ToxSci Advance Access originally published online on July 13, 2006
Toxicological Sciences 2006 93(2):286-297; doi:10.1093/toxsci/kfl060
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Uranyl Nitrilotriacetate, a Stabilized Salt of Uranium, is Genotoxic in Nontransformed Human Colon Cells and in the Human Colon Adenoma Cell Line LT97
* Department of Nutritional Toxicology, Institute for Nutrition, Institute for Human Genetics and Anthropology, and Department of General and Visceral Surgery, Friedrich-Schiller-University Jena, 07743 Jena, Germany
Received March 24, 2006; accepted June 28, 2006
Previous uranium mining in the "Wismut" region in Germany enhanced environmental distribution of heavy metals and radionuclides. Carryover effects may now lead to contamination of locally produced foods. Compounds of "Wismut" origin are probably genotoxic via their irradiating components (radon) or by interacting directly with cellular macromolecules. To assess possible hazards, we investigated the genotoxic effects of uranyl nitrilotriacetate (U-NTA) in human colon tumor cells (HT29 clone 19A), adenoma cells (LT97), and nontransformed primary colon cells. These are target cells of oral exposure to environmentally contaminated foods and represent different cellular stages during colorectal carcinogenesis. Colon cells were incubated with U-NTA. Cell survival, cytotoxicity, cellular glutathione (GSH) levels, genotoxicity, and DNA repair capacity (comet assay), as well as gene- and chromosome-specific damage combination of comet assay and fluorescence in situ hybridization [FISH], 24-color FISH) were determined. U-NTA inhibited growth of HT29 clone 19A cells (75–2000µM, 72 h) and increased GSH (125–2000µM, 24 h). U-NTA was genotoxic (1000µM, 30 min) but did not inhibit the repair of DNA damage caused by hydrogen peroxide (H2O2), 4-hydroxynonenal, and 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]-pyridine. U-NTA was also genotoxic in LT97 cells and primary colon cells, where it additionally increased migration of TP53 into the comet tail. In LT97 cells, 0.5–2mM U-NTA increased chromosomal aberrations in chromosomes 5, 12, and 17, which harbor the tumor-related genes APC, KRAS, and TP53. It may be concluded that uranium compounds could increase alimentary genotoxic exposure in humans if they reach the food chain in sufficient amounts.
Key Words: colon cells; U-NTA; GSH; comet assay; TP53; chromosomal aberrations.
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