Influence of depleted uranium on hepatic cholesterol metabolism in apolipoprotein E-deficient mice.
Depleted uranium (DU) is uranium with a lower content of the fissile isotope U-235 than natural uranium. It is a radioelement and a waste product from the enrichment process of natural uranium. Because of its very high density, it is used in the civil industry and for military purposes. DU exposure can affect many vital systems in the human body, because in addition to being weakly radioactive, uranium is a toxic metal. It should be emphasized that, to be exposed to radiation from DU, you have to eat, drink, or breathe it, or get it on your skin. This particular study is focusing on the health effects of DU for the cholesterol metabolism. Previous studies on the same issue have shown that the cholesterol metabolism was modulated at molecular level in the liver of laboratory rodents contaminated for nine months with DU. However, this modulation was not correlated with some effects at organs or body levels. It was therefore decided to use a "pathological model" such as hypercholesterolemic apolipoprotein E-deficient laboratory mice in order to try to clarify the situation. The purpose of the present study is to assess the effects of a chronic ingestion (during 3 months) of a low level DU-supplemented water (20 mg L(-1)) on the above mentioned mice in order to determine a possible contamination effect. Afterwards the cholesterol metabolism was studied in the liver especially focused on the gene expressions of cholesterol-catabolising enzymes (CYP7A1, CYP27A1 and CYP7B1), as well as those of associated nuclear receptors (LXRα, FXR, PPARα, and SREBP 2). In addition, mRNA levels of other enzymes of interest were measured (ACAT 2, as well as HMGCoA Reductase and HMGCoA Synthase). The gene expression study was completed with SRB1 and LDLr, apolipoproteins A1 and B and membrane transporters ABC A1, ABC G5. The major effect induced by a low level of DU contamination in apo-E deficient mice was a decrease in hepatic gene expression of the enzyme CYP7B1 (-23%) and nuclear receptors LXRα (-24%), RXR (-32%), HNF4α (-21%) when compared to unexposed ones. These modifications on cholesterol metabolism did not lead to increased disturbances that are specific for apolipoprotein E-deficient mice, suggesting that chronic DU exposure did not worsen the pathology in this experimental model. In conclusion, the results of this study indicate that even for a sensitive pathologic model the exposure to a low dose of DU has no relevant impact. The results confirm the results of our first study carried out on healthy laboratory rodents where a sub-chronic contamination with low dose DU did not affect in vivo the metabolism of cholesterol.
Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Direction de la Radioprotection de l'Homme, Service de Radiobiologie et d'Epidémiologie, Laboratoire de Radiotoxicologie Expérimentale, BP no.17, F-92262 Fontenay-aux-Roses Cedex, France. maamar.souidi@irsn.fr
M
M
Souidi
R
R
Racine
L
L
Grandcolas
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S
Grison
J
J
Stefani
P
P
Gourmelon
P
P
Lestaevel
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D014501:Uranium / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*
D001057:Apolipoproteins E; D014501:Uranium; D002784:Cholesterol