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In vivo exposure to uranium induces reversible and irreversible effects on gene expression and epigenetics in adult male rats

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Souidi, M. | Gloaguen, C. | Ibegazene, O. | Kereselidze, D. | Grison, S. | Manens, L. | Elie, C. | Legendre, A. | Tack, K. | Aigueperse, J. | Dublineau, I. | Lestaevel, P.

Edité par CCSD ; Elsevier -

International audience. Introduction: Depleted uranium is a weakly radioactive heavymetal, and its civil and military applications could induce its releaseinto the environment. The consequence is a risk of internal contaminationfor population with possible effects on various organs.Experimental in vivo studies demonstrated that the gene expressionof cytochrome P450 (CYP450) and associated nuclear receptorsinvolved in the metabolism of xenobiotics, cholesterol or vitaminD are biological targets of this radioelement.Objective: The aim of this study was to determine whether theseeffects observed after chronic internal exposure at low levels ofdepleted uranium are reversible after cessation of contamination.Methods: In this study, rats were exposed to depleted uranium(1 mg/rat/day) for 6 months, and then they were unexposed during3 or 6 months, until their sacrifice.Results: The results show that some changes induced byuranium are irreversible at hepatic level after cessation of contamination,such as the mRNA expression of CYP2B1, CYP2C11associated with drug metabolism, CYP27A1 associated with cholesterolmetabolism and CYP2R1 associated with metabolism ofvitamin D. By contrast, changes in the gene expression of CYP3A1/2(brain and kidneys), CYP7A1 (liver), CYP27B1 (kidneys) and DNAmethyltransferases DNMT1/3A (liver and kidneys) are reversible.Concerning the nuclear receptors, uranium induced irreversibleeffects on the hepatic gene expression of FXR or reversible effectson the gene expression of VDR in the brain and LXR˛ in the liver.Epigenetics studies show that uranium induces hyper methylationof the DNA in kidneys but that this effect is reversible when thecontamination was stopped.Conclusions: The results of this studyshowfor the first time thatchronic contamination at low levels of depleted uranium inducedreversible or irreversible effects on gene expression and reversibleDNAmethylation after cessation of exposure. Irreversible biologicaleffects observed in our experimental model could induce metabolicdysfunctions at long-term or may be transmitted to offspring viaother epigenetic mechanisms such as the histone modification orchanges in small RNA content (miRNA).

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