Deposition of Energy

CHEBI:16991

CHEBI deoxyribonucleic acid

RBO:00015021

RBO energy deposition event

GO:0006915

GO apoptotic process

WIKI increased

WIKI functional change

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

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

10090

NCBI Mus musculus

10116

NCBI Rattus norvegicus

9606

NCBI Homo sapiens

6239

NCBI Caenorhabditis elegans

39442

NCBI Mus musculus musculus

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, 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

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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

Activation of Tumor Protein 53

Activation of TP53

Cellular

TP53 is a key player in protecting the integrity of the genome. TP53 protein is present at low levels in all type of cells but become stabilized and transcriptionally active after exposures to DNA-damaging agents. The increase level of TP53 after exposure to ionizing radiation or other stress is primarily regulated at the post-translational level (Kastan MB, Onyekwere O, Sidransky D, Vogelstein B and Craig RW (1991) Cancer Res. 51: 6304–6311.). In response to DNA double-strand breaks activated ATM mediates phosphorylation at multiple sites on p53 including ser 6, 9, 15, 20, 46 and Thr 18 (Saito S, Goodarzi AA, Higashimoto Y, Noda Y, Lees-Miller SP, Appella E and Anderson CW (2002) J. Biol. Chem. 277: 12491–12494.). The phosphorylated P53 escape proteosomal degradation mediated in non stress situation by MDM2, and thus leads to stabilization of the protein (Jackson MW and Berberich SJ (2000) Mol. Cell. Biol. 20: 1001–1007.)

Antibody against phosphorylated TP53 are used to detect the activated form of TP53. This is made by immunocytochemistry techniques through Western Blot analysis on protein extract or by immunocytochemistry on tissue sections.

Somatic and proliferating cells All vertebrates. Consequence of increased and irreparable DNA damages

High Unspecific

High

Pregnancy

High Moderate Kashiwagi, Hiroki, Kazunori Shiraishi, Kenta Sakaguchi, Tomoya Nakahama, and Seiji Kodama. 2018. “Repair Kinetics of DNA Double-Strand Breaks and Incidence of Apoptosis in Mouse Neural Stem/Progenitor Cells and Their Differentiated Neurons Exposed to Ionizing Radiation.” Journal of Radiation Research 59 (3): 261–71. https://doi.org/10.1093/jrr/rrx089. Limoli, Charles L., Erich Giedzinski, Radoslaw Rola, Shinji Otsuka, Theo D. Palmer, and John R. Fike. 2004. “Radiation Response of Neural Precursor Cells: Linking Cellular Sensitivity to Cell Cycle Checkpoints, Apoptosis and Oxidative Stress.” Radiation Research 161 (1): 17–27. https://doi.org/10.1667/rr3112. Kastan MB, Onyekwere O, Sidransky D, Vogelstein B and Craig RW (1991) Cancer Res. 51: 6304–6311 Saito S, Goodarzi AA, Higashimoto Y, Noda Y, Lees-Miller SP, Appella E and Anderson CW (2002) J. Biol. Chem. 277: 12491–12494 Jackson MW and Berberich SJ (2000) Mol. Cell. Biol. 20: 1001–1007 AOPWiki 2022-03-09T08:07:00

