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Modifications of the Expression of Genes Involved in Cerebral Cholesterol Metabolism in the Rat Following Chronic Ingestion of Depleted Uranium

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Abstract

Depleted uranium results from the enrichment of natural uranium for energetic purpose. Its potential dispersion in the environment would set human populations at risk of being contaminated through ingestion. Uranium can build up in the brain and induce behavior disorders. As a major constituent of the myelin sheath, cholesterol is essential to brain function, and several neurological pathologies result from a disruption of cholesterol metabolism. To assess the effect of a chronic contamination with depleted uranium on cerebral cholesterol metabolism, rats were exposed to depleted uranium for 9 months through drinking water at 40 mg/l. The study focuses on gene expression. Cholesterol-catabolizing enzyme CYP46A1 displayed a 39% increase of its messenger RNA (mRNA) level. 3-Hydroxy-3-methylglutamyl CoA synthase gene expression rose from 91%. Concerning cholesterol transport, mRNA levels of scavenger receptor-B1 and adenosine triphosphate-binding cassette transporter A1 increased by 34% and that of apolipoprotein E by 75%. Concerning regulation, gene expression of nuclear receptors peroxisome proliferator-activated receptors α and γ increased by 46% and 36% respectively, whereas that of retinoid-X-receptor decreased by 29%. In conclusion, a chronic internal contamination with depleted uranium does not affect the health status of rats but induces molecular changes in the dynamic equilibrium of the cerebral cholesterol pool.

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Abbreviations

ABC (A1, A2, G1, G5):

adenosine triphosphate binding cassette transporter

ACAT (1, 2):

acylCoenzymeA: cholesterol acyltransferase

Apo E:

apolipoprotein E

CYP:

cytochrome P450

CYP46A1:

cholesterol 24-hydroxylase

CYP7B1:

oxysterol 7alpha-hydroxylase

CYP27A1:

sterol 27-hydroxylase

CYP51:

lanosterol-14-hydroxylase

DU:

depleted uranium

HDL:

high-density lipoprotein

HMGCoA (R/S):

3-hydroxy-3-methylglutaryl Coenzyme A Reductase/Synthase

HNF (1α, 4α):

hepatocyte nuclear factor

HPRT:

hypoxanthine-guanine phosphoribosyltransferase

LDL:

low-density lipoprotein

LDLr:

low-density lipoprotein receptor

LXRβ:

liver-X-receptor β

PPAR(α, γ):

peroxisome proliferator-activated receptor

RXR:

retinoid-X-receptor

SR-B1:

scavenger receptor class B type 1

SREBP (1c, 2):

sterol regulatory element binding protein

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Acknowledgments

The authors thank Dr Philippe Lestaevel for his helpful reading of the manuscript, as well as Cédric Baudelin, Thierry Loizeau, and Frédéric Voyer for animal care and contamination. This work is part of the ENVIRHOM research program supported by the Institute for Radiological Protection and Nuclear Safety (IRSN).

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Authors and Affiliations

  1. Institute for Radiological Protection and Nuclear Safety, Radiological Protection and Human Health Division, Radiobiology and Epidemiology Department, Laboratory of Experimental Nuclear Toxicology, BP n°17, F-92262, Fontenay-aux-Roses Cedex, France

    Radjini Racine, Yann Gueguen, Patrick Gourmelon & Maâmar Souidi

  2. UMR Clermont Université CNRS 6247 INSERM U931 and centre de recherche en nutrition humaine d’Auvergne, 24, avenue des Landais, F-63177, Aubière Cedex, France

    Georges Veyssiere

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  1. Radjini Racine
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  2. Yann Gueguen
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  4. Georges Veyssiere
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Correspondence to Maâmar Souidi.

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Racine, R., Gueguen, Y., Gourmelon, P. et al. Modifications of the Expression of Genes Involved in Cerebral Cholesterol Metabolism in the Rat Following Chronic Ingestion of Depleted Uranium. J Mol Neurosci 38, 159–165 (2009). https://doi.org/10.1007/s12031-008-9145-8

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