Synergistic cytotoxicity and DNA strand breaks in cells and plasmid DNA exposed to uranyl acetate and ultraviolet radiation

Wilson, Janice; Zuniga, Mary C.; Yazzie, Filbert; Stearns, Diane M.

doi:10.1002/jat.3015

Cited by 15 publications

(8 citation statements)

References 87 publications

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“…In cells, uranium causes DNA damage and mutations (Stearns et al, 2005; Coryell and Stearns, 2006; Knobel et al, 2006; Wilson et al, 2014) and we find evidence for strand break in response to 10 μM UA in normal human keratinocytes. Uranium has been shown to cause DNA adducts and strand breaks in the presence of ascorbate (Wilson et al, 2014) and potentiate UV-induced strand breaks through a mechanism involving photoactivation of the uranyl ion (George et al, 2011; Wilson et al, 2015). In addition to these mechanisms, we find that low, non-cytotoxic concentrations of UA inhibit DNA repair and enhance UVR-induced DNA damage indicating that uranium may act as a co-carcinogen when combined with other DNA damaging insults.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of poly(ADP-ribose)polymerase-1 and DNA repair by uranium

Cooper

Dashner

Tsosie

et al. 2016

Toxicology and Applied Pharmacology

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Uranium has radiological and non-radiological effects within biological systems and there is increasing evidence for genotoxic and carcinogenic properties attributable to uranium through its heavy metal properties. In this study, we report that low concentrations of uranium (as uranyl acetate; <10 μM) is not cytotoxic to human embryonic kidney cells or normal human keratinocytes; however, uranium exacerbates DNA damage and cytotoxicity induced by hydrogen peroxide, suggesting that uranium may inhibit DNA repair processes. Concentrations of uranyl acetate in the low micromolar range inhibited the zinc finger DNA repair protein poly(ADP-ribose) polymerase (PARP)-1 and caused zinc loss from PARP-1 protein. Uranyl acetate exposure also led to zinc loss from the zinc finger DNA repair proteins Xeroderma Pigmentosum, Complementation Group A (XPA) and aprataxin (APTX). In keeping with the observed inhibition of zinc finger function of DNA repair proteins, exposure to uranyl acetate enhanced retention of induced DNA damage. Co-incubation of uranyl acetate with zinc largely overcame the impact of uranium on PARP-1 activity and DNA damage. These findings present evidence that low concentrations of uranium can inhibit DNA repair through disruption of zinc finger domains of specific target DNA repair proteins. This may provide a mechanistic basis to account for the published observations that uranium exposure is associated with DNA repair deficiency in exposed human populations.

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Section: Discussionmentioning

confidence: 99%

Inhibition of poly(ADP-ribose)polymerase-1 and DNA repair by uranium

Cooper

Dashner

Tsosie

et al. 2016

Toxicology and Applied Pharmacology

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“…The alkaline version of comet assay is capable to detect various lesions, such as single and/or double stranded, apurinic sites, the oxidative damage in genetic materials [18] even at low IR doses (e.g. -25 cGy) [19].…”

Section: Dna Damage Profile In Peripheral Blood Lymphocytes Of Ir Expmentioning

confidence: 99%

Genotoxicity and DNA repair indicative in blood cells after occupational exposure to ionizing radiation

Silva¹,

Alencar²,

Teixeira³

et al. 2016

Int Arch Med

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Occupational exposure to ionizing radiation (IR) can damage DNA. The study evaluated the genotoxic profile and repair indicatives of DNA from peripheral blood lymphocytes of health workers exposed occupationally to IR by adopting comet assay. Biomonitoring was done with ninety individuals; among them 45 were health professionals and the rests were non-professionals. Blood samples were collected after 48 h (2 d; non-exposed) and 168 h (7 d; exposed). The 7 d IR exposed group significantly increased in the rates and frequency of damage, while 2 d unexposed group exhibited more than 20% of DNA repair as compared to the respective control groups. The DNA damage was observed in more significant to the younger workers (18-27 y). However, the hematological abnormalities were not observed, despite of their positive correlation in genotoxic profile. Significant and positive correlations were observed in relation to the used medicaments, low consumption of vegetables as well as the type and place of work. In conclusion, biomarkers involved in comet assay can be applied in biomonitoring of genetic instability, including IR induced phenomena.

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“…Therefore, it is important to determine cellular responses to uranium-induced toxicity at more environmentally relevant concentrations ranging from 50 – 300 μM or 12 – 72 ppm U. Several studies have shown that uranium is not genotoxic at this lower concentration range and activates cellular stress responses rather than cell-mediated death responses (Wilson 2015, Guéguen 2015, Garmash 2014).…”

Section: Introductionmentioning

confidence: 99%

Uranyl acetate induced DNA single strand breaks and AP sites in Chinese hamster ovary cells

Yellowhair

Romanotto

Stearns

et al. 2018

Toxicology and Applied Pharmacology

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The aim of this study is to characterize the genotoxicity of depleted uranium (DU) in Chinese Hamster Ovary cells (CHO) with mutations in various DNA repair pathways. CHO cells were exposed to 0-300 μM of soluble DU as uranyl acetate (UA) for 0-48 h. Intracellular UA concentrations were measured via inductively coupled mass spectrometry (ICP-MS) and visualized by transmission electron microscopy (TEM). Cytotoxicity was assessed in vitro by clonogenic survival assay. DNA damage response was assessed via Fast Micromethod® to determine UA-induced DNA single strand breaks. Results indicate that UA is entering the CHO cells, with the highest concentration localizing in the nucleus. Clonogenic assays show that UA is cytotoxic in each cell line with the greatest cytotoxicity in the base excision repair deficient EM9 cells and the nuclear excision repair deficient UV5 cells compared to the non-homologous end joining deficient V3.3 cells and the parental AA8 cells after 48 h. This indicates that UA is producing single strand breaks and forming UA-DNA adducts rather than double strand breaks in CHO cells. Fast Micromethod® results indicate an increased amount of single strand breaks in the EM9 cells after 48 h UA exposure compared to the V3.3 and AA8 cells. These results indicate that DU induces DNA damage via strand breaks and uranium-DNA adducts in treated cells. These results suggest that: (1) DU is genotoxic in CHO cells, and (2) DU is inducing single strand breaks rather than double strand breaks in vitro.

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Synergistic cytotoxicity and DNA strand breaks in cells and plasmid DNA exposed to uranyl acetate and ultraviolet radiation

Cited by 15 publications

References 87 publications

Inhibition of poly(ADP-ribose)polymerase-1 and DNA repair by uranium

Inhibition of poly(ADP-ribose)polymerase-1 and DNA repair by uranium

Genotoxicity and DNA repair indicative in blood cells after occupational exposure to ionizing radiation

Uranyl acetate induced DNA single strand breaks and AP sites in Chinese hamster ovary cells

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