In vivo exposure to uranium induces reversible and irreversible effects on gene expression and epigenetics in adult male rats
Résumé
Introduction: Depleted uranium is a weakly radioactive heavy
metal, and its civil and military applications could induce its release
into the environment. The consequence is a risk of internal contamination
for population with possible effects on various organs.
Experimental in vivo studies demonstrated that the gene expression
of cytochrome P450 (CYP450) and associated nuclear receptors
involved in the metabolism of xenobiotics, cholesterol or vitamin
D are biological targets of this radioelement.
Objective: The aim of this study was to determine whether these
effects observed after chronic internal exposure at low levels of
depleted 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 during
3 or 6 months, until their sacrifice.
Results: The results show that some changes induced by
uranium are irreversible at hepatic level after cessation of contamination,
such as the mRNA expression of CYP2B1, CYP2C11
associated with drug metabolism, CYP27A1 associated with cholesterol
metabolism and CYP2R1 associated with metabolism of
vitamin D. By contrast, changes in the gene expression of CYP3A1/2
(brain and kidneys), CYP7A1 (liver), CYP27B1 (kidneys) and DNA
methyltransferases DNMT1/3A (liver and kidneys) are reversible.
Concerning the nuclear receptors, uranium induced irreversible
effects on the hepatic gene expression of FXR or reversible effects
on the gene expression of VDR in the brain and LXR˛ in the liver.
Epigenetics studies show that uranium induces hyper methylation
of the DNA in kidneys but that this effect is reversible when the
contamination was stopped.
Conclusions: The results of this studyshowfor the first time that
chronic contamination at low levels of depleted uranium induced
reversible or irreversible effects on gene expression and reversible
DNAmethylation after cessation of exposure. Irreversible biological
effects observed in our experimental model could induce metabolic
dysfunctions at long-term or may be transmitted to offspring via
other epigenetic mechanisms such as the histone modification or
changes in small RNA content (miRNA).