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

Abstract : 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).
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Submitted on : Wednesday, October 19, 2022 - 9:44:16 AM
Last modification on : Tuesday, November 15, 2022 - 10:58:34 AM

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M. Souidi, C. Gloaguen, O. Ibegazene, D. Kereselidze, S. Grison, et al.. In vivo exposure to uranium induces reversible and irreversible effects on gene expression and epigenetics in adult male rats. Toxicology Letters, 2016, 259, pp.S171. ⟨10.1016/j.toxlet.2016.07.407⟩. ⟨irsn-03820488⟩

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