFGM-UHFFFAOYSA-N

Uranium

Uranium, isotope of mass 238 238U Element UN 2979 (DOT) Uranium I

DTXSID1042522

7440-38-2

RQNWIZPPADIBDY-UHFFFAOYSA-N

Arsenic

As Arsenic black ARSENIC METAL arsenico Grey arsenic UN 1558

DTXSID4023886

7440-22-4

BQCADISMDOOEFD-UHFFFAOYSA-N

Silver

Ag Nanopaste NPS-J 90 Ag Sphere 2 Ag-C-GS Algaedyn Arctic Silver 3 Argentum Astroflake 5 Carey Lea silver Colloidal silver Dotite XA 208 Du Pont 4943 ECM 100AF4810 Enlight 600 Enlight silver plate 600 Epinall Finesphere SVND 102 Fordel DC FP 5369-502 Jelcon SH 1 Jungindai Takasago 300 KS (metal) LCP 1-19SFS Metz 3000-1 Nanomelt AGC-A Nanomelt Ag-XA 301 Nanomelt Ag-XF 301 Nanomelt Ag-XF 301H Nanopaste NPS-J 90 Perfect Silver Puff Silver X 1200 RT 1710S-C1 SD (metal) Shell Silver Silbest E 20 Silbest F 20 Silbest J 18 Silbest TC 12 Silbest TC 20E Silbest TC 25A Silbest TCG 1 Silbest TCG 7 Silcoat AgC 103 Silcoat AgC 2011 Silcoat AgC 209 Silcoat AgC 2190 Silcoat AgC 222 Silcoat AgC 2411 Silcoat AgC 74T Silcoat AgC-A Silcoat AgC-AO Silcoat AgC-B Silcoat AgC-BO Silcoat AgC-D Silcoat AgC-G Silcoat AgC-GS Silcoat AgC-L Silcoat AgC-O Silcoat GS Silcoat RF 200 Silflake 135 Silsphere 514 Silver atom Silver element Silver Flake 1 Silver Flake 25 Silver Flake 52 Silver Flake 7A SILVER FLAKES Silver metal Silvest TCG 11N Technic 299 Technic 450 Techno Alpha 175

DTXSID4024305

7439-96-5

PWHULOQIROXLJO-UHFFFAOYSA-N

Manganese

Colloidal manganese Cutaval Manganese element Manganese fulleride Manganese metal alloy Manganese-55 manganeso

DTXSID2024169

7440-02-0

PXHVJJICTQNCMI-UHFFFAOYSA-N

Nickel

Carbonyl 255 Carbonyl Ni 123 Carbonyl Ni 283 Carbonyl Nickel 123 Carbonyl Nickel 283 Carbonyl Nickel 287 Cerac N 2003 CNS 10 Micron Exmet 4 Ni X-4/0 Fibrex P Incofoam Nickel element NICKEL ROUND ANODES Nicrobraz LM:BNi 2 Ni-Flake 95 Novamet 123 Novamet 4SP Novamet 4SP10 Novamet 525 Novamet CNS 400 Novamet HCA 1 Novamet NI 255 Raney nickel Raney nickel 2800 UN 1325 UN 2881

DTXSID2020925

7440-66-6

HCHKCACWOHOZIP-UHFFFAOYSA-N

Zinc

Zn Asarco L 15 C.I. Pigment Black 16 Merrillite NC-Zinc Rheinzink Stapa TE Zinc AT UF (metal) UN 1436 Zinc dust Zinc Dust 3 Zinc Dust 500 mesh Zinc Dust LS 2 Zinc Dust MCS Zinc Flakes GTT ZINC METAL ZINC MOSSY ZINC STRIP ZINC, MOSSY Zincsalt GTT

DTXSID7035012

CHEBI:16991

CHEBI deoxyribonucleic acid

PCO:0000001

PCO population of organisms

RBO:00015021

RBO energy deposition event

PCO:0000008

PCO population growth rate

MP:0003674

MP oxidative stress

WIKI increased

WIKI functional change

WIKI decreased

Ionizing Radiation Ionizing radiation can vary in energy, dose, charge, and in the spatial distributions of energy transferred to other matter (linear energy transfer per unit length or LET) (ICRU 1970). At the same dose, low and high LET both generate energy deposition events, including many higher energy events (Goodhead and Nikjoo 1989). However, they differ in the spatial distribution and upper range of intensity of energy deposited. Lower LET such as gamma rays sparsely deposit many individual excitations or small clusters of excitations of low energy (Goodhead 1988). In contrast, high LET such as alpha particles have fewer tracks but readily transfer their energy to matter and therefore deposit their energy over a much smaller area (Goodhead 1994). Consequently, alpha and other high LET particles penetrate less deeply into tissue, interactions are densely focused on a narrow track, and individual energy depositions can be large (Goodhead 1988). These different energy deposition patterns can lead to differences in radiation effects including the pattern of DNA damage.

Exposure to ionizing radiation can come from natural and industrial sources. Space and terrestrial radiation includes a range of LET particles, while diagnostic radiation methods such as X-ray imaging, mammography and CT scans use low LET X-rays. Radiation therapy can use an external beam to direct radiation on a focused tissue area, or deposit solid or liquid radioactive materials in the body that release (mostly gamma) radiation internally. External radiotherapy typically uses X-rays but is moving towards higher LET charged particles such as protons and heavy ions (Durante, Orecchia et al. 2017).

2019-05-03T12:36:36

2019-05-07T12:12:13

Estrogen

2019-05-08T11:40:27

Acetaminophen

2016-11-29T18:42:26

Chloroform

2016-11-29T18:42:27

furan

2020-05-01T14:35:22

Platinum

2022-02-04T14:36:54

Aluminum

2022-02-04T14:42:11

Cadmium

2017-10-25T08:33:12

Mercury

2016-11-29T18:42:19

Uranium

2021-08-05T14:28:50

Arsenic

2021-04-27T00:15:21

Silver

2022-02-03T11:20:11

Manganese

2022-02-04T14:47:23

Nickel

2022-02-04T14:47:59

Zinc

2022-02-04T15:05:00

nanoparticles

2016-12-21T09:40:06

WCS_9606

common toxicological species human

10116

NCBI rat

10090

NCBI mouse

6239

NCBI nematode

WCS_7955

common ecological species zebrafish

3702

NCBI thale-cress

3349

NCBI Scotch pine

WCS_35525

common ecological species Daphnia magna

3055

NCBI Chlamydomonas reinhardtii

WCS_6396

common ecological species common brandling worm

WCS_4472

common ecological species Lemna minor

8030

NCBI Salmo salar

WikiUser_22

all species

WikiUser_26

ApacheUser rodents

9606

NCBI Homo sapiens

Deposition of Energy

Energy Deposition

Molecular

Deposition of energy refers to events where energetic subatomic particles, nuclei, or electromagnetic radiation deposit energy in the media through which they transverse. The energy may either be sufficient (e.g. ionizing radiation) or insufficient (e.g. non-ionizing radiation) to ionize atoms or molecules (Beir et al.,1999).  Ionizing radiation can cause the ejection of electrons from atoms and molecules, thereby resulting in their ionization and the breakage of chemical bonds.  The excitation of molecules can also occur without ionization. These events are stochastic and unpredictable. The energy of these subatomic particles or electromagnetic waves ranges from 124 keV to 5.4 MeV and is dependent on the source and type of radiation (Zyla et al., 2020). Not all electromagnetic radiation is ionizing; as the incident radiation must have sufficient energy to free electrons from the electron orbitals of the atom or molecule. The energy deposited can induce direct and indirect ionization events and can result from internal (injections, inhalation, ingestion) or external exposure.  Direct ionization is the principal path where charged particles interact with biological structures such as DNA, proteins or  membranes to cause biological damage. Photons, which are electromagnetic waves can also deposit energy to cause direct which themselves can indirectly damage critical targets such as DNA (Beir et al., 1999; Balagamwala et al., 2013) or alter cellular processes. Given the fundamental nature of energy deposition by radioactive/unstable nuclei, nucleons or elementary particles in material, this process is universal to all biological contexts.  The spatial structure of ionizing energy deposition along the resulting particle track is represented as linear energy transfer (LET) (Hall and Giaccia, 2018 UNSCEAR, 2020). High LET refers to energy mostly above 10 keV μm-1 which produces more complex, dense structural damage than low LET radiation (below 10 keV μm-1). Low-LET particles produce sparse ionization events such as photons (X- and gamma rays), as well as high-energy protons. Low LET radiation travels farther into tissue but deposits smaller amounts of energy, whereas high LET radiation, which includes heavy ions, alpha particles and high-energy neutrons, does not travel as far but deposits larger amounts of energy into tissue at the same absorbed dose. The biological effect of the deposition of energy can be modulated by varying dose and dose rate of exposure, such as acute, chronic, or fractionated exposures (Hall and Giaccia, 2018).  Non-ionizing radiation is electromagnetic waves that does not have enough energy to break bonds and induce ion formation but it can cause molecules to excite and vibrate faster resulting in biological effects. Examples of non-ionizing radiation include radio waves (wavelength: 100 km-1m), microwaves (wavelength: 1m-1mm), infrared radiation (wavelength: 1mm- 1 um), visible light (wavelengths: 400-700 nm), and ultraviolet radiation of longer wavelengths such as UVB (wavelengths: 315-400nm) and UVA (wavelengths: 280-315 nm).

<table border="1"> <tbody> <tr> <td> Radiation type  </td> <td> Assay Name  </td> <td> References  </td> <td> Description  </td> <td> OECD Approved Assay  </td> </tr> <tr> <td> Ionizing radiation  </td> <td> Monte Carlo Simulations (eg. Geant4)  </td> <td> Douglass et al., 2013; Douglass et al., 2012; Zyla et al., 2020  </td> <td> Monte Carlo simulations are based on a computational algorithm that mathematically models the deposition of energy into materials.  </td> <td> No  </td> </tr> <tr> <td> Ionizing radiation  </td> <td> Fluorescent Nuclear Track Detector (FNTD)  </td> <td> Sawakuchi, 2016; Niklas, 2013; Kodaira & Konishi, 2015  </td> <td> FNTDs are biocompatible chips with crystals of aluminum oxide doped with carbon and magnesium; used in conjunction with fluorescent microscopy, these FNTDs allow for the visualization and the linear energy transfer (LET) quantification of tracks produced by the deposition of energy into a material.  </td> <td> No  </td> </tr> <tr> <td> Ionizing radiation  </td> <td> Tissue equivalent proportional counter (TEPC)  </td> <td> Straume et al, 2015  </td> <td> Measure the LET spectrum and calculate the equivalent dose  </td> <td> No  </td> </tr> <tr> <td> Ionizing radiation  </td> <td> alanine dosimeters/NanoDots  </td> <td> Lind et al. 2019  Xie et al., 2022  </td> <td> Alanine dosimeters use the amino acid alanine to detect radiation-induced changes, and nanodots leverage nano-scale technology to provide high precision and sensitivity in radiation dose measurements </td> <td> No  </td> </tr> <tr> <td> Non-ionizing radiation  </td> <td> UV meters or radiometers  </td> <td> Xie et al., 2020  </td> <td> UVA/UVB (irradiance intensity), UV dosimeters (accumulated irradiance over time), Spectrophotometer (absorption of UV by a substance or material)  </td> <td> No  </td> </tr> </tbody> </table>

Energy can be deposited into any substrate, both living and non-living; it is independent of age, taxa, sex, or life-stage.  Taxonomic applicability: This MIE is not taxonomically specific.  Life stage applicability: This MIE is not life stage specific.  Sex applicability: This MIE is not sex specific.

Low Unspecific

High

All life stages

Moderate Moderate Moderate High High High Moderate High Moderate Moderate High Low

Balagamwala, E. H. et al. (2013), “Introduction to radiotherapy and standard teletherapy techniques”, Dev Ophthalmol, Vol. 52, Karger, Basel, https://doi.org/10.1159/000351045  Beir, V. et al. (1999), “The Mechanistic Basis of Radon-Induced Lung Cancer”, in Health Risks of Exposure to Radon: BEIR VI, National Academy Press, Washington, D.C., https://doi.org/10.17226/5499  Douglass, M. et al. (2013), “Monte Carlo investigation of the increased radiation deposition due to gold nanoparticles using kilovoltage and megavoltage photons in a 3D randomized cell model”, Medical Physics, Vol. 40/7, American Institute of Physics, College Park, https://doi.org/10.1118/1.4808150  Douglass, M. et al. (2012), “Development of a randomized 3D cell model for Monte Carlo microdosimetry simulations.”, Medical Physics, Vol. 39/6, American Institute of Physics, College Park, https://doi.org/10.1118/1.4719963  Hall, E. J. and Giaccia, A.J. (2018), Radiobiology for the Radiologist, 8th edition, Wolters Kluwer, Philadelphia.  Kodaira, S. and Konishi, T. (2015), “Co-visualization of DNA damage and ion traversals in live mammalian cells using a fluorescent nuclear track detector.”, Journal of Radiation Research, Vol. 56/2, Oxford University Press, Oxford, https://doi.org/10.1093/jrr/rru091  Lind, O.C., D.H. Oughton and Salbu B. (2019), "The NMBU FIGARO low dose irradiation facility", International Journal of Radiation Biology, Vol. 95/1, Taylor & Francis, London, https://doi.org/10.1080/09553002.2018.1516906.  Sawakuchi, G.O. and Akselrod, M.S. (2016), “Nanoscale measurements of proton tracks using fluorescent nuclear track detectors.”, Medical Physics, Vol. 43/5, American Institute of Physics, College Park, https://doi.org/10.1118/1.4947128  Straume, T. et al. (2015), “Compact Tissue-equivalent Proportional Counter for Deep Space Human Missions.”, Health physics, Vol. 109/4, Lippincott Williams & Wilkins, Philadelphia, https://doi.org/10.1097/HP.0000000000000334   Niklas, M. et al. (2013), “Engineering cell-fluorescent ion track hybrid detectors.”, Radiation Oncology, Vol. 8/104, BioMed Central, London, https://doi.org/10.1186/1748- 717X-8-141  UNSCEAR (2020), Sources, effects and risks of ionizing radiation, United Nations.   Xie, Li. et al. (2022), "Ultraviolet B Modulates Gamma Radiation-Induced Stress Responses in Lemna Minor at Multiple Levels of Biological Organisation", SSRN, Elsevier, Amsterdam, http://dx.doi.org/10.2139/ssrn.4081705 .  Zyla, P.A. et al. (2020), Review of particle physics: Progress of Theoretical and Experimental Physics, 2020 Edition, Oxford University Press, Oxford.      AOPWiki 2019-08-22T09:44:23

2024-08-23T09:20:36

Increase in reactive oxygen and nitrogen species (RONS)

Increase in RONS

Molecular

Reactive oxygen and nitrogen species (RONS) are highly reactive oxygen- and nitrogen-based molecules that often contain or generate free radicals. Key molecules include superoxide ([O2]•−), hydrogen peroxide (H2O2), hydroxyl radical ([OH]•), lipid peroxide (ROOH), nitric oxide ([NO]•, and peroxynitrite ([ONOO-]) (Dickinson and Chang 2011; Egea, Fabregat et al. 2017) RONS are generated in the course of cellular respiration, metabolism, cell signaling, and inflammation (Dickinson and Chang 2011; Egea, Fabregat et al. 2017). Superoxide and hydrogen peroxide are commonly produced by the mitochondrial electron transport chain and cytochrome c and by membrane bound NADPH oxidases and related molecules. Hydrogen peroxide is also made by the endoplasmic reticulum in the course of protein folding. Nitric oxide is produced at the highest levels by nitric oxide synthase in endothelial cells and phagocytes. The other species are produced by reactions with superoxide or peroxide, or by other free radicals or enzymes. RONS activity is principally local. Most reactive oxygen species (ROS) have short half-lives, ranging from nano- to milliseconds, so diffusion is limited, while reactive nitrogen species (RNS) nitric oxide or peroxynitrate can survive long enough to diffuse across membranes (Calcerrada, Peluffo 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, Fabregat et al. 2017). The effects of ROS and RNS are countered by cellular antioxidants, with glutathione and peroxiredoxins playing a major role (Dickinson and Chang 2011). Glutathione is slower but broad acting, while peroxiredoxins act quickly and are specific to peroxides. Peroxiredoxins are effective at low peroxide concentrations but can be deactivated at higher concentrations, suggesting the cellular response to peroxides may sometimes be non-linear. Although their existence is limited temporally and spatially, reactive oxygen species (ROS) interact with other RONS or with other nearby molecules to produce more ROS and participate in a feedback loop to amplify the ROS signal, which can increase Reactive Nitrogen Species (RNS). Both ROS and RNS also move into neighboring cells and ROS can increase intracellular RONS signaling in neighboring cells (Egea, Fabregat et al. 2017). RONS can modify a range of targets including amino acids, lipids, and nucleic acids to inactivate or alter target functionality (Calcerrada, Peluffo et al. 2011; Dickinson and Chang 2011; Go and Jones 2013; Ravanat, Breton et al. 2014; Egea, Fabregat et al. 2017). For example, phosphatases including the tumor suppressor PTEN can be reversibly deactivated by oxidation, and the movement of HDAC4 is peroxide dependent. Elevated ROS are implicated in proliferation and maintenance of stem cell population size (Dickinson and Chang 2011) and conversely in differentiation of stem cells and oncogene-induced senescence (Egea, Fabregat et al. 2017).

