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ToxSci Advance Access originally published online on March 28, 2008
Toxicological Sciences 2008 103(2):397-408; doi:10.1093/toxsci/kfn052
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.
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Renal Anemia Induced by Chronic Ingestion of Depleted Uranium in Rats

Hanaâ Berradi*, Jean-Marc Bertho*, Nicolas Dudoignon*, André Mazur{dagger}, Line Grandcolas*, Cédric Baudelin*, Stéphane Grison*, Philippe Voisin*, Patrick Gourmelon* and Isabelle Dublineau*,1

* Institut de Radioprotection et de Sûreté Nucléaire, Direction de la RadioProtection de l'Homme, Service de Radiobiologie et d'Epidémiologie, F-92262 Fontenay-aux-Roses Cedex, France {dagger} Unité des Maladies Métaboliques et Micronutriments, Institut National de la Recherche Agronomique, Centre de Clermont-Ferrand/Theix, F63122 Saint-Genes Champanelle, France

1 To whom correspondence should be addressed at Institut de Radioprotection et de Sûreté Nucléaire, Direction de la RadioProtection de l'Homme, Service de Radiobiologie et d'Epidémiologie, Laboratoire de Radiotoxicologie Expérimentale, IRSN, B. P. n°17, F 92262 Fontenay-aux-Roses Cedex, France. Fax: +33-1-58-35-84-67. E-mail: isabelle.dublineau{at}irsn.fr.

Received December 5, 2007; accepted March 2, 2008


  Abstract

Kidney disease is a frequent consequence of heavy metal exposure and renal anemia occurs secondarily to the progression of kidney deterioration into chronic disease. In contrast, little is known about effects on kidney of chronic exposure to low levels of depleted uranium (DU). Study was performed with rats exposed to DU at 40 mg/l by chronic ingestion during 9 months. In the present work, a ~20% reduction in red blood cell (RBC) count was observed after DU exposure. Hence, three hypotheses were tested to determinate origin of RBC loss: (1) reduced erythropoiesis, (2) increased RBC degradation, and/or (3) kidney dysfunction. Erythropoiesis was not reduced after exposure to DU as revealed by erythroid progenitors, blood Flt3 ligand and erythropoietin (EPO) blood and kidney levels. Concerning messenger RNA (mRNA) and protein levels of spleen iron recycling markers from RBC degradation (DMT1 [divalent metal transporter 1], iron regulated protein 1, HO1, HO2 [heme oxygenase 1 and 2], cluster of differentiation 36), increase in HO2 and DMT1 mRNA level was induced after chronic exposure to DU. Kidneys of DU-contaminated rats had more frequently high grade tubulo-interstitial and glomerular lesions, accumulated iron more frequently and presented more apoptotic cells. In addition, chronic exposure to DU induced increased gene expression of ceruloplasmin (x12), of DMT1 (x2.5), and decreased mRNA levels of erythropoietin receptor (x0.2). Increased mRNA level of DMT1 was associated to decreased protein level (x0.25). To conclude, a chronic ingestion of DU leads mainly to kidney deterioration that is probably responsible for RBC count decrease in rats. Spleen erythropoiesis and molecules involved in erythrocyte degradation were also modified by chronic DU exposure.

Key Words: metal; iron homeostasis; chronic; ingestion; kidney; depleted uranium.


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