2022-03-17T12:02:31

Increase risk, microcephaly

Microcephaly

Individual

AOPWiki 2022-03-17T12:13:01

2022-03-18T08:38:03

Premature cell differentiation

Premature differentiation

Organ

AOPWiki 2022-03-21T11:48:08

2022-03-21T11:53:52

Apoptosis

Cellular

Apoptosis, the process of programmed cell death, is characterized by distinct morphology with DNA fragmentation and energy dependency [Elmore, 2007]. Apoptosis, also called “physiological cell death”, is involved in cell turnover, physiological involution, and atrophy of various tissues and organs [Kerr et al., 1972]. The formation of apoptotic bodies involves marked condensation of both nucleus and cytoplasm, nuclear fragmentation, and separation of protuberances [Kerr et al., 1972]. Apoptosis is characterized by DNA ladder and chromatin condensation. Several stimuli such as hypoxia, nucleotides deprivation, chemotherapeutical drugs, DNA damage, and mitotic spindle damage induce p53 activation, leading to p21 activation and cell cycle arrest [Pucci et al., 2000]. The SAHA or TSA treatment on neonatal human dermal fibroblasts (NHDFs) for 24 or 72 hrs inhibited proliferation of the NHDF cells [Glaser et al., 2003]. Considering that the acetylation of histone H4 was increased by the treatment of SAHA for 4 hrs, histone deacetylase inhibition may be involved in the inhibition of the cell proliferation [Glaser et al., 2003]. The impaired proliferation was observed in HDAC1-/- ES cells, which was rescued with the reintroduction of HDAC1 [Zupkovitz et al., 2010]. An AOP focuses existes on p21 pathway leading to apoptosis, however, alternative pathways such as NF-kappaB signaling pathways may be involved in the apoptosis of spermatocytes [Wang et al., 2017]. Apoptosis is defined as a programmed cell death.  A decrease in apoptosis or a resistance to cell death is noted is described as a hallmark of cancer by Hanahan et al. It is widely admitted as an essential step in tumor proliferation (Adams, Lowe).  Apoptosis occurs after activation of a number of intrinsic and extrinsic signals which activate the protease caspase system which in turn activates the destruction of the cell.    In mammals, the foetal ovary produces hundreds of thousands of oocytes. But most of them die before birth due to apoptosis (Kaur, S., & Kurokawa, M., 2023). The apoptotic process has a specific pattern at different stages: in foetal ovaries, the majority of apoptotic activity was found in germ cells, whereas in adult quiescent cortical follicles, apoptosis occurred from both granulosa and oocyte cells. The oocyte has been shown to be the one that triggers the apoptotic process and causes follicular atresia (Jin, X., et al. (2011). In humans, the primordial follicles' ovarian endowment is formed throughout foetal development. Apoptotic cell death, which is carried out with the assistance of multiple players and routes conserved from worms to humans, depletes this endowment by at least two-thirds prior to birth. As of right now, apoptosis has been linked to atresia, oocyte loss/selection, folliculogenesis, and oogenesis (Hussein MR, 2005) The Bcl-2 is a protein family suppressing apoptosis by binding and inhibiting two proapoptotic proteins (Bax and Bak) and transferring them to the mitochondrial outer membrane. In the absence of inhibition by Bcl2, Bax and Bak destroy the mitochondrial membrane and releases proapoptotic signaling proteins, such as cytochrome c which activated the caspase system. An increased expression of these antiapoptotic proteins (Bcl-2, Bcl-xL) occurs in cancer (Hanahan, Adams, Lowe). Several others pathways such as the loss of TP53 tumor suppressor function, or the increase of survival signals (Igf1/2), or decrease of proapoptotic factors (Bax, Bim, Puma) can also increase tumor growth (Hanahan, Juntilla). In breast cancer a decrease in apoptosis and a resistance to cell death has been described thoroughly, especially using a dysregulation of the Bcl2 system or TP53 (Parton, Williams, Shahbandi).

Apoptosis is characterized by many morphological and biochemical changes such as homogenous condensation of chromatin to one side or the periphery of the nuclei, membrane blebbing and formation of apoptotic bodies with fragmented nuclei, DNA fragmentation, enzymatic activation of pro-caspases, or phosphatidylserine translocation that can be measured using electron and cytochemical optical microscopy, proteomic and genomic methods, and spectroscopic techniques [Archana et al., 2013; Martinez et al., 2010; Taatjes et al., 2008; Yasuhara et al., 2003]. ・DNA fragmentation can be quantified with comet assay using electrophoresis, where the tail length, head size, tail intensity, and head intensity of the comet are measured [Yasuhara et al., 2003]. ・The apoptosis is detected with the expression alteration of procaspases 7 and 3 by Western blotting using antibodies [Parajuli et al., 2014]. ・The apoptosis is measured with down-regulation of anti-apoptotic gene baculoviral inhibitor of apoptosis protein repeat containing 2 (BIRC2, or cIAP1) [Parajuli et al., 2014]. ・Apoptotic nucleosomes are detected using Cell Death Detection ELISA kit, which was calculated as absorbance subtraction at 405 nm and 490 nm [Parajuli et al., 2014]. ・Cleavage of PARP is detected with Western blotting [Parajuli et al., 2014]. ・Caspase-3 and caspase-9 activity is measured with the enzyme-catalyzed release of p-nitroanilide (pNA) and quantified at 405 nm [Wu et al., 2016]. ・Apoptosis is measured with Annexin V-FITC probes, and the relative percentage of Annexin V-FITC-positive/PI-negative cells is analyzed by flow cytometry [Wu et al., 2016]. ・Apoptosis is detected with the Terminal dUTP Nick End-Labeling (TUNEL) method to assay the endonuclease cleavage products by enzymatically end-labeling the DNA strand breaks [Kressel and Groscurth, 1994]. ・For the detection of apoptosis, the testes are fixed in neutral buffered formalin and embedded in paraffin. Germ cell death is visualized in testis sections by Terminal dUTP Nick End-Labeling (TUNEL) staining method [Wade et al., 2008]. The incidence of TUNEL-positive cells is expressed as the number of positive cells per tubule examined for one entire testis section per animal [Wade et al., 2008]

