Assessment of the Central Effects of Natural Uranium via Behavioural Performances and the Cerebrospinal Fluid Metabolome

International audienceNatural uranium (NU), a component of the earth's crust, is not only a heavy metal but also an alpha particle emitter, with chemical and radiological toxicity. Populations may therefore be chronically exposed to NU through drinking water and food. Since the central nervous system is known to be sensitive to pollutants during its development, we assessed the effects on the behaviour and the cerebrospinal fluid (CSF) metabolome of rats exposed for 9 months from birth to NU via lactation and drinking water (1.5, 10, or 40 mg⋅L −1 for male rats and 40 mg⋅L −1 for female rats). Medium-term memory decreased in comparison to controls in male rats exposed to 1.5, 10, or 40 mg⋅L −1 NU. In male rats, spatial working memory and anxiety-and depressive-like behaviour were only altered by exposure to 40 mg⋅L −1 NU and any significant effect was observed on locomotor activity. In female rats exposed to NU, only locomotor activity was significantly increased in comparison with controls. LC-MS metabolomics of CSF discriminated the fingerprints of the male and/or female NU-exposed and control groups. This study suggests that exposure to environmental doses of NU from development to adulthood can have an impact on rat brain function

Multigenerational effects of chronic low-dose natural uranium contamination: Epigenetic inheritance of methylation signature

International audienceIntroduction: In industrialized countries the high prevalenceand incidence of certain diseases are important topics to social and media actuality. Scientific data suggest that the gradual deteriorationin the quality of our environment may be due to pollution,the increasing use of radioelements, especially nuclear powerplants. The health consequences of epigenetic alterations andits heritability, caused by the chronic ingestion of radionuclides,remain unknown. That creates concerns regarding the effects ofchronic low dose environmental contamination. Indeed, recently,a paradigm shift in the perception of risk of radiotoxicology hasemerged. It is now investigated the possibility of transmission ofbiological effects over generations, in particular by epigenetic pathways.These processes are known for their crucial role associatedto the development of several diseases.Objective: Our hypothesis is that exposure to a chronic lowdosesof radionuclides, such as uranium, could affect the epigeneticprofile and, therefore, could be transmitted across generations.Materials and methods: The first generation (F0) of male andfemale rats was contaminated during 9 months via drinking waterusing a non-toxic concentration (40mgL−1) of natural uranium.The second generation F1 was exposed only until weaning. Thethird generation (F2) was not exposed to uranium. The uraniumeffects on DNA were evaluated on the three generations by analyzingthe DNA methylation profile and DNMT genes expression in theovaries and in the testes.Results: Here we report a significant hypermethylation (F0 17%,F1 41% and F2 42%) of testes DNA (p < 0.005). However, ovaries DNAwas hypomethylated (F0 18%, F1 41% and F2 21%) (p < 0.005). Interestingly,this DNA methylation profile was significantly maintainedacross generations. Quantitative RT-PCR demonstrates a modificationin DNA methyltransferase genes (DNMT 1, DNMT3a/b andDNMT3L).Conclusion: All in all, our work demonstrates for the first time,that the outcome of the exposition to low doses of uranium onmale and female rats was significantly different. This suggests thatmethylation changes are sex- and tissue-dependent mechanisms.Therefore, our results indicate the involvement of an epigeneticmechanism as a biological response to the exposure to chronic lowdoses of uranium. The biological significance of these results andwhich are the uranium effects on reproductive cells is still to beanswered

Lipid atherogenic risk markers can be more favourably influenced by the cis-9,trans-11-octadecadienoate isomer than a conjugated linoleic acid mixture or fish oil in hamsters

The aim of our present study was to compare the efficiency of conjugated linoleic acids (CLA) and fish oil in modulating atherogenic risk markers. Adult male hamsters were given a cholesterol-rich diet (0.6 g/kg) for 8 weeks; the diet was supplemented with 5 g cis-9,trans-11-CLA isomer/kg, 12 g CLA mixture (CLA-mix)/kg, 12 g fish oil/kg or 12 g fish oil + 12 g CLA-mix/kg. The plasma cholesterol status was improved only with the cis-9,trans-11-CLA (HDL-cholesterol and HDL-cholesterol:LDL-cholesterol ratio, P<0.05), but was of borderline significance for CLA-mix (HDL-cholesterol:LDL-cholesterol ratio, P=0.06), with an increase (33-40 %) in the liver lipoprotein receptors (scavenger receptor-type I and LDL ApoB/E receptor) and HDL-binding protein 2 (P<0.05). A 100 % pigment gallstones incidence and a slight insulin resistance (homeostatic model assessment index) were observed in the CLA-mix-fed hamsters (P=-0.031). In comparison, fish-oil feeding alone improved merely the scavenger receptor-type I and HDL-binding protein 2 liver status and faeces sterol output. For most of our present observations, the concomitant intake of fish oil and CLA-mix gave dominant effects that were exclusive and specific to one or the other oil. In conclusion, part of the beneficial effects of CLA in the present study can be ascribed to the cis-9,trans-11-isomer, and these did not generally overlap with those of fish oil. In addition, the CLA-mix effects are clearly affected by the marine (n-3) fatty acids. © The Authors 2004

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

International audienceIntroduction: 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)