RONS is typically measured using fluorescent or other probes that react with RONS to change state, or by measuring the redox state of proteins or DNA (Dickinson and Chang 2011; Wang, Fang et al. 2013; Griendling, Touyz et al. 2016). Optimal methods for RONS detection have high sensitivity, selectivity, and spatiotemporal resolution to distinguish transient and localized activity, but most methods lack one or more of these parameters. Molecular probes that indicate the presence of RONS species vary in specificity and kinetics (Dickinson and Chang 2011; Wang, Fang et al. 2013; Griendling, Touyz et al. 2016). Small molecule fluorescent probes can be applied to any tissue in vitro, but cannot be finely targeted to different cellular compartments. The non-selective probe DCHF was widely used in the past, but can produce false positive signals and is no longer recommended. Newer more selective small molecule probes such as boronate-based molecules are being developed but are not yet widely used. Alternatively, fluorescent protein-based probes can be genetically engineered, expressed in vivo, and targeted to cellular compartments and specific cells. However, these probes are very sensitive to pH in the physiological range and must be carefully controlled.  EPR (electron paramagnetic resonance spectroscopy) provide the most direct and specific detection of free radicals, but requires specialized equipment. Alternative methods involve the detection of redox-dependent changes to cellular constituents such as proteins, DNA, lipids, or glutathione (Dickinson and Chang 2011; Wang, Fang et al. 2013; Griendling, Touyz et al. 2016). However, these methods cannot generally distinguish between the oxidative species behind the changes, and cannot provide good resolution for kinetics of oxidative activity. Table 1. Common methods for detecting oxidative activity <table border="1" cellpadding="0" cellspacing="0"> <tbody> <tr> <td style="height:22px; width:133px"> Target </td> <td style="height:22px; width:126px"> Name </td> <td style="height:22px; width:144px"> Method </td> <td style="height:22px; width:235px"> Strengths/Weaknesses </td> </tr> <tr> <td style="height:22px; width:133px"> Hydrogen peroxide- extracellular </td> <td style="height:22px; width:126px"> AmplexRed </td> <td style="height:22px; width:144px"> Small molecule fluorescent probes </td> <td style="height:22px; width:235px"> Can be applied to any tissue in vitro. </td> </tr> <tr> <td style="height:22px; width:133px"> Hydrogen peroxide- mitochondrial </td> <td style="height:22px; width:126px"> MitoPy1 </td> <td style="height:22px; width:144px"> Small molecule fluorescent probes </td> <td style="height:22px; width:235px"> Can be applied to any tissue in vitro. </td> </tr> <tr> <td style="height:22px; width:133px"> Hydrogen peroxide </td> <td style="height:22px; width:126px"> HyPer </td> <td style="height:22px; width:144px"> Protein-based fluorescent probes </td> <td style="height:22px; width:235px"> Sensitive, can be targeted to specific cells and compartments. Slower and pH sensitive. </td> </tr> <tr> <td style="height:22px; width:133px"> Hydrogen peroxide </td> <td style="height:22px; width:126px"> HyPer3 </td> <td style="height:22px; width:144px"> Protein-based fluorescent probes </td> <td style="height:22px; width:235px"> Rapid kinetics and larger dynamic range, can be targeted to specific cells and compartments. Sensitive to pH, less sensitive to H2O2. </td> </tr> <tr> <td style="height:22px; width:133px"> Hydrogen peroxide </td> <td style="height:22px; width:126px"> Boronate-based indicators </td> <td style="height:22px; width:144px"> Small molecule fluorescent probe </td> <td style="height:22px; width:235px"> Selective for H2O2 but can interact with peroxynitrite. </td> </tr> <tr> <td style="height:22px; width:133px"> Superoxide- intracellular </td> <td style="height:22px; width:126px"> DHE (dihydroethidium) </td> <td style="height:22px; width:144px"> Small molecule fluorescent probe </td> <td style="height:22px; width:235px"> Can be applied to any tissue in vitro, but not targeted to different compartments. </td> </tr> <tr> <td style="height:22px; width:133px"> Superoxide- intracellular </td> <td style="height:22px; width:126px"> cpYFP </td> <td style="height:22px; width:144px"> Protein-based fluorescent probes </td> <td style="height:22px; width:235px"> Reversible. Can be targeted to specific cells and compartments. </td> </tr> <tr> <td style="height:22px; width:133px"> Superoxide- mitochondrial </td> <td style="height:22px; width:126px"> MitoSox </td> <td style="height:22px; width:144px"> Small molecule fluorescent probe </td> <td style="height:22px; width:235px"> Can be applied to any tissue in vitro. </td> </tr> <tr> <td style="height:22px; width:133px"> Superoxide- mitochondrial </td> <td style="height:22px; width:126px"> mt-cpYFP </td> <td style="height:22px; width:144px"> Protein-based fluorescent probes </td> <td style="height:22px; width:235px"> Reversible. Can be targeted to specific cells and compartments. </td> </tr> <tr> <td style="height:22px; width:133px"> Superoxide- extracellular </td> <td style="height:22px; width:126px"> nitroblue tetrazolium </td> <td style="height:22px; width:144px"> Small molecule fluorescent probe </td> <td style="height:22px; width:235px"> Can be applied to any tissue in vitro. </td> </tr> <tr> <td style="height:22px; width:133px"> Superoxide- intracellular or extracelluar </td> <td style="height:22px; width:126px"> various trityl probes </td> <td style="height:22px; width:144px"> EPR </td> <td style="height:22px; width:235px"> Very specific, but requires specialized equipment, not as sensitive in tissue. </td> </tr> <tr> <td style="height:22px; width:133px"> Nitric oxide </td> <td style="height:22px; width:126px"> Fe[DETC]2 and Fe[MGD]2, </td> <td style="height:22px; width:144px"> EPR </td> <td style="height:22px; width:235px"> Very specific, but requires specialized equipment, not as sensitive in tissue. </td> </tr> <tr> <td style="height:22px; width:133px"> Nitric oxide </td> <td style="height:22px; width:126px"> DAF-FM </td> <td style="height:22px; width:144px"> Small molecule fluorescent probe </td> <td style="height:22px; width:235px"> Can be applied to any tissue in vitro, but not targeted to different compartments </td> </tr> <tr> <td style="height:22px; width:133px"> Peroxynitrite </td> <td style="height:22px; width:126px"> EMPO </td> <td style="height:22px; width:144px"> EPR </td> <td style="height:22px; width:235px"> Very specific, but requires specialized equipment, not as sensitive in tissue. </td> </tr> <tr> <td style="height:22px; width:133px"> Peroxynitrite </td> <td style="height:22px; width:126px"> Boronate-based indicators </td> <td style="height:22px; width:144px"> Small molecule fluorescent probe </td> <td style="height:22px; width:235px"> Selective for H2O2 but can interact with (is inhibited by) peroxynitrite. </td> </tr> <tr> <td style="height:22px; width:133px"> Peroxynitrite </td> <td style="height:22px; width:126px"> 8-nitroguanine (DNA) content </td> <td style="height:22px; width:144px"> HPLC-MS/MS </td> <td style="height:22px; width:235px"> Destruction of sample required for measurement. </td> </tr> <tr> <td style="height:22px; width:133px"> Non-specific oxidation </td> <td style="height:22px; width:126px"> DCHF </td> <td style="height:22px; width:144px"> Small molecule fluorescent probe </td> <td style="height:22px; width:235px"> Very non selective, and can produce false positive signals. </td> </tr> <tr> <td style="height:22px; width:133px"> Non-specific oxidation </td> <td style="height:22px; width:126px"> roGFP or FRET </td> <td style="height:22px; width:144px"> Protein-based fluorescent probes </td> <td style="height:22px; width:235px"> Slow acting. Good to look at steady state activity. </td> </tr> <tr> <td style="height:22px; width:133px"> Non-specific oxidation </td> <td style="height:22px; width:126px"> ratio of reduced to oxidized glutathione or cysteine </td> <td style="height:22px; width:144px"> Redox state detectors </td> <td style="height:22px; width:235px"> Slow acting. Good to look at steady state activity. Destruction of sample required for measurement. </td> </tr> <tr> <td style="height:22px; width:133px"> Non-specific oxidation </td> <td style="height:22px; width:126px"> 8-oxoguanine (DNA) or protein carbonyl content </td> <td style="height:22px; width:144px"> HPLC-MS/MS </td> <td style="height:22px; width:235px"> Destruction of sample required for measurement. </td> </tr> <tr> <td style="height:22px; width:133px"> Non-specific oxidation </td> <td style="height:22px; width:126px"> TBARS (thiobarbituric acid reactive substance) </td> <td style="height:22px; width:144px"> Lipid peroxidation </td> <td style="height:22px; width:235px"> Destruction of sample required for measurement. </td> </tr> </tbody> </table>

This KE is broadly applicable across species.

<a name="_ENREF_1">Calcerrada, P., G. Peluffo, et al. (2011). "Nitric oxide-derived oxidants with a focus on peroxynitrite: molecular targets, cellular responses and therapeutic implications." Curr Pharm Des 17(35): 3905-3932.</a> <a name="_ENREF_2">Dickinson, B. C. and C. J. Chang (2011). "Chemistry and biology of reactive oxygen species in signaling or stress responses." Nature chemical biology 7(8): 504-511.</a> <a name="_ENREF_3">Egea, J., I. Fabregat, et al. (2017). "European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)." Redox biology 13: 94-162.</a> <a name="_ENREF_4">Go, Y. M. and D. P. Jones (2013). "The redox proteome." J Biol Chem 288(37): 26512-26520.</a> <a name="_ENREF_5">Griendling, K. K., R. M. Touyz, et al. (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.</a> <a name="_ENREF_6">Ravanat, J. L., J. Breton, et al. (2014). "Radiation-mediated formation of complex damage to DNA: a chemical aspect overview." Br J Radiol 87(1035): 20130715.</a> <a name="_ENREF_7">Wang, X., H. Fang, et al. (2013). "Imaging ROS signaling in cells and animals." Journal of molecular medicine 91(8): 917-927.</a> AOPWiki 2019-05-03T14:00:04

2019-05-08T12:30:20

Increase, DNA damage

Increase, DNA Damage

Molecular

DNA nucleotide damage, single, and double strand breaks occur in the course of cellular operations such as DNA repair and replication and can be induced directly and in neighboring “bystander” cells by internal or external stressors like reactive oxygen species, chemicals, and radiation. Ionizing radiation and RONS such as hydroxyl radicals or peroxide can create a range of lesions (a change in molecular structure) in the base of the nucleotide, with guanine particularly vulnerable because of its low redox potential (David, O'Shea et al. 2007). The same stressors can also break the sugar (deoxyribose)-phosphate backbone creating a single strand break. Simultaneous proximal breaks in both strands of DNA form double strand breaks, which are considered to be more destructive and mutagenic than lesions or single strand breaks. Double strand breaks can generate chromosomal abnormalities including changes in chromosomal number, breaks and gaps, translocations, inversions, and deletions (Yang, Craise et al. 1992; Haag, Hsu et al. 1996; Ponnaiya, Cornforth et al. 1997; Yang, Georgy et al. 1997; Unger, Wienberg et al. 2010; Behjati, Gundem et al. 2016; Morishita, Muramatsu et al. 2016). However, DNA lesions and single strand breaks can also be destructive and mutagenic. Lesions can lead to point mutations (David, O'Shea et al. 2007) or single strand breaks (Regulus, Duroux et al. 2007). Lesions and single strand breaks can also promote the formation of double strand breaks: replication fork collapse and double strand breaks sometimes occur during mitosis when the replisome encounters an unrepaired single strand break (Kuzminov 2001), and clustered lesions and closely opposed single strand breaks can also form double strand breaks (Chaudhry and Weinfeld 1997; Vispe and Satoh 2000; Shiraishi, Shikazono et al. 2017). Complex damage consists of any combination of closely opposed DNA lesions, abasic sites, crosslinks, single, or double strand breaks in proximity. While classically induced by ionizing radiation, there is also evidence that it can be induced by oxidative activity (Sharma, Collins et al. 2016) or even by a single oxidizing particle (Ravanat, Breton et al. 2014). Complex damage is more difficult to repair (Kuhne, Rothkamm et al. 2000; Stenerlow, Hoglund et al. 2000; Pinto, Prise et al. 2005; Rydberg, Cooper et al. 2005). DNA damage and resulting repair activity can trigger a halt in the cell cycle, cell death (apoptosis), and cause permanent changes to DNA including deletions, translocations, and sequence changes. DNA damage is also associated with an increase in genomic instability - the new appearance of DNA damage including double strand breaks, mutations, and chromosomal damage following repair of initial damage in affected cells or in clonal descendants or neighbors of DNA damaged cells. The mechanism behind this long term DNA damage is not clear, but telomere erosion appears to play a major role (Murnane 2012; Sishc, Nelson et al. 2015). Genomic instability is more common and longer lasting following complex damage (Ponnaiya, Cornforth et al. 1997), and is influenced by multiple factors including variants in DNA repair genes (Ponnaiya, Cornforth et al. 1997; Yu, Okayasu et al. 2001; Yin, Menendez et al. 2012), RONS (Dayal, Martin et al. 2008), estrogen (Kutanzi and Kovalchuk 2013), caspases (Liu, He et al. 2015), and telomeres (Sishc, Nelson et al. 2015).