・Apoptosis is induced in human prostate cancer cell lines (Homo sapiens) [Parajuli et al., 2014]. ・Apoptosis occurs in B6C3F1 mouse (Mus musculus) [Elmore, 2007]. ・Apoptosis occurs in Sprague-Dawley rat (Rattus norvegicus) [Elmore, 2007]. ・Apoptosis occurs in the nematode (Caenorhabditis elegans) [Elmore, 2007]. <ul> <li>Apoptosis occurs in breast cancer cells, human and mouse (Parton)</li> <li style="text-align:justify">Apoptosis applicable to fishes, hence be used to study as models (dos Santos, N. M., et al. (2008).</li> <li style="text-align:justify">Apoptosis in humans and baboon ovaries (Kugu, K., et al. (1998)</li> <li style="text-align:justify">Apoptosis in amphibians during metamorphosis (Ishizuya-Oka, A., et al. (2010).</li> <li style="text-align:justify">Apoptosis in Drosophila melanogaster (Steller, H. (2008)</li> <li style="text-align:justify">Apoptosis is a highly conserved and essential process across a broad taxonomic range, from unicellular eukaryotes to complex multicellular animals, it is also evident in metazoans (Suraweera, C. D., et al. (2022).</li> <li> Sex Applicability: Both sexes. Apoptosis occurs in male and female systems (e.g., oocyte and sperm cell turnover). </li> <li> Life Stage Applicability: All stages. Especially critical during embryonic development and in maintaining adult tissue homeostasis. </li> </ul>

