Effects of cell cycle specific exposure to 3 H-thymidine or 3 H-arginine on development and cell proliferation of mouse embryos

Müller, W.-U.; Heckeley, N.; Streffer, C.

doi:10.1007/s004110050039

Cited by 5 publications

(4 citation statements)

References 17 publications

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“…Among such biomarkers are probes of DNA replication. Radioactive precursors of DNA such as tritium [ 3 H]‐thymidine or [ 14 C]‐thymidine, used in the early studies utilizing autoradiography, have been shown to induce DNA radiation damage, including formation of DNA double‐strand breaks (DSBs), and to perturb the cell cycle progression . The most widely used DNA precursor 5‐bromo‐2′‐deoxyuridine (BrdU) introduced with the down of flow cytometry was also shown to induce cytostatic and cytotoxic effects .…”

mentioning

confidence: 99%

DNA damage signaling, impairment of cell cycle progression, and apoptosis triggered by 5‐ethynyl‐2′‐deoxyuridine incorporated into DNA

Zhao

Halicka

et al. 2013

Cytometry Pt A

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The “click chemistry” approach utilizing 5-ethynyl-2′-deoxyuridine (EdU) as a DNA precursor was recently introduced to assess DNA replication and adapted to flow- and imaging-cytometry. In the present study, we observed that EdU, once incorporated into DNA, induces DNA damage signaling (DDS) such as phosphorylation of ATM on Ser1981, of histone H2AX on Ser139, of p53 on Ser15, and of Chk2 on Thr68. It also perturbs progression of cells through the cell cycle and subsequently induces apoptosis. These effects were observed in non-small cell lung adenocarcinoma A549 as well as in B-cell human lymphoblastoid TK6 and WTK1 cells, differing in the status of p53 (wt versus mutated). After 1 h EdU pulse-labeling, the most affected was cells progression through the S phase subsequent to that at which they had incorporated EdU. This indicates that DNA replication using the template containing incorporated EdU is protracted and triggers DDS. Furthermore, progression of cells having DNA pulse-labeled with EdU led to accumulation of cells in G2, likely by activating G2 checkpoint. Consistent with the latter was activation of p53 and Chk2. Although a correlation was observed in A549 cells between the degree of EdU incorporation and the extent of γH2AX induction, such correlation was weak in TK6 and WTK1 cells. The degree of perturbation of the cell cycle kinetics by the incorporated EdU was different in the wt p53 TK6 cells as compared to their sister WTK1 cell line having mutated p53. The data are thus consistent with the role of p53 in modulating activation of cell cycle checkpoints in response to impaired DNA replication. The confocal microscopy analysis of the 3D images of cells exposed to EdU for 1 h pulse and then grown for 24 or 48 h revealed an increased number of colocalized γH2AX and p53BP1 foci considered to be markers of DNA double-strand breaks and enlarged nuclei.

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mentioning

confidence: 99%

DNA damage signaling, impairment of cell cycle progression, and apoptosis triggered by 5‐ethynyl‐2′‐deoxyuridine incorporated into DNA

Zhao

Halicka

et al. 2013

Cytometry Pt A

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“…The intranuclear distribution of radionuclides is not unique to iodine isotopes. Depending on their injected chemical form, 51 Cr, 55 Fe, 57 Co, 65 Zn, 67 Ga, 77 Br, 99m Tc, 111 In and 195m Pm isotopes are all Auger-emitting radionuclides able to bind to the cell nuclei or even the DNA [23]. Similarly, among beta emitters, tritium and 59 Fe can concentrate within cell nuclei or even within the DNA molecule, depending on their chemical form at the time of intake [24].…”

Section: 21mentioning

confidence: 99%

“…Toxicity of tritium bound to DNA precursors. Tritiated thymidine can cause in vitro cell death [50,51], chromosomal aberrations [52] and cancers in animals [53][54][55]. These effects are therefore not qualitatively different from those observed with tritiated water.…”

Section: 222mentioning

confidence: 99%

“…Many experiments have been performed with 123 I and 125 I as well as the beta emitter 131 I, associated with many vectors traditionally used in medicine. These studies have been complemented with other conducted in vivo with 59 Fe, 99m Tc, 111 In, 114m In and 201 Ta [61][62][63][64] or in vitro with 75 Se, 51 Cr, 67 Ga and 77 Br [23,[65][66][67][68]. All these studies provide an improved understanding of the toxicity of Auger emitters and permit conclusions to be drawn on the general toxicity of Auger emitters [21,[69][70][71].…”

Section: 222mentioning

confidence: 99%

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The assessment and management of risks associated with exposures to short-range Auger- and beta-emitting radionuclides. State of the art and proposals for lines of research

Paquet¹,

Barbey²,

Bardiès³

et al. 2013

J. Radiol. Prot.

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The assessment and management of risks associated with exposures to ionising radiation are defined by the general radiological protection system, proposed by the International Commission on Radiological Protection (ICRP). This system is regarded by a large majority of users as a robust system although there are a number of dissenting voices, claiming that it is not suitable for estimating the risks resulting from internal exposures. One of the specific issues of internal exposure involves short-range radiations such as Auger and beta particles. Auger- and beta-emitting radionuclides can be distributed preferentially in certain tissue structures and even in certain cellular organelles, according to their chemical nature and the vector with which they are associated. Given the limited range of the low-energy electrons in biological matter, this heterogeneous distribution can generate highly localised energy depositions and exacerbate radiotoxic responses at cellular level. These particularities in energy distribution and cellular responses are not taken into account by the conventional methods for the assessment of risk.Alternative systems have been proposed, based on dosimetry conducted at the cellular or even molecular level, whose purpose is to determine the energy deposition occurring within the DNA molecule. However, calculation of absorbed doses at the molecular level is not sufficient to ensure a better assessment of the risks incurred. Favouring such a microdosimetric approach for the risk assessments would require a comprehensive knowledge of the biological targets of radiation, the dose-response relationships at the various levels of organisation, and the mechanisms leading from cellular energy deposition to the appearance of a health detriment. The required knowledge is not fully available today and it is not yet possible to link an intracellular energy deposition to a probability of occurrence of health effects or to use methods based on cellular dosimetry directly.The imperfections of the alternative approaches proposed so far should not discourage efforts. Protection against exposure to Auger and low-energy beta emitters would benefit from mechanistic studies, dedicated to the study of energy depositions of the radionuclides in various cellular structures, but also from radiotoxicological studies to define the relative biological effectiveness of the various Auger emitters used in medicine and of certain low-energy beta emitters, whose behaviour may depend greatly on their chemical form during intake. The scientific expertise, as well as the human and physical resources needed to conduct these studies, is available. They could be now mobilised into international low-dose research programmes, in order to ultimately improve the protection of people exposed to these specific radionuclides.

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Radiation-induced malformations after exposure of murine germ cells in various stages of spermatogenesis

Müller¹,

Streffer²,

Wójcik³

et al. 1999

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Effects of cell cycle specific exposure to 3 H-thymidine or 3 H-arginine on development and cell proliferation of mouse embryos

Cited by 5 publications

References 17 publications

DNA damage signaling, impairment of cell cycle progression, and apoptosis triggered by 5‐ethynyl‐2′‐deoxyuridine incorporated into DNA

DNA damage signaling, impairment of cell cycle progression, and apoptosis triggered by 5‐ethynyl‐2′‐deoxyuridine incorporated into DNA

The assessment and management of risks associated with exposures to short-range Auger- and beta-emitting radionuclides. State of the art and proposals for lines of research

Radiation-induced malformations after exposure of murine germ cells in various stages of spermatogenesis

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