DNA damage can be studied in isolated DNA, fixed cells, or living cells. Types of damage that can be detected include single and double strand breaks, nucleotide damage, complex damage, and chromosomal or telomere damage. The OECD test guideline for DNA synthesis Test No. 486 (OECD 1997) detects nucleotide excision repair, so it will reflect the formation of bulky DNA adducts but not the majority of oxidative damage to nucleotides, which is typically repaired via the Base Excision Repair pathway. The OECD test guideline alkaline comet assay Test No. 489 (OECD 2016) detects single and double strand breaks, including those arising from repair as well as some (alkali sensitive) nucleotide lesions including some lesions from oxidative damage. OECD tests for chromosomal damage and micronuclei Test No. 473, 475, 483, and 487 measure longer term effects of DNA damage but these tests require the damaged cell to subsequently undergo replication (OECD 2016; OECD 2016; OECD 2016; OECD 2016).  They can therefore reflect a wider range of sources of DNA damage including changes in mitosis. Finally, tests for mutations reveal past DNA damage that resulted in a heritable change, and these are described in the key event ‘Increase in Mutation’. Many other (non-test guideline) techniques have been used to examine specific forms of DNA damage (Table 1). Double strand breaks are commonly reported because of the significant risk attributed to breaks and the relative ease of detecting and quantifying them. Historically, single and double strand breaks were measured using gel electrophoresis, but are now commonly visualized microscopically using fluorescent or other labeled probes for double and single strand break repair such as H2AX and XRCC2.  Base lesions can also be detected using labeled probes for base excision repair enzymes, or by chemical methods such as mass spectroscopy. Refinements on these methods can be used to characterize complex or clustered damage, in which various forms of damage occur in close proximity on a DNA molecule (Lorat, Timm et al. 2016; Nikitaki, Nikolov et al. 2016). Certain challenges are common to all methods of detecting DNA damage. In the time required to initiate the detection method, some DNA may already be repaired, leading to undercounting of damage. On the other hand, apoptotic DSBs may be incorrectly included in a measurement of direct (non-apoptotic) induction of DSB damage unless controlled. All methods have difficulty distinguishing individual components of clustered lesions, and microscopic methods may undercount disparate breaks that are processed together in repair centers (Barnard, Bouffler et al. 2013). Methods that use isolated DNA (gel electrophoresis, analytical chemistry) are vulnerable to artifacts and must ensure that the DNA sample is protected from oxidative damage during extraction (Pernot, Hall et al. 2012; Barnard, Bouffler et al. 2013; Ravanat, Breton et al. 2014). Table 1. Common methods of detecting DNA damage <table border="1" cellpadding="0" cellspacing="0"> <tbody> <tr> <td style="height:22px; width:127px"> Target </td> <td style="height:22px; width:167px"> Name </td> <td style="height:22px; width:133px"> Method </td> <td style="height:22px; width:211px"> Strengths/Weaknesses </td> </tr> <tr> <td style="height:22px; width:127px"> Nucleotide damage </td> <td style="height:22px; width:167px"> Single cell gel electrophoresis (comet assay) with restriction enzymes (Collins 2004) </td> <td style="height:22px; width:133px"> Gel electrophoresis   </td> <td style="height:22px; width:211px"> A variant of the comet assay in which restriction enzymes allow the identification of different types of nucleotide damage. The comet assay is more sensitive than PFGE, detecting damage from 0.1 Gy ionizing radiation (Pernot, Hall et al. 2012). A reproducible high-throughput application of the assay is available (Ge, Prasongtanakij et al. 2014; Sykora, Witt et al. 2018), and the test requires only a small (single cell) sample. Requires destruction of the cell. </td> </tr> <tr> <td style="height:22px; width:127px"> Nucleotide damage </td> <td style="height:22px; width:167px"> Labeled probes including Biotrin OxyDNA and anti- 8-oxoguanine-DNA glycosylase (OGG1) for oxidative damage and AP endonuclease (APE1) for Base Excision Repair of less bulky lesions such as oxidative damage. </td> <td style="height:22px; width:133px"> Microscopy, FACS </td> <td style="height:22px; width:211px"> Most useful with FACS or other measures of average or relative intensity, as locations and numbers of damaged nucleotides can be difficult to distinguish using fluorescence microscopy. (Ogawa, Kobayashi et al. 2003; Nikitaki, Nikolov et al. 2016). </td> </tr> <tr> <td style="height:22px; width:127px"> Nucleotide damage </td> <td style="height:22px; width:167px"> High performance liquid chromatography (HPLC), tandem mass spectrometry (MS/MS) </td> <td style="height:22px; width:133px"> Analytical chemistry </td> <td style="height:22px; width:211px"> Capable of quantifying low levels of specific nucleotide lesions (Madugundu, Cadet et al. 2014; Ravanat, Breton et al. 2014). Requires destruction of the cell. </td> </tr> <tr> <td style="height:22px; width:127px"> Nucleotide damage </td> <td style="height:22px; width:167px"> Unscheduled DNA synthesis test OECD Test Guideline 486 (OECD 1997) </td> <td style="height:22px; width:133px"> Autoradiography </td> <td style="height:22px; width:211px"> Measures DNA damage that is repaired using Nucleotide Excision Repair - mostly bulky adducts (OECD (Organisation for Economic Co-operation and Development) 2016). </td> </tr> <tr> <td style="height:22px; width:127px"> Non-specific DNA strand breaks </td> <td style="height:22px; width:167px"> Single cell gel electrophoresis (comet assay), alkali conditions OECD Test Guideline 489 (OECD 2016) </td> <td style="height:22px; width:133px"> Gel electrophoresis </td> <td style="height:22px; width:211px"> When used in alkali conditions, the comet assay reveals single and double strand breaks and alkali-sensitive nucleotide lesions. See single cell gel electrophoresis (comet assay) with restriction enzymes above for further comments.     </td> </tr> <tr> <td style="height:22px; width:127px"> Single strand breaks </td> <td style="height:22px; width:167px"> Labeled probe pXRCC1 (Lorat, Brunner et al. 2015) </td> <td style="height:22px; width:133px"> Microscopy </td> <td style="height:22px; width:211px"> Fluorescent probes can label single strand breaks in cells, while immunogold labeling is able to distinguish multiple single strand breaks in clusters (Lorat, Timm et al. 2016; Nikitaki, Nikolov et al. 2016). </td> </tr> <tr> <td style="height:22px; width:127px"> Double strand breaks </td> <td style="height:22px; width:167px"> Single cell gel electrophoresis (comet assay), neutral conditions </td> <td style="height:22px; width:133px"> Gel electrophoresis </td> <td style="height:22px; width:211px"> Neutral conditions help minimize the release of single strand breaks coiled DNA and alkali lesions, allowing the measurement of double strand breaks. Since single strand breaks can still appear, assay is not very sensitive or specific to double strand breaks (Pernot, Hall et al. 2012). See single cell gel electrophoresis (comet assay) with restriction enzymes above for further comments. </td> </tr> <tr> <td style="height:22px; width:127px"> Double strand breaks </td> <td style="height:22px; width:167px"> Pulsed field gel electrophoresis (PFGE) </td> <td style="height:22px; width:133px"> Gel electrophoresis </td> <td style="height:22px; width:211px"> Permits the quantitative measurement of double strand breaks, and can be combined with immunoblotting to detect DNA-associated proteins (Lobrich, Rydberg et al. 1995; Kawashima, Yamaguchi et al. 2017). Considered less sensitive than comet assay, but detected damage from 0.25 Gy ionizing radiation (Gradzka and Iwanenko 2005). Requires destruction of the cell. </td> </tr> <tr> <td style="height:22px; width:127px"> Double strand breaks </td> <td style="height:22px; width:167px"> Labeled probes including phosphorylated H2AX, 53BP1, Ku70, ATM (Lorat, Brunner et al. 2015) </td> <td style="height:22px; width:133px"> Microscopy </td> <td style="height:22px; width:211px"> Fluorescent probes can label individual double breaks in cells allowing for quantification, with immunogold labeling resolving breaks in clusters (Lorat, Timm et al. 2016; Nikitaki, Nikolov et al. 2016). Sensitive: detects damage from 0.001 Gy ionizing radiation (Rothkamm and Lobrich 2003; Ojima, Ban et al. 2008). </td> </tr> <tr> <td style="height:22px; width:127px"> Chromosomal damage </td> <td style="height:22px; width:167px"> Chromosomal aberrations and micronuclei OECD Test Guidelines 473, 475, 483, and 487 (OECD 2016; OECD 2016; OECD 2016; OECD 2016) </td> <td style="height:22px; width:133px"> Microscopy </td> <td style="height:22px; width:211px"> Detects major DNA damage resulting from large breaks and rearrangements, or mitotic failures. Damage does not appear until DNA undergoes mitosis, so slower and limited to damage in replicating cells. Insensitive tosmall deletions and substitutions. </td> </tr> </tbody> </table>

CL:0000255

CL eukaryotic cell

<a name="_ENREF_1">Barnard, S., S. Bouffler, et al. (2013). "The shape of the radiation dose response for DNA double-strand break induction and repair." Genome integrity 4(1): 1.</a> <a name="_ENREF_2">Behjati, S., G. Gundem, et al. (2016). "Mutational signatures of ionizing radiation in second malignancies." Nat Commun 7: 12605.</a> <a name="_ENREF_3">Chaudhry, M. A. and M. Weinfeld (1997). "Reactivity of human apurinic/apyrimidinic endonuclease and Escherichia coli exonuclease III with bistranded abasic sites in DNA." The Journal of biological chemistry 272(25): 15650-15655.</a> <a name="_ENREF_4">Collins, A. R. (2004). "The comet assay for DNA damage and repair: principles, applications, and limitations." Molecular biotechnology 26(3): 249-261.</a> <a name="_ENREF_5">David, S. S., V. L. O'Shea, et al. (2007). "Base-excision repair of oxidative DNA damage." Nature 447(7147): 941-950.</a> <a name="_ENREF_6">Dayal, D., S. M. Martin, et al. (2008). "Hydrogen peroxide mediates the radiation-induced mutator phenotype in mammalian cells." Biochem J 413(1): 185-191.</a> <a name="_ENREF_7">Ge, J., S. Prasongtanakij, et al. (2014). "CometChip: a high-throughput 96-well platform for measuring DNA damage in microarrayed human cells." Journal of visualized experiments : JoVE(92): e50607.</a> <a name="_ENREF_8">Gradzka, I. and T. Iwanenko (2005). "A non-radioactive, PFGE-based assay for low levels of DNA double-strand breaks in mammalian cells." DNA repair 4(10): 1129-1139.</a> <a name="_ENREF_9">Haag, J. D., L. C. Hsu, et al. (1996). "Allelic imbalance in mammary carcinomas induced by either 7,12-dimethylbenz[a]anthracene or ionizing radiation in rats carrying genes conferring differential susceptibilities to mammary carcinogenesis." Mol Carcinog 17(3): 134-143.</a> <a name="_ENREF_10">Kawashima, Y., N. Yamaguchi, et al. (2017). "Detection of DNA double-strand breaks by pulsed-field gel electrophoresis." Genes to cells : devoted to molecular & cellular mechanisms 22(1): 84-93.</a> <a name="_ENREF_11">Kuhne, M., K. Rothkamm, et al. (2000). "No dose-dependence of DNA double-strand break misrejoining following alpha-particle irradiation." International journal of radiation biology 76(7): 891-900.</a> <a name="_ENREF_12">Kutanzi, K. and O. Kovalchuk (2013). "Exposure to estrogen and ionizing radiation causes epigenetic dysregulation, activation of mitogen-activated protein kinase pathways, and genome instability in the mammary gland of ACI rats." Cancer Biol Ther 14(7): 564-573.</a> <a name="_ENREF_13">Kuzminov, A. (2001). "Single-strand interruptions in replicating chromosomes cause double-strand breaks." Proceedings of the National Academy of Sciences of the United States of America 98(15): 8241-8246.</a> <a name="_ENREF_14">Liu, X., Y. He, et al. (2015). "Caspase-3 promotes genetic instability and carcinogenesis." Mol Cell 58(2): 284-296.</a> <a name="_ENREF_15">Lobrich, M., B. Rydberg, et al. (1995). "Repair of x-ray-induced DNA double-strand breaks in specific Not I restriction fragments in human fibroblasts: joining of correct and incorrect ends." Proceedings of the National Academy of Sciences of the United States of America 92(26): 12050-12054.</a> <a name="_ENREF_16">Lorat, Y., C. U. Brunner, et al. (2015). "Nanoscale analysis of clustered DNA damage after high-LET irradiation by quantitative electron microscopy--the heavy burden to repair." DNA repair 28: 93-106.</a> <a name="_ENREF_17">Lorat, Y., S. Timm, et al. (2016). "Clustered double-strand breaks in heterochromatin perturb DNA repair after high linear energy transfer irradiation." Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 121(1): 154-161.</a> <a name="_ENREF_18">Madugundu, G. S., J. Cadet, et al. (2014). "Hydroxyl-radical-induced oxidation of 5-methylcytosine in isolated and cellular DNA." Nucleic acids research 42(11): 7450-7460.</a> <a name="_ENREF_19">Morishita, M., T. Muramatsu, et al. (2016). "Chromothripsis-like chromosomal rearrangements induced by ionizing radiation using proton microbeam irradiation system." Oncotarget 7(9): 10182-10192.</a> <a name="_ENREF_20">Murnane, J. P. (2012). "Telomere dysfunction and chromosome instability." Mutation research 730(1-2): 28-36.</a> <a name="_ENREF_21">Nikitaki, Z., V. Nikolov, et al. (2016). "Measurement of complex DNA damage induction and repair in human cellular systems after exposure to ionizing radiations of varying linear energy transfer (LET)." Free radical research 50(sup1): S64-S78.</a> <a name="_ENREF_22">OECD (1997). Test No. 486: Unscheduled DNA Synthesis (UDS) Test with Mammalian Liver Cells in vivo.</a> <a name="_ENREF_23">OECD (2016). Test No. 473: In Vitro Mammalian Chromosomal Aberration Test.</a> <a name="_ENREF_24">OECD (2016). Test No. 475: Mammalian Bone Marrow Chromosomal Aberration Test.</a> <a name="_ENREF_25">OECD (2016). Test No. 483: Mammalian Spermatogonial Chromosomal Aberration Test.</a> <a name="_ENREF_26">OECD (2016). Test No. 487: In Vitro Mammalian Cell Micronucleus Test.</a> <a name="_ENREF_27">OECD (2016). Test No. 489: In Vivo Mammalian Alkaline Comet Assay.</a> <a name="_ENREF_28">OECD (Organisation for Economic Co-operation and Development) (2016). Overview of the set of OECD Genetic Toxicology Test Guidelines and updates performed in 2014–2015. No. 238.</a> <a name="_ENREF_29">Ogawa, Y., T. Kobayashi, et al. (2003). "Radiation-induced oxidative DNA damage, 8-oxoguanine, in human peripheral T cells." International journal of molecular medicine 11(1): 27-32.</a> <a name="_ENREF_30">Ojima, M., N. Ban, et al. (2008). "DNA double-strand breaks induced by very low X-ray doses are largely due to bystander effects." Radiation research 170(3): 365-371.</a> <a name="_ENREF_31">Pernot, E., J. Hall, et al. (2012). "Ionizing radiation biomarkers for potential use in epidemiological studies." Mutation research 751(2): 258-286.</a> <a name="_ENREF_32">Pinto, M., K. M. Prise, et al. (2005). "Evidence for complexity at the nanometer scale of radiation-induced DNA DSBs as a determinant of rejoining kinetics." Radiation research 164(1): 73-85.</a> <a name="_ENREF_33">Ponnaiya, B., M. N. Cornforth, et al. (1997). "Induction of chromosomal instability in human mammary cells by neutrons and gamma rays." Radiation research 147(3): 288-294.</a> <a name="_ENREF_34">Ponnaiya, B., M. N. Cornforth, et al. (1997). "Radiation-induced chromosomal instability in BALB/c and C57BL/6 mice: the difference is as clear as black and white." Radiation research 147(2): 121-125.</a> <a name="_ENREF_35">Ravanat, J. L., J. Breton, et al. (2014). "Radiation-mediated formation of complex damage to DNA: a chemical aspect overview." Br J Radiol 87(1035): 20130715.</a> <a name="_ENREF_36">Regulus, P., B. Duroux, et al. (2007). "Oxidation of the sugar moiety of DNA by ionizing radiation or bleomycin could induce the formation of a cluster DNA lesion." Proceedings of the National Academy of Sciences of the United States of America 104(35): 14032-14037.</a> <a name="_ENREF_37">Rothkamm, K. and M. Lobrich (2003). "Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses." Proceedings of the National Academy of Sciences of the United States of America 100(9): 5057-5062.</a> <a name="_ENREF_38">Rydberg, B., B. Cooper, et al. (2005). "Dose-dependent misrejoining of radiation-induced DNA double-strand breaks in human fibroblasts: experimental and theoretical study for high- and low-LET radiation." Radiation research 163(5): 526-534.</a> <a name="_ENREF_39">Sharma, V., L. B. Collins, et al. (2016). "Oxidative stress at low levels can induce clustered DNA lesions leading to NHEJ mediated mutations." Oncotarget 7(18): 25377-25390.</a> <a name="_ENREF_40">Shiraishi, I., N. Shikazono, et al. (2017). "Efficiency of radiation-induced base lesion excision and the order of enzymatic treatment." International journal of radiation biology 93(3): 295-302.</a> <a name="_ENREF_41">Sishc, B. J., C. B. Nelson, et al. (2015). "Telomeres and Telomerase in the Radiation Response: Implications for Instability, Reprograming, and Carcinogenesis." Front Oncol 5: 257.</a> <a name="_ENREF_42">Stenerlow, B., E. Hoglund, et al. (2000). "Rejoining of DNA fragments produced by radiations of different linear energy transfer." International journal of radiation biology 76(4): 549-557.</a> <a name="_ENREF_43">Sykora, P., K. L. Witt, et al. (2018). "Next generation high throughput DNA damage detection platform for genotoxic compound screening." Sci Rep 8(1): 2771.</a> <a name="_ENREF_44">Unger, K., J. Wienberg, et al. (2010). "Novel gene rearrangements in transformed breast cells identified by high-resolution breakpoint analysis of chromosomal aberrations." Endocrine-related cancer 17(1): 87-98.</a> <a name="_ENREF_45">Vispe, S. and M. S. Satoh (2000). "DNA repair patch-mediated double strand DNA break formation in human cells." The Journal of biological chemistry 275(35): 27386-27392.</a> <a name="_ENREF_46">Yang, T.-H., L. M. Craise, et al. (1992). "Chromosomal changes in cultured human epithelial cells transformed by low- and high-LET radiation." Adv Space Res 12(2-3): 127-136.</a> <a name="_ENREF_47">Yang, T. C., K. A. Georgy, et al. (1997). "Initiation of oncogenic transformation in human mammary epithelial cells by charged particles." Radiat Oncol Investig 5(3): 134-138.</a> <a name="_ENREF_48">Yin, Z., D. Menendez, et al. (2012). "RAP80 is critical in maintaining genomic stability and suppressing tumor development." Cancer research 72(19): 5080-5090.</a> <a name="_ENREF_49">Yu, Y., R. Okayasu, et al. (2001). "Elevated breast cancer risk in irradiated BALB/c mice associates with unique functional polymorphism of the Prkdc (DNA-dependent protein kinase catalytic subunit) gene." Cancer Res 61(5): 1820-1824.</a> AOPWiki 2016-11-29T18:41:30

