Comparative investigations of sodium arsenite, arsenic trioxide and cadmium sulphate in combination with gamma-radiation on apoptosis, micronuclei induction and DNA damage in a human lymphoblastoid cell line

BfS-Federal Office for Radiation Protection, Department of Radiation Protection and Health, Ingolstädter Landstr. 1, 85764 Oberschleissheim, Germany.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis (Impact Factor: 3.68). 09/2006; 600(1-2):165-76. DOI: 10.1016/j.mrfmmm.2006.04.002
Source: PubMed


In the field of radiation protection the combined exposure to radiation and other toxic agents is recognised as an important research area. To elucidate the basic mechanisms of simultaneous exposure, the interaction of the carcinogens and environmental toxicants cadmium and two arsenic compounds, arsenite and arsenic trioxide, in combination with gamma-radiation in human lymphoblastoid cells (TK6) were investigated. Gamma-radiation induced significant genotoxic effects such as micronuclei formation, DNA damage and apoptosis, whereas arsenic and cadmium had no significant effect on these indicators of cellular damage at non-toxic concentrations. However, in combination with gamma-radiation arsenic trioxide induced a more than additive apoptotic rate compared to the sum of the single effects. Here, the level of apoptotic cells was increased, in a dose-dependent way, up to two-fold compared to the irradiated control cells. Arsenite did not induce a significant additive effect at any of the concentrations or radiation doses tested. On the other hand, arsenic trioxide was less effective than arsenite in the induction of DNA protein cross-links. These data indicate that the two arsenic compounds interact through different pathways in the cell. Cadmium sulphate, like arsenite, had no significant effect on apoptosis in combination with gamma-radiation at low concentrations and, at high concentrations, even reduced the radiation-induced apoptosis. An additive effect on micronuclei induction was observed with 1muM cadmium sulphate with an increase of up to 80% compared to the irradiated control cells. Toxic concentrations of cadmium and arsenic trioxide seemed to reduce micronuclei induction. The results presented here indicate that relatively low concentrations of arsenic and cadmium, close to those occuring in nature, may interfere with radiation effects. Differences in action of the two arsenic compounds were identified.

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Available from: Sabine Hornhardt, Feb 26, 2014
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    • "Hornhardt et al. (2006) showed that the combination of arsenic trioxide in the concentration close to that occurring in nature induces MN in human lymphoblastoid cells if combined with gamma-radiation. Similar observations were made for genotoxicity of chelate complexes of mercury (II) employed in detoxification of some polluted areas. "
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    ABSTRACT: Micronuclei (MN) are extra-nuclear bodies that contain damaged chromosome fragments and/or whole chromosomes that were not incorporated into the nucleus after cell division. MN can be induced by defects in the cell repair machinery and accumulation of DNA damages and chromosomal aberrations. A variety of genotoxic agents may induce MN formation leading to cell death, genomic instability, or cancer development. In this review, the genetic and epigenetic mechanisms of MN formation after various clastogenic and aneugenic effects on cell division and cell cycle are described. The knowledge accumulated in literature on cytotoxicity of various genotoxins is precisely reflected and individual sensitivity to MN formation due to single gene polymorphisms is discussed. The importance of rapid MN scoring with respect to the cytokinesis-block micronucleus assay is also evaluated.
    Full-text · Article · Jul 2013 · Frontiers in Genetics
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    • "The multiple stressor effects of Cd and gamma rays on Wistar rats were studied through their enzyme activities, where a synergistic increase was reported (Salovsky et al 1993). Another study on human lymphoblastoid cells through the frequency of micronucleus formation showed an additive effect of Cd and gamma-ray exposure (Hornhardt et al 2006). An in vivo antagonistic effect was reported by Privezentsev et al (1996). "
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    ABSTRACT: An adaptive response is a biological response where the exposure of cells or animals to a low priming exposure induces mechanisms that protect the cells or animals against the detrimental effects of a subsequent larger challenging exposure. In realistic environmental situations, living organisms can be exposed to a mixture of stressors, and the resultant effects due to such exposures are referred to as multiple stressor effects. In the present work we demonstrated, via quantification of apoptosis in the embryos, that embryos of the zebrafish (Danio rerio) subjected to a priming exposure provided by one environmental stressor (cadmium in micromolar concentrations) could undergo an adaptive response against a subsequent challenging exposure provided by another environmental stressor (alpha particles). We concluded that zebrafish embryos treated with 1 to 10 μM Cd at 5 h postfertilisation (hpf) for both 1 and 5 h could undergo an adaptive response against subsequent ∼4.4 mGy alpha-particle irradiation at 10 hpf, which could be interpreted as an antagonistic multiple stressor effect between Cd and ionising radiation. The zebrafish has become a popular vertebrate model for studying the in vivo response to ionising radiation. As such, our results suggested that multiple stressor effects should be carefully considered for human radiation risk assessment since the risk may be perturbed by another environmental stressor such as a heavy metal.
    Full-text · Article · Jan 2013 · Journal of Radiological Protection
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    • "Additive, synergistic and antagonistic effects had been reported for Cd and gamma rays through in vitro and in vivo studies. Hornhardt et al. (2006) showed an additive effect of Cd and gamma ray exposure on human lymphoblastoid cells through the frequency of micronuclei formation. A synergistic effect between Cd and gamma ray on Wistar rats in terms of their enzyme activities were reported by Salovsky et al. (1993). "
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    ABSTRACT: The aim of this study was to demonstrate that zebrafish embryos subjected to a priming exposure provided by one environmental stressor (low-dose alpha particles) can induce an adaptive response against a subsequent challenging exposure provided by another environmental stressor (heavy metal Cd). The effect thus identified would be an antagonistic multiple stressor effect. The effects of alpha particle radiation and/or Cd on whole embryos were studied through quantification of apoptotic signals at 24 h post-fertilization (hpf). Embryos were stained with the vital dye acridine orange, followed by counting the stained cells. For each set of experiments, 30 dechorionated embryos were divided into three groups, each having ten embryos. The three groups of embryos were referred to as (A) the control group, which received no more further treatments after dechorionation, (B) Cd-treated group, which did not receive any priming exposure and would receive a challenging exposure at 10 hpf and (C) (alpha + Cd)-treated group, which would receive both priming and challenging exposures. We defined the normalized net number of apoptotic signals in the (alpha + Cd)-treated group as N (C) * = [(apoptotic signals for (alpha + Cd)-treated group - average apoptotic signals for the corresponding control group)/average apoptotic signals for the corresponding control group] and that in the Cd-treated group as N (B)* = [(apoptotic signals for Cd-treated group - average apoptotic signals for the corresponding control group)/ average apoptotic signals for the corresponding control group]. By using the non-parametric Mann-Whitney U statistic, we were able to show that N (C) * was significantly smaller than N (B) *(p = 0.006). These demonstrated an antagonistic multiple stressor effect between ionizing radiation and Cd through the induction of an adaptive response by the ionizing radiation against subsequent exposures to Cd.
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