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ToxSci Advance Access originally published online on May 23, 2007
Toxicological Sciences 2007 98(2):479-487; doi:10.1093/toxsci/kfm130
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Uranium Induces Apoptosis and Is Genotoxic to Normal Rat Kidney (NRK-52E) Proximal Cells

Céline Thiébault1, Marie Carrière, Sarah Milgram, Angélique Simon, Laure Avoscan and Barbara Gouget

Laboratoire Pierre Sue, CEA-CNRS UMR 9956, 91191 Gif sur Yvette, France

1 To whom correspondence should be addressed at Laboratoire Pierre Sue, Bat 639, CEA Saclay, 91191 Gif sur Yvette, France. Fax: +33-1-69086923. E-mail: celine.thiebault{at}cea.fr.

Received February 1, 2007; accepted May 1, 2007


  Abstract

Uranium (U) is a heavy metal used in the nuclear industry and for military applications. U compounds are toxic. Their toxicity is mediated either by their radioactivity or their chemical properties. Mammalian kidneys and bones are the main organs affected by U toxicity. Although the most characteristic response to U exposure is renal dysfunction, little information is available on the mechanisms of its toxicity at the molecular level. This report studied the genotoxicity of U. Apoptosis induction in normal rat kidney (NRK-52E) proximal cells was investigated as a function of exposure time or concentrations (0–800µM). In parallel, DNA damage was evaluated by several methods. In order to distinguish between the intrinsic and the extrinsic pathways of apoptosis, caspases-8, -9, -10 assays were conducted and the mitochondrial membrane potential was measured. Three methods were selected for their complementarities in the detection of genetic lesions. The comet assay was used for the detection of primary lesions of DNA. {gamma}-H2AX immunostaining was achieved to detect DNA double-strand breaks. The micronucleus assay was used to detect chromosomic breaks or losses. DNA damage and apoptosis were observed in a concentration-dependent manner. This study demonstrated that U is genotoxic from 300µM and induces caspase-dependent apoptosis cell death from 200µM mainly through the intrinsic pathway in NRK-52E cells. These results suggest that the DNA damage caused by U is reversible at low concentration (200–400µM) but becomes irreversible and leads to cell death for higher concentrations (500–800µM).

Key Words: uranium; genotoxicity; apoptosis; DNA damage; renal cells; comet assay.


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