2019-05-08T12:28:46

Increase, Apoptosis

Cellular

AOPWiki 2017-04-15T16:17:34

2017-04-15T16:17:34

Decreased spermatogenesis

Organ

AOPWiki 2020-07-13T04:32:49

2021-02-09T08:36:06

Decrease, Fecundity

Individual

AOPWiki 2016-11-29T18:41:24

2018-06-12T04:39:53

Decrease, Reproduction

Individual

AOPWiki 2021-04-11T08:21:37

2021-04-11T17:38:35

Decrease, Population growth rate

Population

A population can be defined as a group of interbreeding organisms, all of the same species, occupying a specific space during a specific time (Vandermeer and Goldberg 2003, Gotelli 2008).  As the population is the biological level of organization that is often the focus of ecological risk assessments, population growth rate (and hence population size over time) is important to consider within the context of applied conservation practices. If N is the size of the population and t is time, then the population growth rate (dN/dt) is proportional to the instantaneous rate of increase, r, which measures the per capita rate of population increase over a short time interval. Therefore, r, is a difference between the instantaneous birth rate (number of births per individual per unit of time; b) and the instantaneous death rate (number of deaths per individual per unit of time; d) [Equation 1]. Because  r is an instantaneous rate, its units can be changed via division.  For example, as there are 24 hours in a day, an r of 24 individuals/(individual x day) is equal to an r of 1 individual/(individual/hour) (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020).  Equation 1:  r = b - d This key event refers to scenarios where r < 0 (instantaneous death rate exceeds instantaneous birth rate). Examining r in the context of population growth rate: ● A population will decrease to extinction when the instantaneous death rate exceeds the instantaneous birth rate (r < 0).              ● The smaller the value of r below 1, the faster the population will decrease to zero.   ● A population will increase when resources are available and the instantaneous birth rate exceeds the instantaneous death rate (r > 0)            ● The larger the value that r exceeds 1, the faster the population can increase over time       ● A population will neither increase or decrease when the population growth rate equals 0 (either due to N = 0, or if the per capita birth and death rates are exactly balanced).  For example, the per capita birth and death rates could become exactly balanced due to density dependence and/or to the effect of a stressor that reduces survival and/or reproduction (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020).      Effects incurred on a population from a chemical or non-chemical stressor could have an impact directly upon birth rate (reproduction) and/or death rate (survival), thereby causing a decline in population growth rate.   ● Example of direct effect on r:  Exposure to 17b-trenbolone reduced reproduction (i.e., reduced b) in the fathead minnow over 21 days at water concentrations ranging from 0.0015 to about 41 mg/L (Ankley et al. 2001; Miller and Ankley 2004).              Alternatively, a stressor could indirectly impact survival and/or reproduction.   ● Example of indirect effect on r:  Exposure of non-sexually differentiated early life stage fathead minnow to the fungicide prochloraz has been shown to produce male-biased sex ratios based on gonad differentiation, and resulted in projected change in population growth rate (decrease in reproduction due to a decrease in females and thus recruitment) using a population model. (Holbech et al., 2012; Miller et al. 2022) Density dependence can be an important consideration: ● The effect of density dependence depends upon the quantity of resources present within a landscape.  A change in available resources could increase or decrease the effect of density dependence and therefore cause a change in population growth rate via indirectly impacting survival and/or reproduction.   ● This concept could be thought of in terms of community level interactions whereby one species is not impacted but a competitor species is impacted by a chemical stressor resulting in a greater availability of resources for the unimpacted species.  In this scenario, the impacted species would experience a decline in population growth rate. The unimpacted species would experience an increase in population growth rate (due to a smaller density dependent effect upon population growth rate for that species).        Closed versus open systems: ● The above discussion relates to closed systems (there is no movement of individuals between population sites) and thus a declining population growth rate cannot be augmented by immigration.   ● When individuals depart (emigrate out of a population) the loss will diminish population growth rate.   Population growth rate applies to all organisms, both sexes, and all life stages.

Population growth rate (instantaneous growth rate) can be measured by sampling a population over an interval of time (i.e. from time t = 0 to time t = 1).  The interval of time should be selected to correspond to the life history of the species of interest (i.e. will be different for rapidly growing versus slow growing populations). The population growth rate, r, can be determined by taking the difference (subtracting) between the initial population size, Nt=0 (population size at time t=0), and the population size at the end of the interval, Nt=1 (population size at time t = 1), and then subsequently dividing by the initial population size.  Equation 2:  r = (Nt=1 - Nt=0) / Nt=0 The diversity of forms, sizes, and life histories among species has led to the development of a vast number of field techniques for estimation of population size and thus population growth over time (Bookhout 1994, McComb et al. 2021).   ● For stationary species an observational strategy may involve dividing a habitat into units. After setting up the units, samples are performed throughout the habitat at a select number of units (determined using a statistical sampling design) over a time interval (at time t = 0 and again at time t = 1), and the total number of organisms within each unit are counted. The numbers recorded are assumed to be representative for the habitat overall, and can be used to estimate the population growth rate within the entire habitat over the time interval.   ● For species that are mobile throughout a large range, a strategy such as using a mark-recapture method may be employed (i.e. tags, bands, transmitters) to determine a count over a time interval (at time = 0 and again at time =1).    Population growth rate can also be estimated using mathematical model constructs (for example, ranging from simple differential equations to complex age or stage structured matrix projection models and individual based modeling approaches), and may assume a linear or nonlinear population increase over time (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020). The AOP framework can be used to support the translation of pathway-specific mechanistic data into responses relevant to population models and output from the population models, such as changing (declining) population growth rate, can be used to assess and manage risks of chemicals (Kramer et al. 2011). As such, this translational capability can increase the capacity and efficiency of safety assessments both for single chemicals and chemical mixtures (Kramer et al. 2011).   Some examples of modeling constructs used to investigate population growth rate: ● A modeling construct could be based upon laboratory toxicity tests to determine effect(s) that are then linked to the population model and used to estimate decline in population growth rate.  Miller et al. (2007) used concentration–response data from short term reproductive assays with fathead minnow (Pimephales promelas) exposed to endocrine disrupting chemicals in combination with a population model to examine projected alterations in population growth rate.   ● A model construct could be based upon a combination of effects-based monitoring at field sites (informed by an AOP) and a population model.  Miller et al. (2015) applied a population model informed by an AOP to project declines in population growth rate for white suckers (Catostomus commersoni) using observed changes in sex steroid synthesis in fish exposed to a complex pulp and paper mill effluent in Jackfish Bay, Ontario, Canada. Furthermore, a model construct could be comprised of a series of quantitative models using KERs that culminates in the estimation of change (decline) in population growth rate.   ● A quantitative adverse outcome pathway (qAOP) has been defined as a mathematical construct that models the dose–response or response–response relationships of all KERs described in an AOP (Conolly et al. 2017, Perkins et al. 2019). Conolly et al. (2017) developed a qAOP using data generated with the aromatase inhibitor fadrozole as a stressor and then used it to predict potential population‐level impacts (including decline in population growth rate). The qAOP modeled aromatase inhibition (the molecular initiating event) leading to reproductive dysfunction in fathead minnow (Pimephales promelas) using 3 computational models: a hypothalamus–pituitary–gonadal axis model (based on ordinary differential equations) of aromatase inhibition leading to decreased vitellogenin production (Cheng et al. 2016), a stochastic model of oocyte growth dynamics relating vitellogenin levels to clutch size and spawning intervals (Watanabe et al. 2016), and a population model (Miller et al. 2007). ● Dynamic energy budget (DEB) models offer a methodology that reverse engineers stressor effects on growth, reproduction, and/or survival into modular characterizations related to the acquisition and processing of energy resources (Nisbet et al. 2000, Nisbet et al. 2011).  Murphy et al. (2018) developed a conceptual model to link DEB and AOP models by interpreting AOP key events as measures of damage-inducing processes affecting DEB variables and rates. ● Endogenous Lifecycle Models (ELMs), capture the endogenous lifecycle processes of growth, development, survival, and reproduction and integrate these to estimate and predict expected fitness (Etterson and Ankley, 2021).  AOPs can be used to inform ELMs of effects of chemical stressors on the vital rates that determine fitness, and to decide what hierarchical models of endogenous systems should be included within an ELM (Etterson and Ankley, 2021).

Consideration of population size and changes in population size over time is potentially relevant to all living organisms.

Not Specified Unspecific

Not Specified

All life stages

High

<ul> <li>Ankley GT, Jensen KM, Makynen EA, Kahl MD, Korte JJ, Hornung MW, Henry TR, Denny JS, Leino RL, Wilson VS, Cardon MD, Hartig PC, Gray LE. 2003. Effects of the androgenic growth promoter 17b-trenbolone on fecundity and reproductive endocrinology of the fathead minnow. Environ. Toxicol. Chem. 22: 1350–1360.</li> <li>Bookhout TA. 1994. Research and management techniques for wildlife and habitats. The Wildlife Society, Bethesda, Maryland. 740 pp.</li> <li>Caswell H. 2001. Matrix Population Models. Sinauer Associates, Inc., Sunderland, MA, USA</li> <li>Cheng WY, Zhang Q, Schroeder A, Villeneuve DL, Ankley GT, Conolly R.  2016.  Computational modeling of plasma vitellogenin alterations in response to aromatase inhibition in fathead minnows. Toxicol Sci 154: 78–89.</li> <li>Conolly RB, Ankley GT, Cheng W-Y, Mayo ML, Miller DH, Perkins EJ, Villeneuve DL, Watanabe KH. 2017. Quantitative adverse outcome pathways and their application to predictive toxicology. Environ. Sci. Technol. 51:  4661-4672.</li> <li>Etterson MA, Ankley GT.  2021.  Endogenous Lifecycle Models for Chemical Risk Assessment. Environ. Sci. Technol. 55:  15596-15608. </li> <li>Gotelli NJ, 2008. A Primer of Ecology. Sinauer Associates, Inc., Sunderland, MA, USA.</li> <li>Holbech H, Kinnberg KL, Brande-Lavridsen N, Bjerregaard P, Petersen GI, Norrgren L, Orn S, Braunbeck T, Baumann L, Bomke C, Dorgerloh M, Bruns E, Ruehl-Fehlert C, Green JW, Springer TA, Gourmelon A. 2012 Comparison of zebrafish (Danio rerio) and fathead minnow (Pimephales promelas) as test species in the Fish Sexual Development Test (FSDT). Comp. Biochem. Physiol. C Toxicol. Pharmacol. 155:  407–415.</li> <li>Kramer VJ, Etterson MA, Hecker M, Murphy CA, Roesijadi G, Spade DJ, Stromberg JA, Wang M, Ankley GT.  2011.  Adverse outcome pathways and risk assessment: Bridging to population level effects.  Environ. Toxicol. Chem. 30, 64-76.</li> <li>McComb B, Zuckerberg B, Vesely D, Jordan C.  2021.  Monitoring Animal Populations and their Habitats: A Practitioner's Guide.  Pressbooks, Oregon State University, Corvallis, OR Version 1.13, 296 pp. </li> <li>Miller DH, Villeneuve DL, Santana Rodriguez KJ, Ankley GT. 2022.  A multidimensional matrix model for predicting the effect of male biased sex ratios on fish populations. Environmental Toxicology and Chemistry 41(4): 1066-1077.</li> <li>Miller DH, Tietge JE, McMaster ME, Munkittrick KR, Xia X, Griesmer DA, Ankley GT. 2015. Linking mechanistic toxicology to population models in forecasting recovery from chemical stress: A case study from Jackfish Bay, Ontario, Canada. Environmental Toxicology and Chemistry 34(7):  1623-1633.</li> <li>Miller DH, Jensen KM, Villeneuve DE, Kahl MD, Makynen EA, Durhan EJ, Ankley GT. 2007. Linkage of biochemical responses to population-level effects: A case study with vitellogenin in the fathead minnow (Pimephales promelas). Environ Toxicol Chem 26:  521–527.</li> <li>Miller DH, Ankley GT. 2004. Modeling impacts on populations: Fathead minnow (Pimephales promelas) exposure to the endocrine disruptor 17b-trenbolone as a case study. Ecotox Environ Saf 59: 1–9.</li> <li>Murphy CA, Nisbet RM, Antczak P, Garcia-Reyero N, Gergs A, Lika K, Mathews T, Muller EB, Nacci D, Peace A, Remien CH, Schultz IR, Stevenson LM, Watanabe KH.  2018.  Incorporating suborganismal processes into dynamic energy budget models for ecological risk assessment.  Integrated Environmental Assessment and Management 14(5):  615–624.</li> <li>Murray DL, Sandercock BK (editors).  2020.  Population ecology in practice.  Wiley-Blackwell, Oxford UK, 448 pp.</li> <li>Nisbet RM, Jusup M, Klanjscek T, Pecquerie L.  2011.  Integrating dynamic energy budget (DEB) theory with traditional bioenergetic models.  The Journal of Experimental Biology 215: 892-902.</li> <li>Nisbet RM, Muller EB, Lika K, Kooijman SALM. 2000. From molecules to ecosystems through dynamic energy budgets. J Anim Ecol 69:  913–926.</li> <li>Perkins EJ,  Ashauer R, Burgoon L, Conolly R, Landesmann B,, Mackay C, Murphy CA, Pollesch N, Wheeler JR, Zupanic A, Scholzk S.  2019.  Building and applying quantitative adverse outcome pathway models for chemical hazard and risk assessment.  Environmental Toxicology and Chemistry 38(9): 1850–1865. </li> <li>Vandermeer JH, Goldberg DE. 2003.  Population ecology: first principles.  Princeton University Press, Princeton NJ, 304 pp.</li> <li>Villeneuve DL, Crump D, Garcia-Reyero N, Hecker M, Hutchinson TH, LaLone CA, Landesmann B, Lattieri T, Munn S, Nepelska M, Ottinger MA, Vergauwen L, Whelan M. Adverse outcome pathway (AOP) development 1: Strategies and principles. Toxicol Sci. 2014: 142:312–320</li> <li>Watanabe KH, Mayo M, Jensen KM, Villeneuve DL, Ankley GT, Perkins EJ.  2016.  Predicting fecundity of fathead minnows (Pimephales promelas) exposed to endocrine‐disrupting chemicals using a MATLAB(R)‐based model of oocyte growth dynamics. PLoS One 11:  e0146594.</li> </ul> AOPWiki 2016-11-29T18:41:24