UBERON:0000062

UBERON organ

CL:0000000

CL cell

High Unspecific

High

Not Otherwise Specified

High High High High

Archana, M. et al. (2013), "Various methods available for detection of apoptotic cells", Indian J Cancer 50:274-283 Elmore, S. (2007), "Apoptosis: a review of programmed cell death", Toxicol Pathol 35:495-516 Glaser, K.B. et al. (2003), "Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines", Mol Cancer Ther 2:151-163 Kerr, J.F.R. et al. (1972), "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics", Br J Cancer 26:239-257 Kressel, M. and Groscurth, P. (1994), "Distinction of apoptotic and necrotic cell death by in situ labelling of fragmented DNA", Cell Tissue Res 278:549-556 Martinez, M.M. et al. (2010), "Detection of apoptosis: A review of conventioinal and novel techniques", Anal Methods 2:996-1004 Parajuli, K.R. et al. (2014), "Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis", Am J Clin Exp Urol 2:300-313 Pucci, B. et al. (2000), "Cell cycle and apoptosis", Neoplasia 2:291-299 Taatjes, D.J. et al. (2008), "Morphological and cytochemical determination of cell death by apoptosis", Histochem Cell Biol 129:33-43 Wade, M.G. et al. (2008), "Methoxyacetic acid-induced spermatocyte death is associated with histone hyperacetylation in rats", Biol Reprod 78:822-831 Wang, C. et al. (2017), "CD147 regulates extrinsic apoptosis in spermatocytes by modulating NFkB signaling pathways", Oncotarget 8:3132-3143 Wu, R. et al. (2016), "microRNA-497 induces apoptosis and suppressed proliferation via the Bcl-2/Bax-caspase9-caspase 3 pathway and cyclin D2 protein in HUVECs", PLoS One 11:e0167052 Yasuhara, S. et al. (2003), "Comparison of comet assay, electron microscopy, and flow cytometry for detection of apoptosis", J Histochem Cytochem 51:873-885 Zupkovitz, G. et al. (2010), "The cyclin-dependent kinase inhibitor p21 is a crucial target for histone deacetylase 1 as a regulator of cellular proliferation", Mol Cell Biol 30:1171-1181   Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013. PMID: 21376230 Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007 Feb 26;26(9):1324-37. doi: 10.1038/sj.onc.1210220. PMID: 17322918; PMCID: PMC2930981. Lowe, S., Cepero, E. & Evan, G. Intrinsic tumour suppression. Nature 432, 307–315 (2004). <a href="https://doi.org/10.1038/nature03098" style="color:#467886; text-decoration:underline">https://doi.org/10.1038/nature03098</a> Parton M, Dowsett M, Smith I. Studies of apoptosis in breast cancer. BMJ. 2001 Jun 23;322(7301):1528-32. doi: 10.1136/bmj.322.7301.1528. PMID: 11420276; PMCID: PMC1120573. Junttila MR, Evan GI. p53--a Jack of all trades but master of none. Nat Rev Cancer. 2009 Nov;9(11):821-9. doi: 10.1038/nrc2728. Epub 2009 Sep 24. PMID: 19776747. Williams MM, Cook RS. Bcl-2 family proteins in breast development and cancer: could Mcl-1 targeting overcome therapeutic resistance? Oncotarget. 2015 Feb 28;6(6):3519-30. doi: 10.18632/oncotarget.2792. PMID: 25784482; PMCID: PMC4414133. Shahbandi A, Nguyen HD, Jackson JG. TP53 Mutations and Outcomes in Breast Cancer: Reading beyond the Headlines. Trends Cancer. 2020 Feb;6(2):98-110. doi: 10.1016/j.trecan.2020.01.007. Epub 2020 Feb 5. PMID: 32061310; PMCID: PMC7931175. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013. PMID: 21376230 Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007 Feb 26;26(9):1324-37. doi: 10.1038/sj.onc.1210220. PMID: 17322918; PMCID: PMC2930981. Lowe, S., Cepero, E. & Evan, G. Intrinsic tumour suppression. Nature 432, 307–315 (2004). <a href="https://doi.org/10.1038/nature03098" style="color:#467886; text-decoration:underline">https://doi.org/10.1038/nature03098</a> Parton M, Dowsett M, Smith I. Studies of apoptosis in breast cancer. BMJ. 2001 Jun 23;322(7301):1528-32. doi: 10.1136/bmj.322.7301.1528. PMID: 11420276; PMCID: PMC1120573. Junttila MR, Evan GI. p53--a Jack of all trades but master of none. Nat Rev Cancer. 2009 Nov;9(11):821-9. doi: 10.1038/nrc2728. Epub 2009 Sep 24. PMID: 19776747. Williams MM, Cook RS. Bcl-2 family proteins in breast development and cancer: could Mcl-1 targeting overcome therapeutic resistance? Oncotarget. 2015 Feb 28;6(6):3519-30. doi: 10.18632/oncotarget.2792. PMID: 25784482; PMCID: PMC4414133. Shahbandi A, Nguyen HD, Jackson JG. TP53 Mutations and Outcomes in Breast Cancer: Reading beyond the Headlines. Trends Cancer. 2020 Feb;6(2):98-110. doi: 10.1016/j.trecan.2020.01.007. Epub 2020 Feb 5. PMID: 32061310; PMCID: PMC7931175.   Parton M, Dowsett M, Smith I. Studies of apoptosis in breast cancer. BMJ. 2001 Jun 23;322(7301):1528-32. doi: 10.1136/bmj.322.7301.1528. PMID: 11420276; PMCID: PMC1120573.   <ul> <li>Kaur S, Kurokawa M. Regulation of Oocyte Apoptosis: A View from Gene Knockout Mice. Int J Mol Sci. 2023;24(2).</li> <li>Jin X, Xiao LJ, Zhang XS, Liu YX. Apotosis in ovary. Front Biosci (Schol Ed). 2011;3(2):680-97.</li> <li>Hussein MR. Apoptosis in the ovary: molecular mechanisms. Hum Reprod Update. 2005;11(2):162-77.</li> <li>dos Santos NM, do Vale A, Reis MI, Silva MT. Fish and apoptosis: molecules and pathways. Curr Pharm Des. 2008;14(2):148-69.</li> <li>Kugu K, Ratts VS, Piquette GN, Tilly KI, Tao XJ, Martimbeau S, et al. Analysis of apoptosis and expression of bcl-2 gene family members in the human and baboon ovary. Cell Death Differ. 1998;5(1):67-76.</li> <li>Ishizuya-Oka A, Hasebe T, Shi YB. Apoptosis in amphibian organs during metamorphosis. Apoptosis. 2010;15(3):350-64.</li> <li>Steller H. Regulation of apoptosis in Drosophila. Cell Death & Differentiation. 2008;15(7):1132-8.</li> <li>Suraweera CD, Banjara S, Hinds MG, Kvansakul M. Metazoans and Intrinsic Apoptosis: An Evolutionary Analysis of the Bcl-2 Family. International Journal of Molecular Sciences. 2022;23(7):3691.</li> </ul> AOPWiki 2017-02-07T13:21:50

