Uranyl acetate induces hprt mutations and uranium-DNA adducts in Chinese hamster ovary EM9 cells

Diane M Stearns, Monica Yazzie, Andrew S. Bradley, Virginia H. Coryell, Jake T. Shelley, Adam Ashby, Craig S. Asplund, R. Clark Lantz

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Abstract

Questions about possible adverse health effects from exposures to uranium have arisen as a result of uranium mining, residual mine tailings and use of depleted uranium in the military. The purpose of the current study was to measure the toxicity of depleted uranium as uranyl acetate (UA) in mammalian cells. The activity of UA in the parental CHO AA8 line was compared with that in the XRCC1-deficient CHO EM9 line. Cytotoxicity was measured by clonogenic survival. A dose of 200 μM UA over 24 h produced 3.1-fold greater cell death in the CHO EM9 than the CHO AA8 line, and a dose of 300 μM was 1.7-fold more cytotoxic. Mutagenicity at the hypoxanthine (guanine) phosphoribosyltransferase (hprt) locus was measured by selection with 6-thioguanine. A dose of 200 μM UA produced ∼5-fold higher averaged induced mutant frequency in the CHO EM9 line relative to the CHO AA8 line. The generation of DNA strand breaks was measured by the alkaline comet assay at 40 min and 24 h exposures. DNA strand breaks were detected in both lines; however a dose response may have been masked by U-DNA adducts or crosslinks. Uranium-DNA adducts were measured by inductively coupled plasma optical emission spectroscopy (ICP-OES) at 24 and 48 h exposures. A maximum adduct level of 8 U atoms/103 DNA-P for the 300 μM dose was found in the EM9 line after 48 h. This is the first report of the formation of uranium-DNA adducts and mutations in mammalian cells after direct exposure to a depleted uranium compound. Data suggest that uranium could be chemically genotoxic and mutagenic through the formation of strand breaks and covalent U-DNA adducts. Thus the health risks for uranium exposure could go beyond those for radiation exposure.

Original languageEnglish (US)
Pages (from-to)417-423
Number of pages7
JournalMutagenesis
Volume20
Issue number6
DOIs
StatePublished - Nov 2005

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Stearns, D. M., Yazzie, M., Bradley, A. S., Coryell, V. H., Shelley, J. T., Ashby, A., Asplund, C. S., & Lantz, R. C. (2005). Uranyl acetate induces hprt mutations and uranium-DNA adducts in Chinese hamster ovary EM9 cells. Mutagenesis, 20(6), 417-423. https://doi.org/10.1093/mutage/gei056