2023-01-03T09:09:06

Increase, Oxidative Stress

Molecular

Oxidative stress is defined as an imbalance in the production of reactive oxygen species (ROS) and antioxidant defenses. High levels of oxidizing free radicals can be very damaging to cells and molecules within the cell.  As a result, the cell has important defense mechanisms to protect itself from ROS. For example, Nrf2 is a transcription factor and master regulator of the oxidative stress response. During periods of oxidative stress, Nrf2-dependent changes in gene expression are important in regaining cellular homeostasis (Nguyen, et al., 2009) and can be used as indicators of the presence of oxidative stress in the cell.  In addition to the directly damaging actions of ROS, cellular oxidative stress also changes cellular activities on a molecular level. Redox sensitive proteins have altered physiology in the presence and absence of ROS, which is caused by the oxidation of sulfhydryls to disulfides on neighboring amino acids (Antelmann & Helmann 2011). Importantly Keap1, the negative regulator of Nrf2, is regulated in this manner (Itoh, et al. 2010).  ROS also undermine the mitochondrial defense system from oxidative damage. The antioxidant systems consist of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, as well as antioxidants such as α-tocopherol and ubiquinol, or antioxidant vitamins and minerals including vitamin E, C, carotene, lutein, zeaxanthin, selenium, and zinc (Fletcher, 2010). The enzymes, vitamins and minerals catalyze the conversion of ROS to non-toxic molecules such as water and O2. However, these antioxidant systems are not perfect and endogenous metabolic processes and/or exogenous oxidative influences can trigger cumulative oxidative injuries to the mitochondria, causing a decline in their functionality and efficiency, which further promotes cellular oxidative stress (Balasubramanian, 2000; Ganea & Harding, 2006; Guo et al., 2013; Karimi et al., 2017).   However, an emerging viewpoint suggests that ROS-induced modifications may not be as detrimental as previously thought, but rather contribute to signaling processes (Foyer et al., 2017).    Sources of ROS Production  Direct Sources: Direct sources involve the deposition of energy onto water molecules, breaking them into active radical species. When ionizing radiation hits water, it breaks it into hydrogen (H*) and hydroxyl (OH*) radicals by destroying its bonds. The hydrogen will create hydroxyperoxyl free radicals (HO2*) if oxygen is available, which can then react with another of itself to form hydrogen peroxide (H2O2) and more O2 (Elgazzar and Kazem, 2015). Antioxidant mechanisms are also affected by radiation, with catalase (CAT) and peroxidase (POD) levels rising as a result of exposure (Seen et al. 2018; Ahmad et al. 2021).   Indirect Sources: An indirect source of ROS is the mitochondria, which is one of the primary producers in eukaryotic cells (Powers et al., 2008).  As much as 2% of the electrons that should be going through the electron transport chain in the mitochondria escape, allowing them an opportunity to interact with surrounding structures. Electron-oxygen reactions result in free radical production, including the formation of hydrogen peroxide (H2O2) (Zhao et al., 2019). The electron transport chain, which also creates ROS, is activated by free adenosine diphosphate (ADP), O2, and inorganic phosphate (Pi) (Hargreaves et al. 2020; Raimondi et al. 2020; Vargas-Mendoza et al. 2021). The first and third complexes of the transport chain are the most relevant to mammalian ROS production (Raimondi et al., 2020). The mitochondria has its own set of DNA and it is a prime target of oxidative damage (Guo et al., 2013). ROS is also produced through nicotinamide adenine dinucleotide phosphate oxidase (Nox) stimulation, an event commenced by angiotensin II, a product/effector of the renin-angiotensin system (Nguyen Dinh Cat et al. 2013; Forrester et al. 2018). Other ROS producers include xanthine oxidase, immune cells (macrophage, neutrophils, monocytes, and eosinophils), phospholipase A2 (PLA2), monoamine oxidase (MAO), and carbon-based nanomaterials (Powers et al. 2008; Jacobsen et al. 2008; Vargas-Mendoza et al. 2021).

Oxidative Stress: Direct measurement of ROS is difficult because ROS are unstable. The presence of ROS can be assayed indirectly by measurement of cellular antioxidants, or by ROS-dependent cellular damage. Listed below are common methods for detecting the KE, however there may be other comparable methods that are not listed  <ul> <li>Detection of ROS by chemiluminescence (https://www.sciencedirect.com/science/article/abs/pii/S0165993606001683) </li> <li>Detection of ROS by chemiluminescence is also described in OECD TG 495 to assess phototoxic potential. </li> <li>Glutathione (GSH) depletion. GSH can be measured by assaying the ratio of reduced to oxidized glutathione (GSH:GSSG) using a commercially available kit (e.g., http://www.abcam.com/gshgssg-ratio-detection-assay-kit-fluorometric-green- ab138881.html). </li> <li>TBARS. Oxidative damage to lipids can be measured by assaying for lipid peroxidation using TBARS (thiobarbituric acid reactive substances) using a commercially available kit. </li> <li>8-oxo-dG. Oxidative damage to nucleic acids can be assayed by measuring 8-oxo-dG adducts (for which there are a number of ELISA based commercially available kits),or HPLC, described in Chepelev et al. (Chepelev, et al. 2015). </li> </ul>    Molecular Biology: Nrf2. Nrf2’s transcriptional activity is controlled post-translationally by oxidation of Keap1. Assay for Nrf2 activity include:  <ul> <li>Immunohistochemistry for increases in Nrf2 protein levels and translocation into the nucleus Western blot for increased Nrf2 protein levels </li> <li>Western blot of cytoplasmic and nuclear fractions to observe translocation of Nrf2 protein from the cytoplasm to the nucleus qPCR of Nrf2 target genes (e.g., Nqo1, Hmox-1, Gcl, Gst, Prx, TrxR, Srxn), or by commercially available pathway-based qPCR array (e.g., oxidative stress array from SABiosciences) </li> <li>Whole transcriptome profiling by microarray or RNA-seq followed by pathway analysis (in IPA, DAVID, metacore, etc.) for enrichment of the Nrf2 oxidative stress response pathway (e.g., Jackson et al. 2014) </li> <li>OECD TG422D describes an ARE-Nrf2 Luciferase test method </li> </ul> In general, there are a variety of commercially available colorimetric or fluorescent kits for detecting Nrf2 activation. <table border="1"> <tbody> <tr> <td> Assay Type & Measured Content  </td> <td> Description  </td> <td> Dose Range Studied  </td> <td> Assay Characteristics (Length/Ease of use/Accuracy)  </td> </tr> <tr> <td> ROS  Formation in the Mitochondria assay (Shaki et al., 2012)  </td> <td> “The mitochondrial ROS measurement was performed flow cytometry using DCFH-DA. Briefly, isolated kidney mitochondria were incubated with UA (0, 50, 100 and 200 µM) in respiration buffer containing (0.32 mM sucrose, 10mM Tris, 20 mM Mops, 50 µM EGTA, 0.5 mM MgCl2, 0.1 mM KH2PO4 and 5 mM sodium succinate) [32]. In the interval times of 5, 30 and 60 min following the UA addition, a sample was taken and DCFH-DA was added (final concentration, 10 µM) to mitochondria and was then incubated for 10 min.Uranyl acetate-induced ROS generation in isolated kidney mitochondria were determined through the flow cytometry (Partec, Deutschland) equipped with a 488-nm argon ion laser and supplied with the Flomax software and the signals were obtained using a 530-nm bandpass filter (FL-1 channel). Each determination is based on the mean fluorescence intensity of 15,000 counts.”    </td> <td> 0, 50,100 and 200 µM of Uranyl Acetate    </td> <td>  Long/ Easy High accuracy    </td> </tr> <tr> <td> Mitochondrial Antioxidant Content Assay Measuring GSH content (Shaki et al., 2012)    </td> <td> “GSH content was determined using DTNB as the indicator and spectrophotometer method for the isolated mitochondria. The mitochondrial fractions (0.5 mg protein/ml) were incubated with various concentrations of uranyl acetate for 1 h at 30 °C and then 0.1 ml of mitochondrial fractions was added into 0.1 mol/l of phosphate buffers and 0.04% DTNB in a total volume of 3.0 ml (pH 7.4). The developed yellow color was read at 412 nm on a spectrophotometer (UV-1601 PC, Shimadzu, Japan). GSH content was expressed as µg/mg protein.”  </td> <td> 0, 50,  100, or  200 µM  Uranyl Acetate  </td> <td>   </td> </tr> <tr> <td> H2O2 Production Assay Measuring H2O2 Production in isolated mitochondria (Heyno et al., 2008)    </td> <td> “Effect of CdCl2 and antimycin A (AA) on H2O2 production in isolated mitochondria from potato. H2O2 production was measured as scopoletin oxidation. Mitochondria were incubated for 30 min in the measuring buffer  (see the Materials and Methods) containing 0.5 mM succinate as an electron donor and 0.2 µM mesoxalonitrile 3‐chlorophenylhydrazone (CCCP) as an uncoupler, 10 U horseradish peroxidase and 5 µM scopoletin.”   </td> <td> 0, 10, 30  µM Cd2+     2 µM antimycin A  </td> <td>   </td> </tr> <tr> <td> Flow Cytometry ROS & Cell Viability (Kruiderig et al., 1997)    </td> <td> “For determination of ROS, samples taken at the indicated time points were directly transferred to FACScan tubes. Dih123 (10 mM, final concentration) was added and cells were incubated at 37°C in a humidified atmosphere (95% air/5% CO2) for 10 min. At t 5 9, propidium iodide (10 mM, final concentration) was added, and cells were analyzed by flow cytometry at 60 ml/min. Nonfluorescent Dih123 is cleaved by ROS to fluorescent R123 and detected by the FL1 detector as described above for Dc (Van de Water 1995)”“For determination of ROS, samples taken at the indicated time points were directly transferred to FACScan tubes. Dih123 (10 mM, final concentration) was added and cells were incubated at 37°C in a humidified atmosphere (95% air/5% CO2) for 10 min. At t 5 9, propidium iodide (10 mM, final concentration) was added, and cells were analyzed by flow cytometry at 60 ml/min. Nonfluorescent Dih123 is cleaved by ROS to fluorescent R123 and detected by the FL1 detector as described above for Dc (Van de Water 1995)”  </td> <td>   </td> <td>           Strong/easy medium  </td> </tr> <tr> <td> DCFH-DA  Assay Detection of hydrogen peroxide production (Yuan et al.,  2016)  </td> <td> Intracellular ROS production was measured using DCFH-DA as a probe. Hydrogen peroxide oxidizes DCFH to DCF. The probe is hydrolyzed intracellularly to DCFH carboxylate anion. No direct reaction with H2O2 to form fluorescent production.    </td> <td> 0-400  µM  </td> <td> Long/ Easy High accuracy  </td> </tr> <tr> <td> H2-DCF-DAAssay Detection of superoxide production (Thiebault etal., 2007)    </td> <td> This dye is a stable nonpolar compound which diffuses readily into the cells and yields H2-DCF. Intracellular OH or ONOO- react with H2-DCF when cells contain peroxides, to form the highly fluorescent compound DCF, which effluxes the cell. Fluorescence intensity of DCF is measured using a fluorescence spectrophotometer.  </td> <td> 0–600  µM  </td> <td> Long/ Easy High accuracy  </td> </tr> <tr> <td> CM-H2DCFDA  Assay (Eruslanov  & Kusmartsev, 2009)  </td> <td> The dye (CM-H2DCFDA) diffuses into the cell and is cleaved by esterases, the thiol reactive chlormethyl group reacts with intracellular glutathione which can be detected using flow cytometry.  </td> <td>   </td> <td> Long/Easy/ High Accuracy  </td> </tr> </tbody> </table>   <table border="1"> <tbody> <tr> <td> Method of Measurement   </td> <td> References   </td> <td> Description   </td> <td colspan="2"> OECD-Approved Assay  </td> </tr> <tr> <td> Chemiluminescence   </td> <td> (Lu, C. et al., 2006;   Griendling, K. K., et al., 2016)  </td> <td> ROS can induce electron transitions in molecules, leading to electronically excited products. When the electrons transition back to ground state, chemiluminescence is emitted and can be measured. Reagents such as luminol and lucigenin are commonly used to amplify the signal.   </td> <td colspan="2"> No    </td> </tr> <tr> <td> Spectrophotometry   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> NO has a short half-life. However, if it has been reduced to nitrite (NO2-), stable azocompounds can be formed via the Griess Reaction, and further measured by spectrophotometry.   </td> <td colspan="2"> No  </td> </tr> <tr> <td> Direct or Spin Trapping-Based electron paramagnetic resonance (EPR) Spectroscopy   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> The unpaired electrons (free radicals) found in ROS can be detected with EPR and is known as electron paramagnetic resonance. A variety of spin traps can be used.   </td> <td colspan="2"> No  </td> </tr> <tr> <td> Nitroblue Tetrazolium Assay   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> The Nitroblue Tetrazolium assay is used to measure O2.− levels. O2.− reduces nitroblue tetrazolium (a yellow dye) to formazan (a blue dye), and can be measured at 620 nm.   </td> <td colspan="2"> No  </td> </tr> <tr> <td> Fluorescence analysis of dihydroethidium (DHE) or Hydrocyans   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> Fluorescence analysis of DHE is used to measure O2.− levels.  O2.− is reduced to O2 as DHE is oxidized to 2-hydroxyethidium, and this reaction can be measured by fluorescence. Similarly, hydrocyans can be oxidized by any ROS, and measured via fluorescence.   </td> <td colspan="2"> No  </td> </tr> <tr> <td> Amplex Red Assay   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> Fluorescence analysis to measure extramitochondrial or extracellular H2O2 levels. In the presence of horseradish peroxidase and H2O2, Amplex Red is oxidized to resorufin, a fluorescent molecule measurable by plate reader.   </td> <td colspan="2"> No  </td> </tr> <tr> <td> Dichlorodihydrofluorescein Diacetate (DCFH-DA)   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> An indirect fluorescence analysis to measure intracellular H2O2 levels.  H2O2 interacts with peroxidase or heme proteins, which further react with DCFH, oxidizing it to dichlorofluorescein (DCF), a fluorescent product.   </td> <td colspan="2"> No  </td> </tr> <tr> <td> HyPer Probe   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> Fluorescent measurement of intracellular H2O2 levels. HyPer is a genetically encoded fluorescent sensor that can be used for in vivo and in situ imaging.   </td> <td colspan="2"> No  </td> </tr> <tr> <td> Cytochrome c Reduction Assay   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> The cytochrome c reduction assay is used to measure O2.− levels. O O2.− is reduced to O2 as ferricytochrome c is oxidized to ferrocytochrome c, and this reaction can be measured by an absorbance increase at 550 nm.   </td> <td colspan="2"> No  </td> </tr> <tr> <td> Proton-electron double-resonance imaging (PEDRI)   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> The redox state of tissue is detected through nuclear magnetic resonance/magnetic resonance imaging, with the use of a nitroxide spin probe or biradical molecule.   </td> <td colspan="2"> No              </td> </tr> <tr> <td> Glutathione (GSH) depletion   </td> <td> (Biesemann, N. et al., 2018)   </td> <td> A downstream target of the Nrf2 pathway is involved in GSH synthesis. As an indication of oxidation status, GSH can be measured by assaying the ratio of reduced to oxidized glutathione (GSH:GSSG) using a commercially available kit (e.g., <a href="http://www.abcam.com/gshgssg-ratio-detection-assay-kit-fluorometric-green-ab138881.html" rel="noreferrer noopener" target="_blank">http://www.abcam.com/gshgssg-ratio-detection-assay-kit-fluorometric-green-ab138881.html</a>).    </td> <td colspan="2"> No  </td> </tr> <tr> <td> Thiobarbituric acid reactive substances (TBARS)   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> Oxidative damage to lipids can be measured by assaying for lipid peroxidation with TBARS using a commercially available kit.    </td> <td colspan="2"> No  </td> </tr> <tr> <td> Protein oxidation (carbonylation)  </td> <td> (Azimzadeh et al., 2017; Azimzadeh et al., 2015; Ping et al., 2020)  </td> <td> Can be determined with ELISA or a commercial assay kit. Protein oxidation can indicate the level of oxidative stress.  </td> <td colspan="2"> No  </td> </tr> <tr> <td> Seahorse XFp Analyzer  </td> <td> Leung et al. 2018  </td> <td> The Seahorse XFp Analyzer provides information on mitochondrial function, oxidative stress, and metabolic dysfunction of viable cells by measuring respiration (oxygen consumption rate; OCR) and extracellular pH (extracellular acidification rate; ECAR).  </td> <td> No  </td> </tr> </tbody> </table>   Molecular Biology: Nrf2. Nrf2’s transcriptional activity is controlled post-translationally by oxidation of Keap1. Assays for Nrf2 activity include:   <table border="1"> <tbody> <tr> <td> Method of Measurement   </td> <td> References   </td> <td> Description   </td> <td> OECD-Approved Assay  </td> </tr> <tr> <td> Immunohistochemistry   </td> <td> (Amsen, D., de Visser, K. E., and Town, T., 2009)  </td> <td> Immunohistochemistry for increases in Nrf2 protein levels and translocation into the nucleus    </td> <td> No  </td> </tr> <tr> <td> qPCR   </td> <td> (Forlenza et al., 2012)  </td> <td> qPCR of Nrf2 target genes (e.g., Nqo1, Hmox-1, Gcl, Gst, Prx, TrxR, Srxn), or by commercially available pathway-based qPCR array (e.g., oxidative stress array from SABiosciences)   </td> <td> No  </td> </tr> <tr> <td> Whole transcriptome profiling via microarray or via RNA-seq followed by a pathway analysis  </td> <td> (Jackson, A. F. et al., 2014)  </td> <td> Whole transcriptome profiling by microarray or RNA-seq followed by pathway analysis (in IPA, DAVID, metacore, etc.) for enrichment of the Nrf2 oxidative stress response pathway  </td> <td> No  </td> </tr> </tbody> </table>