2025-05-31T08:50:09

decline, neural progenitor cells

Organ

AOPWiki 2024-01-10T04:44:24

2024-01-10T04:44:24

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AOPWiki 2022-01-21T07:18:45

2022-01-21T07:18:45

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AOPWiki 2022-03-17T12:16:34

2022-03-17T12:16:34

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AOPWiki 2022-03-09T08:20:00

2022-03-09T08:20:00

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AOPWiki 2022-03-21T11:48:52

2022-03-21T11:48:52

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AOPWiki 2024-01-10T04:45:15

2024-01-10T04:45:15

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AOPWiki 2024-01-10T04:46:04

2024-01-10T04:46:04

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AOPWiki 2024-01-10T04:46:26

2024-01-10T04:46:26

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AOPWiki 2024-01-10T04:47:01

2024-01-10T04:47:01

Ionizing radiation-induced DNA damage leads to microcephaly via apoptosis and premature cell differentiation

Increased DNA damages during embryonic development lead to microcephaly

Olivier ARMANT

Olivier ARMANT (IRSN) Christelle ADAM-GUILLERMIN (IRSN) Karine AUDOUZE (Univ Paris Cité) Omid AZIMZADEH (Bfs) Rafi Benotmane (CSK CEN) Christelle DURAND (IRSN) Chrystelle IBANEZ (IRSN) Thomas JAYLET (Univ Paris Cité) Olivier LAURENT (IRSN) Jukka LUUKKONEN (UEF) Roel QUINTENS (SCK CEN) Magdalini SACHANA (OECD) Ingacia TANAKA (IES) Knut Erik Tollefsen (NIVA) Vinita Chauhan (Health Canada)

BY-SA

2.0

Exposures to ionizing radiations during the early phase of embryonic development can alter the process of brain development, increasing the risk of microcephaly. Excessive accumulation of DNA damages in cycling progenitors in the ventricular zone (VZ) and in the subventricular zone (SVZ) activates P53 leading primarily to cellular death via apoptosis and premature neuronal differentiation. Reduction of the progenitors pool consequently affect brain growth leading to microcephaly

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.

adjacent

Not Specified

High adjacent

Not Specified

High adjacent

Not Specified

Moderate adjacent

Low

Moderate adjacent

Low

High adjacent

Low

Low adjacent

Low

High non-adjacent

Not Specified

High

High Unspecific

High

Pregnancy

High High Low

Term                           Scientific Term                                    Evidence         NCBI taxonid mouse                         Mus musculus                                     High                 10090 human                         Homo sapiens                                     High                 9606 rat                               Rattus norvegicus                               High                 10114

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

High

AOPWiki 2022-03-09T07:33:35

2025-10-10T09:18:04