Uranyl Acetate Causes DNA Single Strand Breaks In Vitro in the Presence of Ascorbate (Vitamin C)

Abstract

Uranium is a radioactive heavy metal with isotopes that decay on the geological time scale. People are exposed to uranium through uranium mining, processing, the resulting mine tailings, and the use of depleted uranium in the military. Acute exposures to uranium are chemically toxic to the kidney; however, little is known about chronic exposures, for example, if there is a direct chemical genotoxicity of uranium. The hypothesis that is being tested in the current work is that hexavalent uranium, as uranyl ion, may have a chemical genotoxicity similar to that of hexavalent chromium. In the current study, reactions of uranyl acetate (UA) and ascorbate (vitamin C) were observed to produce plasmid relaxation in pBluescript DNA. DNA strand breaks increased with increasing concentrations of a 1:1 reaction of UA and ascorbate but were not affected by increasing the ratio of ascorbate. Plasmid relaxation was inhibited by coincubation of reactions with catalase but not by coincubation with the radical scavengers mannitol, sodium azide, or 5,5-dimethyl-1-pyrroline-N-oxide. Reactions of UA and ascorbate monitored by (1)H NMR spectroscopy showed formation of a uranyl ascorbate complex, with no evidence of a dehydroascorbate product. A previous study inferred that hydroxyl radical formation was responsible for oxidative DNA damage in the presence of reactions of uranyl ion, hydrogen peroxide, and ascorbate [Miller et al. (2002) J. Bioinorg. Chem. 91, 246-252]. Current results, in the absence of added hydrogen peroxide, were not completely consistent with the interpretation that strand breaks were produced by a Fenton type generation of reactive oxygen species. Data were also consistent with the interpretation that a uranyl ascorbate complex was catalyzing hydrolysis of the DNA-phosphate backbone, in a manner similar to that known for the lanthanides. These data suggest that uranium may be directly genotoxic and may, like chromium, react with DNA by more than one pathway.

Does uranium exposure induce genotoxicity in the teleostean Danio rerio? First experimental results

“…Among experiments focused on uranium toxicity evaluation, Yazzie et al [3] also demonstrated uranium-induced genotoxicity (via an in vitro experiment carried out on plasmid DNA). Theses authors hypothesized that hexavalent uranium, as uranyl ion, may have a chemical genotoxicity similar to that of hexavalent chromium (a known human carcinogen), since there are some parallels between their chemistry.…”

“…Indeed, uranium is categorized as a heavy metal with a radiotoxic potential, it is the heaviest naturally occurring element and its typical concentration range in surface waters is 3.10 -2 to 2 µg/L [1]. Considering uranium chemical characteristics, as any heavy metal, this radioelement is a potent genotoxic compound via the formation of oxidative DNA damages due to the redox chemistry of transition metals and their ability to activate oxygen species in the course of redox reactions [2] [3]. In the same way, its radiological properties being characterized by ionising radiations (mainly via the emission of α particles) can enhance this free radical production [4].…”

Uranium induces oxidative stress in lung epithelial cells

“…In addition, it has been found that people subjected to heavy amounts of stress are more susceptible to uranium toxicity (Albina et al 2003). Previous studies have shown cancer mortality in men living in counties of Colorado where uranium tailings were used as construction fills (Yazzie et al 2003). It is further demonstrated that uranium can be correlated with their mutagenicity in a dose and time dependent manner (Stearns et al 2005).…”

“…Exposure to uranium often occurs during mining, processing, and from mine tailings (Yazzie et al 2003). Therefore, effective management of waste uranium compounds is necessary to prevent exposure and adverse health effects cause a growing concern.…”

“…The occurrence of a genomic instability in lymphocytes of uranium miners, especially those who developed cancer was observed by studying the cytogenetic endpoint: marker micronuclei (Mn) (Kryscio et al 2001). Further in vitro analysis with uranium acetate have shown significant increase in DNA single strand breaks in presence of ascorbic acid (Yazzie et al 2003). Treatment of DU to J774 macrophage cells resulted in the apoptotic death of these cells as confirmed by both DNA ladder and annexin V staining (Kalinich et al 2002).…”