Taxonomic applicability: Occurrence of oxidative stress is not species specific.   Life stage applicability: Occurrence of oxidative stress is not life stage specific.  Sex applicability: Occurrence of oxidative stress is not sex specific.  Evidence for perturbation by prototypic stressor: There is evidence of the increase of oxidative stress following perturbation from a variety of stressors including exposure to ionizing radiation and altered gravity (Bai et al., 2020; Ungvari et al., 2013; Zhang et al., 2009).

High Mixed

High

All life stages

High High

Ahmad, S. et al. (2021), “60Co-γ Radiation Alters Developmental Stages of Zeugodacus cucurbitae (Diptera: Tephritidae) Through Apoptosis Pathways Gene Expression”, Journal Insect Science, Vol. 21/5, Oxford University Press, Oxford, <a href="https://doi.org/10.1093/jisesa/ieab080" rel="noreferrer noopener" target="_blank">https://doi.org/10.1093/jisesa/ieab080</a>  Antelmann, H. and J. D. Helmann (2011), “Thiol-based redox switches and gene regulation.”, Antioxidants & Redox Signaling, Vol. 14/6, Mary Ann Leibert Inc., Larchmont, <a href="https://doi.org/10.1089/ars.2010.3400" rel="noreferrer noopener" target="_blank">https://doi.org/10.1089/ars.2010.3400</a>  Amsen, D., de Visser, K. E., and Town, T. (2009), “Approaches to determine expression of inflammatory cytokines”, in Inflammation and Cancer, Humana Press, Totowa, <a href="https://doi.org/10.1007/978-1-59745-447-6_5" rel="noreferrer noopener" target="_blank">https://doi.org/10.1007/978-1-59745-447-6_5</a>   Azimzadeh, O. et al. (2015), “Integrative Proteomics and Targeted Transcriptomics Analyses in Cardiac Endothelial Cells Unravel Mechanisms of Long-Term Radiation-Induced Vascular Dysfunction”, Journal of Proteome Research, Vol. 14/2, American Chemical Society, Washington, <a href="https://doi.org/10.1021/pr501141b" rel="noreferrer noopener" target="_blank">https://doi.org/10.1021/pr501141b</a>  Azimzadeh, O. et al. (2017), “Proteome analysis of irradiated endothelial cells reveals persistent alteration in protein degradation and the RhoGDI and NO signalling pathways”, International Journal of Radiation Biology, Vol. 93/9, Informa, London, <a href="https://doi.org/10.1080/09553002.2017.1339332" rel="noreferrer noopener" target="_blank">https://doi.org/10.1080/09553002.2017.1339332</a>  Azzam, E. I. et al. (2012), “Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury”, Cancer Letters, Vol. 327/1-2, Elsevier, Ireland, https://doi.org/10.1016/j.canlet.2011.12.012  Bai, J. et al. (2020), “Irradiation-induced senescence of bone marrow mesenchymal stem cells aggravates osteogenic differentiation dysfunction via paracrine signaling”, American Journal of Physiology - Cell Physiology, Vol. 318/5, American Physiological Society, Rockville, <a href="https://doi.org/10.1152/ajpcell.00520.2019." rel="noreferrer noopener" target="_blank">https://doi.org/10.1152/ajpcell.00520.2019.</a>  Balasubramanian, D (2000), “Ultraviolet radiation and cataract”, Journal of ocular pharmacology and therapeutics, Vol. 16/3, Mary Ann Liebert Inc., Larchmont, <a href="https://doi.org/10.1089/jop.2000.16.285.%22%20/t%20%22_blank" rel="noreferrer noopener" target="_blank">https://doi.org/10.1089/jop.2000.16.285.</a>    Biesemann, N. et al., (2018), “High Throughput Screening of Mitochondrial Bioenergetics in Human Differentiated Myotubes Identifies Novel Enhancers of Muscle Performance in Aged Mice”, Scientific Reports, Vol. 8/1, Nature Portfolio, London, <a href="https://doi.org/10.1038/s41598-018-27614-8" rel="noreferrer noopener" target="_blank">https://doi.org/10.1038/s41598-018-27614-8</a>.   Elgazzar, A. and N. Kazem. (2015), “Chapter 23: Biological effects of ionizing radiation” in The Pathophysiologic Basis of Nuclear Medicine, Springer, New York, pp. 540-548  Eruslanov, E., & Kusmartsev, S. (2010). Identification of ROS using oxidized DCFDA and flow-cytometry. Methods in molecular biology ,N.J.,  Vol. 594,  https://doi.org/10.1007/978-1-60761-411-1_4  Fletcher, A. E (2010), “Free radicals, antioxidants and eye diseases: evidence from epidemiological studies on cataract and age-related macular degeneration”, Ophthalmic Research, Vol. 44, Karger International, Basel, <a href="https://doi.org/10.1159/000316476.%22%20/t%20%22_blank" rel="noreferrer noopener" target="_blank">https://doi.org/10.1159/000316476.</a>   Forlenza, M. et al. (2012), “The use of real-time quantitative PCR for the analysis of cytokine mRNA levels” in Cytokine Protocols, Springer, New York, https://doi.org/10.1007/978-1-61779-439-1_2   Forrester, S.J. et al. (2018), “Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology”, Physiological Reviews, Vol. 98/3, American Physiological Society, Rockville, <a href="https://doi.org/10.1152/physrev.00038.201" rel="noreferrer noopener" target="_blank">https://doi.org/10.1152/physrev.00038.201</a>  Foyer, C. H., A. V. Ruban, and G. Noctor (2017), “Viewing oxidative stress through the lens of oxidative signalling rather than damage”, Biochemical Journal, Vol. 474/6, Portland Press, England, https://doi.org/10.1042/BCJ20160814  Ganea, E. and J. J. Harding (2006), “Glutathione-related enzymes and the eye”, Current eye research, Vol. 31/1, Informa, London, <a href="https://doi.org/10.1080/02713680500477347.%22%20/t%20%22_blank" rel="noreferrer noopener" target="_blank">https://doi.org/10.1080/02713680500477347.</a>   Griendling, K. K. et al. (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, Vol. 119/5, Lippincott Williams & Wilkins, Philadelphia, <a href="https://doi.org/10.1161/RES.0000000000000110" rel="noreferrer noopener" target="_blank">https://doi.org/10.1161/RES.0000000000000110</a>   Guo, C. et al. (2013), “Oxidative stress, mitochondrial damage and neurodegenerative diseases”, Neural regeneration research, Vol. 8/21, Publishing House of Neural Regeneration Research, China, <a href="https://doi.org/10.3969/j.issn.1673-5374.2013.21.009" rel="noreferrer noopener" target="_blank">https://doi.org/10.3969/j.issn.1673-5374.2013.21.009</a>  Hargreaves, M., and L. L. Spriet (2020), “Skeletal muscle energy metabolism during exercise.”, Nature Metabolism, Vol. 2, Nature Portfolio, London, <a href="https://doi.org/10.1038/s42255-020-0251-4" rel="noreferrer noopener" target="_blank">https://doi.org/10.1038/s42255-020-0251-4</a>  Hladik, D. and S. Tapio (2016), “Effects of ionizing radiation on the mammalian brain”, Mutation Research/Reviews in Mutation Research, Vol. 770, Elsevier, Amsterdam, <a href="https://doi.org/10.1016/j.mrrev.2016.08.003" rel="noreferrer noopener" target="_blank">https://doi.org/10.1016/j.mrrev.2016.08.003</a>  Itoh, K., J. Mimura and M. Yamamoto (2010), “Discovery of the negative regulator of Nrf2, Keap1: a historical overview”, Antioxidants & Redox Signaling, Vol. 13/11, Mary Ann Leibert Inc., Larchmont, <a href="https://doi.org/10.1089/ars.2010.3222" rel="noreferrer noopener" target="_blank">https://doi.org/10.1089/ars.2010.3222</a>   Jackson, A.F. et al. (2014), “Case study on the utility of hepatic global gene expression profiling in the risk assessment of the carcinogen furan.”, Toxicology and Applied Pharmacology, Vol. 274/11, Elsevier, Amsterdam, <a href="https://doi.org/10.1016/j.taap.2013.10.019" rel="noreferrer noopener" target="_blank">https://doi.org/10.1016/j.taap.2013.10.019</a>  Jacobsen, N.R. et al. (2008), “Genotoxicity, cytotoxicity, and reactive oxygen species induced by single-walled carbon nanotubes and C60 fullerenes in the FE1-MutaTM Mouse lung epithelial cells”, Environmental and Molecular Mutagenesis, Vol. 49/6, John Wiley & Sons, Inc., Hoboken, <a href="https://doi.org/10.1002/em.20406" rel="noreferrer noopener" target="_blank">https://doi.org/10.1002/em.20406</a>  Karimi, N. et al. (2017), “Radioprotective effect of hesperidin on reducing oxidative stress in the lens tissue of rats”, International Journal of Pharmaceutical Investigation, Vol. 7/3, Phcog Net, Bengaluru, <a href="https://doi.org/10.4103/jphi.JPHI_60_17.%E2%80%AF" rel="noreferrer noopener" target="_blank">https://doi.org/10.4103/jphi.JPHI_60_17. </a>  Leung, D.T.H., and Chu, S. (2018), “Measurement of Oxidative Stress: Mitochondrial Function Using the Seahorse System” In: Murthi, P., Vaillancourt, C. (eds) Preeclampsia. Methods in Molecular Biology, vol 1710. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7498-6_22  Lu, C., G. Song, and J. Lin (2006), “Reactive oxygen species and their chemiluminescence-detection methods”, TrAC Trends in Analytical Chemistry, Vol. 25/10, Elsevier, Amsterdam, <a href="https://doi.org/10.1016/j.trac.2006.07.007" rel="noreferrer noopener" target="_blank">https://doi.org/10.1016/j.trac.2006.07.007</a>  Nguyen Dinh Cat, A. et al. (2013), “Angiotensin II, NADPH oxidase, and redox signaling in the vasculature”, Antioxidants & redox signaling, Vol. 19/10, Mary Ann Liebert, Larchmont, <a href="https://doi.org/10.1089/ars.2012.4641" rel="noreferrer noopener" target="_blank">https://doi.org/10.1089/ars.2012.4641</a>  Ping, Z. et al. (2020), “Oxidative Stress in Radiation-Induced Cardiotoxicity”, Oxidative Medicine and Cellular Longevity, Vol. 2020, Hindawi, <a href="https://doi.org/10.1155/2020/3579143" rel="noreferrer noopener" target="_blank">https://doi.org/10.1155/2020/3579143</a>  Powers, S.K. and M.J. Jackson. (2008), “Exercise-Induced Oxidative Stress: Cellular Mechanisms and Impact on Muscle Force Production”, Physiological Reviews, Vol. 88/4, American Physiological Society, Rockville, <a href="https://doi.org/10.1152/physrev.00031.2007" rel="noreferrer noopener" target="_blank">https://doi.org/10.1152/physrev.00031.2007</a>  Raimondi, V., F. Ciccarese and V. Ciminale. (2020), “Oncogenic pathways and the electron transport chain: a dangeROS liason”, British Journal of Cancer, Vol. 122/2, Nature Portfolio, London, <a href="https://doi.org/10.1038/s41416-019-0651-y" rel="noreferrer noopener" target="_blank">https://doi.org/10.1038/s41416-019-0651-y</a>  Seen, S. and L. Tong. (2018), “Dry eye disease and oxidative stress”, Acta Ophthalmologica, Vol. 96/4, John Wiley & Sons, Inc., Hoboken, <a href="https://doi.org/10.1111/aos.13526" rel="noreferrer noopener" target="_blank">https://doi.org/10.1111/aos.13526</a>  Ungvari, Z. et al. (2013), “Ionizing Radiation Promotes the Acquisition of a Senescence-Associated Secretory Phenotype and Impairs Angiogenic Capacity in Cerebromicrovascular Endothelial Cells: Role of Increased DNA Damage and Decreased DNA Repair Capacity in Microvascular Radiosensitivity”, The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, Vol. 68/12, Oxford University Press, Oxford, <a href="https://doi.org/10.1093/gerona/glt057." rel="noreferrer noopener" target="_blank">https://doi.org/10.1093/gerona/glt057.</a>     Vargas-Mendoza, N. et al. (2021), “Oxidative Stress, Mitochondrial Function and Adaptation to Exercise: New Perspectives in Nutrition”, Life, Vol. 11/11, Multidisciplinary Digital Publishing Institute, Basel, <a href="https://doi.org/10.3390/life11111269" rel="noreferrer noopener" target="_blank">https://doi.org/10.3390/life11111269</a>  Wang, H. et al. (2019), “Radiation-induced heart disease: a review of classification, mechanism and prevention”, International Journal of Biological Sciences, Vol. 15/10, Ivyspring International Publisher, Sydney, <a href="https://doi.org/10.7150/ijbs.35460" rel="noreferrer noopener" target="_blank">https://doi.org/10.7150/ijbs.35460</a>   Zhang, R. et al. (2009), “Blockade of AT1 receptor partially restores vasoreactivity, NOS expression, and superoxide levels in cerebral and carotid arteries of hindlimb unweighting rats”, Journal of applied physiology, Vol. 106/1, American Physiological Society, Rockville, <a href="https://doi.org/10.1152/japplphysiol.01278.2007" rel="noreferrer noopener" target="_blank">https://doi.org/10.1152/japplphysiol.01278.2007</a>.  Zhao, R. Z. et al. (2019), “Mitochondrial electron transport chain, ROS generation and uncoupling”, International journal of molecular medicine, Vol. 44/1, Spandidos Publishing Ltd., Athens, <a href="https://doi.org/10.3892/ijmm.2019.4188" rel="noreferrer noopener" target="_blank">https://doi.org/10.3892/ijmm.2019.4188</a>  AOPWiki 2017-05-30T13:58:17

2026-02-11T07:05:27

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AOPWiki 2022-03-28T07:19:51

2022-03-28T07:19:51

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AOPWiki 2022-03-28T07:46:41

2022-03-28T07:46:41

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AOPWiki 2022-01-21T07:18:45

2022-01-21T07:18:45

<upstream-id>da462cf8-d2d7-44b1-b1ad-dfc892302a8c</upstream-id> <downstream-id>2080b84b-01df-4c6a-86c2-4d5f4aca393a</downstream-id>

AOPWiki 2019-04-22T05:00:22

2019-04-22T05:00:22

<upstream-id>0e77e460-e1a8-4a64-af7f-26b306fd1478</upstream-id> <downstream-id>428bbc27-9e02-42be-ada0-74dcd9e344df</downstream-id> Increased RONS leads to an increase in DNA damage.

Biological plausibiltiy is High. Reactive oxygen and nitrogen species from oxygen and respiratory activity are generally acknowledged to damage DNA under a range of cellular conditions. Empirical support is High. Multiple studies show an increase in DNA damage with RONS treatment as well as dependent changes in both RONS and DNA damage in response to stressors. DNA damage increases with RONS dose, and temporal concordance between RONS and DNA damage events following ionizing radiation is consistent with a causative relationship, although few studies examine multiple doses and time points. A small number of studies do not find double strand breaks at physiological doses, or report an increase in one key event but not the other.

High. Reactive oxygen and nitrogen species from oxygen and respiratory activity are generally acknowledged to damage DNA under typical cellular conditions (Dickinson and Chang 2011; Aziz, Nowsheen et al. 2012; Tubbs and Nussenzweig 2017). Damage commonly occurs via oxidation of a nucleotide by the hydroxyl radical (or by radicals created by nitric oxide), or can occur indirectly in nearby nucleotides following the secondary reaction of a radical created in nucleotides (Cadet, Davies et al. 2017). Oxidative damage predominantly consists of DNA lesions (structural modifications to nucleotides) including single strand breaks, although double strand breaks can occur when transcription or translation machinery encounters damaged strands (Tubbs and Nussenzweig 2017).

High. Multiple studies show an increase in DNA damage with RONS treatment as well as dependent changes in both RONS and DNA damage in response to stressors. DNA damage increases with RONS dose, and temporal concordance between RONS and DNA damage events following ionizing radiation is consistent with a causative relationship, although few studies examine multiple doses and time points. A small number of studies do not find double strand breaks at physiological doses, or report an increase in one key event but not the other. Treatment with H2O2 or other RONS inducers increase DNA damage and double strand breaks. H2O2 treatment reaches the nucleus where it can damage DNA (Ameziane-El-Hassani, Boufraqech et al. 2010; Ameziane-El-Hassani, Talbot et al. 2015). Oxidized nucleotides (including clusters) and single strand breaks are commonly reported following H2O2 treatment (Dahm-Daphi, Sass et al. 2000; Nakamura, Purvis et al. 2003; Yang, Durando et al. 2013; Sharma, Collins et al. 2016), and double strand breaks can occur when transcription and translation machinery encounters damaged strands (Berdelle, Nikolova et al. 2011; Yang, Durando et al. 2013; Tubbs and Nussenzweig 2017). However, it is less clear whether H2O2 or RONS cause a measurable increase in double strand breaks, particularly at physiologically relevant concentrations (in the range of 12 uM) (Liu and Zweier 2001; Ameziane-El-Hassani, Talbot et al. 2015). Studies report double strand breaks following treatment with 15 uM- 1mM H2O2 (Oya, Yamamoto et al. 1986; Driessens, Versteyhe et al. 2009; Seager, Shah et al. 2012; Werner, Wang et al. 2014; Ameziane-El-Hassani, Talbot et al. 2015; Sharma, Collins et al. 2016) as well as parallel increases in RONS and double strand breaks (Han, Chen et al. 2010; Berdelle, Nikolova et al. 2011; Stanicka, Russell et al. 2015). DNA damage including double strand breaks and mutations increase with H2O2 dose (Sandhu and Birnboim 1997; Dahm-Daphi, Sass et al. 2000; Driessens, Versteyhe et al. 2009; Seager, Shah et al. 2012; Lorat, Brunner et al. 2015; Sharma, Collins et al. 2016). RONS is dose-dependently and reversibly associated with increased genomic instability (Dayal, Martin et al. 2008; Dayal, Martin et al. 2009; Buonanno, de Toledo et al. 2011; Pazhanisamy, Li et al. 2011; Datta, Suman et al. 2012; Bensimon, Biard et al. 2016) and with DNA damage in bystander cells (Azzam, De Toledo et al. 2002; Yang, Asaad et al. 2005; Yang, Anzenberg et al. 2007; Han, Chen et al. 2010; Buonanno, de Toledo et al. 2011) although other non-RONS factors such as telomere erosion and breakage-fusion-bridge events may be sufficient to maintain genomic instability (Suzuki, Kashino et al. 2009; Murnane 2012). To our knowledge no experiments have tested whether elevating intracellular RONS alone in one group of cells can cause DNA damage in nearby cells. Antioxidants and other interventions to reduce RONS production also reduce or block the effect of RONS treatment on DNA base damage (Berdelle, Nikolova et al. 2011) and double-strand breaks (Ameziane-El-Hassani, Boufraqech et al. 2010; Ameziane-El-Hassani, Talbot et al. 2015; Stanicka, Russell et al. 2015). Similarly, nitric oxide scavengers can reduce DNA damage in cells treated with nitric oxide producers (Han, Chen et al. 2010) or in bystander cells. Further support for a causative relationship between RONS and DNA damage comes from many studies showing that antioxidants and other interventions capable of reducing RONS can also reduce DNA damage following IR. Antioxidant reduction of nucleotide damage from IR occurs in isolated DNA (Winyard, Faux et al. 1992; Douki, Ravanat et al. 2006), and in vitro and in vivo antioxidants reduce nucleotide damage, double strand breaks, micronuclei, chromosomal damage, and mutations when added before (Azzam, De Toledo et al. 2002; Choi, Kang et al. 2007; Jones, Riggs et al. 2007; Ameziane-El-Hassani, Boufraqech et al. 2010; Ozyurt, Cevik et al. 2014; Ameziane-El-Hassani, Talbot et al. 2015; Fetisova, Antoschina et al. 2015; Manna, Das et al. 2015), or in the case of delayed (15 min to days) or bystander DNA damage, added after radiation (Yang, Asaad et al. 2005; Han, Chen et al. 2010; Pazhanisamy, Li et al. 2011; Ameziane-El-Hassani, Talbot et al. 2015). Interestingly, NO specific blockers reduce DNA damage and mutations in bystander cells but not in directly IR cells, suggesting that NO specifically contributes to the bystander effect (Zhou, Ivanov et al. 2008; Han, Chen et al. 2010). Temporal concordance between RONS and DNA damage events following a stressor (ionizing radiation) is consistent with a causative relationship between RONS and DNA damage. Following ionizing radiation, an increase in RONS typically occurs coincident with DNA damage. Few studies examine multiple doses and time points, and detection methods have differing sensitivities. However, both RONS and double strand breaks appear rapidly after IR (Ameziane-El-Hassani, Boufraqech et al. 2010; Denissova, Nasello et al. 2012; Martin, Nakamura et al. 2014), and in several studies RONS and DNA single and double strand breaks, chromosomal damage, and micronuclei appear at the same time points over several days following IR (Choi, Kang et al. 2007; Jones, Riggs et al. 2007; Du, Gao et al. 2009; Saenko, Cieslar-Pobuda et al. 2013; Ameziane-El-Hassani, Talbot et al. 2015; Manna, Das et al. 2015). RONS also appears coincident with longer term DNA damage including nucleotide damage, double strand breaks, and micronuclei, both in IR exposed (Dayal, Martin et al. 2008; Pazhanisamy, Li et al. 2011; Datta, Suman et al. 2012; Werner, Wang et al. 2014; Ameziane-El-Hassani, Talbot et al. 2015) and in bystander cells not directly exposed to IR (Buonanno, de Toledo et al. 2011).

While the bulk of the evidence support a mechanism where RONS increases DNA damage, including double strand DNA breaks, not all studies report these effects. Some studies report the induction of single strand breaks by H2O2, but only show double strand breaks with H2O2 doses at or above 1 mM H2O2 (Dahm-Daphi, Sass et al. 2000; Lorat, Brunner et al. 2015) or do not find an effect of H2O2 on double strand breaks at any concentration (Gradzka and Iwanenko 2005; Ismail, Nystrom et al. 2005). These conflicting results may be partially explained by experimental variations including temperature (two of the studies showing reduced or no effect were exposed to H2O2 at 4C or colder) or other factors including catalysts required to transform H2O2 into DNA damaging OH radicals (Nakamura, Purvis et al. 2003). The reduction of IR-induced DNA damage (including double strand breaks) by antioxidants is strong evidence for an essential role of RONS in DNA damage, but antioxidants don’t reduce all DNA damage from IR and anti-oxidants that reduce double strand breaks and chromosomal aberrations after IR don’t necessarily reduce baseline DNA damage (Fetisova, Antoschina et al. 2015). This incomplete effect suggests either that antioxidants are unable to fully reduce endogenous RONS, or that additional sources of DNA damage are also at work. Furthermore, RONS can be observed following IR in the absence of DNA nucleotide damage (Yoshida, Goto et al. 2012) and counter to expectations lower (10 uM) doses of H2O2 applied six days after IR were associated with a decrease in detectable micronuclei (Werner, Wang et al. 2014), suggesting that additional factors (such as repair and apoptosis or changes in endogenous antioxidants) may influence the effect of RONS on IR-induced DNA damage. Finally, double strand breaks and chromosomal damage can be observed following IR in the absence of measured RONS (Suzuki, Kashino et al. 2009), although since antioxidants are still capable of reducing DNA damage in the absence of measurable RONS, such a discrepancy might be attributable to a lack of sensitivity in RONS detection methods (Yang, Asaad et al. 2005).

RONS activates or is essential to many inflammatory pathways including TGF-β  (Barcellos-Hoff and Dix 1996; Jobling, Mott et al. 2006), TNF (Blaser, Dostert et al. 2016), Toll-like receptor (TLR) (Park, Jung et al. 2004; Nakahira, Kim et al. 2006; Powers, Szaszi et al. 2006; Miller, Goodson et al. 2017; Cavaillon 2018), and NF-kB signaling (Gloire, Legrand-Poels et al. 2006; Morgan and Liu 2011). These interactions principally involve ROS, but RNS can indirectly activate TLRs and possibly NF-kB. Since inflammatory signaling and activated immune cells can also increase the production of RONS, positive feedback and feedforward loops can occur (Zhao and Robbins 2009; Ratikan, Micewicz et al. 2015; Blaser, Dostert et al. 2016). Damage inflicted by RONS on cells activate TLRs and other receptors to promote release of cytokines (Ratikan, Micewicz et al. 2015). For example, oxidized lipids or oxidative stress-induced heat shock proteins can activate TLR4 (Miller, Goodson et al. 2017; Cavaillon 2018). ROS is essential to TLR4 activation of downstream signals including NF-kB. Activation of TLR4 promotes the surface expression and movement of TLR4 into signal-promoting lipid rafts (Nakahira, Kim et al. 2006; Powers, Szaszi et al. 2006). This signal promotion requires NADPH-oxidase and ROS (Park, Jung et al. 2004; Nakahira, Kim et al. 2006; Powers, Szaszi et al. 2006). ROS is also required for the TLR4/TRAF6/ASK-1/p38 dependent activation of inflammatory cytokines (Matsuzawa, Saegusa et al. 2005). ROS therefore amplifies the inflammatory process. RONS can also fail to activate or actively inhibit inflammatory pathways, and the circumstances determining response to RONS are not well known (Gloire, Legrand-Poels et al. 2006).   <a name="_ENREF_1">Barcellos-Hoff, M. H. and T. A. Dix (1996). "Redox-mediated activation of latent transforming growth factor-beta 1." Mol Endocrinol 10(9): 1077-1083.</a> <a name="_ENREF_2">Blaser, H., C. Dostert, et al. (2016). "TNF and ROS Crosstalk in Inflammation." Trends in cell biology 26(4): 249-261.</a> <a name="_ENREF_3">Cavaillon, J.-M. (2018). Damage-associated Molecular Patterns. Inflammation: From Molecular and Cellular Mechanisms to the Clinic. J.-M. Cavaillon and M. Singer, Wiley-VCHVerlagGmbH&Co.KGaA.: 57-80.</a> <a name="_ENREF_4">Gloire, G., S. Legrand-Poels, et al. (2006). "NF-kappaB activation by reactive oxygen species: fifteen years later." Biochem Pharmacol 72(11): 1493-1505.</a> <a name="_ENREF_5">Jobling, M. F., J. D. Mott, et al. (2006). "Isoform-specific activation of latent transforming growth factor beta (LTGF-beta) by reactive oxygen species." Radiation research 166(6): 839-848.</a> <a name="_ENREF_6">Matsuzawa, A., K. Saegusa, et al. (2005). "ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity." Nat Immunol 6(6): 587-592.</a> <a name="_ENREF_7">Miller, M. F., W. H. Goodson, et al. (2017). "Low-Dose Mixture Hypothesis of Carcinogenesis Workshop: Scientific Underpinnings and Research Recommendations." Environmental health perspectives 125(2): 163-169.</a> <a name="_ENREF_8">Morgan, M. J. and Z. G. Liu (2011). "Crosstalk of reactive oxygen species and NF-kappaB signaling." Cell Res 21(1): 103-115.</a> <a name="_ENREF_9">Nakahira, K., H. P. Kim, et al. (2006). "Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts." J Exp Med 203(10): 2377-2389.</a> <a name="_ENREF_10">Park, H. S., H. Y. Jung, et al. (2004). "Cutting edge: direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-kappa B." J Immunol 173(6): 3589-3593.</a> <a name="_ENREF_11">Powers, K. A., K. Szaszi, et al. (2006). "Oxidative stress generated by hemorrhagic shock recruits Toll-like receptor 4 to the plasma membrane in macrophages." J Exp Med 203(8): 1951-1961.</a> <a name="_ENREF_12">Ratikan, J. A., E. D. Micewicz, et al. (2015). "Radiation takes its Toll." Cancer Lett 368(2): 238-245.</a> <a name="_ENREF_13">Zhao, W. and M. E. Robbins (2009). "Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: therapeutic implications." Curr Med Chem 16(2): 130-143.</a>

<a name="_ENREF_1">Ameziane-El-Hassani, R., M. Boufraqech, et al. (2010). "Role of H2O2 in RET/PTC1 chromosomal rearrangement produced by ionizing radiation in human thyroid cells." Cancer Res 70(10): 4123-4132.</a> <a name="_ENREF_2">Ameziane-El-Hassani, R., M. Talbot, et al. (2015). "NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation." Proceedings of the National Academy of Sciences of the United States of America 112(16): 5051-5056.</a> <a name="_ENREF_3">Aziz, K., S. Nowsheen, et al. (2012). "Targeting DNA damage and repair: embracing the pharmacological era for successful cancer therapy." Pharmacology & therapeutics 133(3): 334-350.</a> <a name="_ENREF_4">Azzam, E. I., S. M. De Toledo, et al. (2002). "Oxidative metabolism modulates signal transduction and micronucleus formation in bystander cells from alpha-particle-irradiated normal human fibroblast cultures." Cancer research 62(19): 5436-5442.</a> <a name="_ENREF_5">Bensimon, J., D. Biard, et al. (2016). "Forced extinction of CD24 stem-like breast cancer marker alone promotes radiation resistance through the control of oxidative stress." Mol Carcinog 55(3): 245-254.</a> <a name="_ENREF_6">Berdelle, N., T. Nikolova, et al. (2011). "Artesunate induces oxidative DNA damage, sustained DNA double-strand breaks, and the ATM/ATR damage response in cancer cells." Molecular cancer therapeutics 10(12): 2224-2233.</a> <a name="_ENREF_7">Buonanno, M., S. M. de Toledo, et al. (2011). "Long-term consequences of radiation-induced bystander effects depend on radiation quality and dose and correlate with oxidative stress." Radiation research 175(4): 405-415.</a> <a name="_ENREF_8">Cadet, J., K. J. A. Davies, et al. (2017). "Formation and repair of oxidatively generated damage in cellular DNA." Free radical biology & medicine 107: 13-34.</a> <a name="_ENREF_9">Choi, K. M., C. M. Kang, et al. (2007). "Ionizing radiation-induced micronucleus formation is mediated by reactive oxygen species that are produced in a manner dependent on mitochondria, Nox1, and JNK." Oncol Rep 17(5): 1183-1188.</a> <a name="_ENREF_10">Dahm-Daphi, J., C. Sass, et al. (2000). "Comparison of biological effects of DNA damage induced by ionizing radiation and hydrogen peroxide in CHO cells." International journal of radiation biology 76(1): 67-75.</a> <a name="_ENREF_11">Datta, K., S. Suman, et al. (2012). "Exposure to heavy ion radiation induces persistent oxidative stress in mouse intestine." PLoS One 7(8): e42224.</a> <a name="_ENREF_12">Dayal, D., S. M. Martin, et al. (2008). "Hydrogen peroxide mediates the radiation-induced mutator phenotype in mammalian cells." Biochem J 413(1): 185-191.</a> <a name="_ENREF_13">Dayal, D., S. M. Martin, et al. (2009). "Mitochondrial complex II dysfunction can contribute significantly to genomic instability after exposure to ionizing radiation." Radiation research 172(6): 737-745.</a> <a name="_ENREF_14">Denissova, N. G., C. M. Nasello, et al. (2012). "Resveratrol protects mouse embryonic stem cells from ionizing radiation by accelerating recovery from DNA strand breakage." Carcinogenesis 33(1): 149-155.</a> <a name="_ENREF_15">Dickinson, B. C. and C. J. Chang (2011). "Chemistry and biology of reactive oxygen species in signaling or stress responses." Nature chemical biology 7(8): 504-511.</a> <a name="_ENREF_16">Douki, T., J. L. Ravanat, et al. (2006). "Minor contribution of direct ionization to DNA base damage inducedby heavy ions." International journal of radiation biology 82(2): 119-127.</a> <a name="_ENREF_17">Driessens, N., S. Versteyhe, et al. (2009). "Hydrogen peroxide induces DNA single- and double-strand breaks in thyroid cells and is therefore a potential mutagen for this organ." Endocrine-related cancer 16(3): 845-856.</a> <a name="_ENREF_18">Du, C., Z. Gao, et al. (2009). "Mitochondrial ROS and radiation induced transformation in mouse embryonic fibroblasts." Cancer Biol Ther 8(20): 1962-1971.</a> <a name="_ENREF_19">Fetisova, E. K., M. M. Antoschina, et al. (2015). "Radioprotective effects of mitochondria-targeted antioxidant SkQR1." Radiation research 183(1): 64-71.</a> <a name="_ENREF_20">Gradzka, I. and T. Iwanenko (2005). "A non-radioactive, PFGE-based assay for low levels of DNA double-strand breaks in mammalian cells." DNA repair 4(10): 1129-1139.</a> <a name="_ENREF_21">Han, W., S. Chen, et al. (2010). "Nitric oxide mediated DNA double strand breaks induced in proliferating bystander cells after alpha-particle irradiation." Mutation research 684(1-2): 81-89.</a> <a name="_ENREF_22">Ismail, I. H., S. Nystrom, et al. (2005). "Activation of ataxia telangiectasia mutated by DNA strand break-inducing agents correlates closely with the number of DNA double strand breaks." J Biol Chem 280(6): 4649-4655.</a> <a name="_ENREF_23">Jones, J. A., P. K. Riggs, et al. (2007). "Ionizing radiation-induced bioeffects in space and strategies to reduce cellular injury and carcinogenesis." Aviat Space Environ Med 78(4 Suppl): A67-78.</a> <a name="_ENREF_24">Liu, X. and J. L. Zweier (2001). "A real-time electrochemical technique for measurement of cellular hydrogen peroxide generation and consumption: evaluation in human polymorphonuclear leukocytes." Free radical biology & medicine 31(7): 894-901.</a> <a name="_ENREF_25">Lorat, Y., C. U. Brunner, et al. (2015). "Nanoscale analysis of clustered DNA damage after high-LET irradiation by quantitative electron microscopy--the heavy burden to repair." DNA repair 28: 93-106.</a> <a name="_ENREF_26">Manna, K., U. Das, et al. (2015). "Naringin inhibits gamma radiation-induced oxidative DNA damage and inflammation, by modulating p53 and NF-kappaB signaling pathways in murine splenocytes." Free Radic Res 49(4): 422-439.</a> <a name="_ENREF_27">Martin, N. T., K. Nakamura, et al. (2014). "Homozygous mutation of MTPAP causes cellular radiosensitivity and persistent DNA double-strand breaks." Cell Death Dis 5: e1130.</a> <a name="_ENREF_28">Murnane, J. P. (2012). "Telomere dysfunction and chromosome instability." Mutation research 730(1-2): 28-36.</a> <a name="_ENREF_29">Nakamura, J., E. R. Purvis, et al. (2003). "Micromolar concentrations of hydrogen peroxide induce oxidative DNA lesions more efficiently than millimolar concentrations in mammalian cells." Nucleic acids research 31(6): 1790-1795.</a> <a name="_ENREF_30">Oya, Y., K. Yamamoto, et al. (1986). "The biological activity of hydrogen peroxide. I. Induction of chromosome-type aberrations susceptible to inhibition by scavengers of hydroxyl radicals in human embryonic fibroblasts." Mutation research 172(3): 245-253.</a> <a name="_ENREF_31">Ozyurt, H., O. Cevik, et al. (2014). "Quercetin protects radiation-induced DNA damage and apoptosis in kidney and bladder tissues of rats." Free Radic Res 48(10): 1247-1255.</a> <a name="_ENREF_32">Pazhanisamy, S. K., H. Li, et al. (2011). "NADPH oxidase inhibition attenuates total body irradiation-induced haematopoietic genomic instability." Mutagenesis 26(3): 431-435.</a> <a name="_ENREF_33">Saenko, Y., A. Cieslar-Pobuda, et al. (2013). "Changes of reactive oxygen and nitrogen species and mitochondrial functioning in human K562 and HL60 cells exposed to ionizing radiation." Radiation research 180(4): 360-366.</a> <a name="_ENREF_34">Sandhu, J. K. and H. C. Birnboim (1997). "Mutagenicity and cytotoxicity of reactive oxygen and nitrogen species in the MN-11 murine tumor cell line." Mutation research 379(2): 241-252.</a> <a name="_ENREF_35">Seager, A. L., U. K. Shah, et al. (2012). "Pro-oxidant induced DNA damage in human lymphoblastoid cells: homeostatic mechanisms of genotoxic tolerance." Toxicological sciences : an official journal of the Society of Toxicology 128(2): 387-397.</a> <a name="_ENREF_36">Sharma, V., L. B. Collins, et al. (2016). "Oxidative stress at low levels can induce clustered DNA lesions leading to NHEJ mediated mutations." Oncotarget 7(18): 25377-25390.</a> <a name="_ENREF_37">Stanicka, J., E. G. Russell, et al. (2015). "NADPH oxidase-generated hydrogen peroxide induces DNA damage in mutant FLT3-expressing leukemia cells." The Journal of biological chemistry 290(15): 9348-9361.</a> <a name="_ENREF_38">Suzuki, K., G. Kashino, et al. (2009). "Long-term persistence of X-ray-induced genomic instability in quiescent normal human diploid cells." Mutation research 671(1-2): 33-39.</a> <a name="_ENREF_39">Tubbs, A. and A. Nussenzweig (2017). "Endogenous DNA Damage as a Source of Genomic Instability in Cancer." Cell 168(4): 644-656.</a> <a name="_ENREF_40">Werner, E., H. Wang, et al. (2014). "Opposite roles for p38MAPK-driven responses and reactive oxygen species in the persistence and resolution of radiation-induced genomic instability." PLoS One 9(10): e108234.</a> <a name="_ENREF_41">Winyard, P. G., S. P. Faux, et al. (1992). "Bleomycin-induced unscheduled DNA synthesis in non-permeabilized human and rat hepatocytes is not paralleled by 8-oxo-7,8-dihydrodeoxyguanosine formation." Biochem Pharmacol 44(7): 1255-1260.</a> <a name="_ENREF_42">Yang, H., V. Anzenberg, et al. (2007). "The time dependence of bystander responses induced by iron-ion radiation in normal human skin fibroblasts." Radiation research 168(3): 292-298.</a> <a name="_ENREF_43">Yang, H., N. Asaad, et al. (2005). "Medium-mediated intercellular communication is involved in bystander responses of X-ray-irradiated normal human fibroblasts." Oncogene 24(12): 2096-2103.</a> <a name="_ENREF_44">Yang, Y., M. Durando, et al. (2013). "Cell cycle stage-specific roles of Rad18 in tolerance and repair of oxidative DNA damage." Nucleic acids research 41(4): 2296-2312.</a> <a name="_ENREF_45">Yoshida, T., S. Goto, et al. (2012). "Mitochondrial dysfunction, a probable cause of persistent oxidative stress after exposure to ionizing radiation." Free Radic Res 46(2): 147-153.</a> <a name="_ENREF_46">Zhou, H., V. N. Ivanov, et al. (2008). "Mitochondrial function and nuclear factor-kappaB-mediated signaling in radiation-induced bystander effects." Cancer Res 68(7): 2233-2240.</a> AOPWiki 2019-05-07T14:43:41

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Ionizing radiation leads to reduced reproduction in Eisenia fetida via reduced spermatogenesis and cocoon hatchability

Deposition of energy leads to reduced cocoon hatchability

Deborah Oughton

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It is well documented that ionizing radiation( (eg. X-rays, gamma, photons, alpha, beta, neutrons, heavy ions) leads to energy deposition on the atoms and molecules of the substrate. Many studies, have demonstrated that the type of radiation and distance from source has an impact on the pattern of energy deposition (Alloni, et al. 2014). High linear energy transfer (LET) radiation has been associated with higher-energy deposits (Liamsuwan et al., 2014) that are more densely-packed and cause more complex effects within the particle track (Hada and Georgakilas, 2008; Okayasu, 2012ab; Lorat et al., 2015; Nikitaki et al., 2016) in comparison to low LET radiation. Parameters such as mean lineal energy, dose mean lineal energy, frequency mean specific energy and dose mean specific energy can impact track structure of the traversed energy into a medium (Friedland et al., 2017). The detection of energy deposition by ionizing radiation can be demonstrated with the use of fluorescent nuclear track detectors (FNTDs). FNTDs used in conjunction with fluorescent microscopy, are able to visualize radiation tracks produced by ionizing radiation (Niklas et al., 2013; Kodaira et al., 2015; Sawakuchi and Akselrod, 2016). In addition, these FNTD chips can quantify the LET of primary and secondary radiation tracks up to 0.47 keV/um (Sawakuchi and Akselrod, 2016). This co-visualization of the radiation tracks and the cell markers enable the mapping of the radiation trajectory to specific cellular compartments, and the identification of accrued damage (Niklas et al., 2013; Kodaira et al., 2015). There are no known chemical initiators or prototypes that can mimic the MIE.

The following stressors increase this key event: ionizing radiation.

Stressors include: Ionizing radiation Estrogen

Maintenance of sustainable fish and wildlife populations (i.e., adequate to ensure long-term delivery of valued ecosystem services) is a widely accepted regulatory goal upon which risk assessments and risk management decisions are based.

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AOPWiki 2022-03-28T07:05:35

2024-07-04T11:06:49