Intracellular uranium distribution: Comparison of cryogenic fixation versus chemical fixation methods for SIMS analysis.

Localization of uranium within cells is mandatory for the comprehension of its cellular mechanism of toxicity. Secondary Ion Mass Spectrometry (SIMS) has recently shown its interest to detect and localize uranium at very low levels within the cells. This technique requires a specific sample preparation similar to the one used for Transmission Electronic Microscopy, achieved by implementing different chemical treatments to preserve as much as possible the living configuration uranium distribution into the observed sample. This study aims to compare the bioaccumulation sites of uranium within liver or kidney cells after chemical fixation and cryomethods preparations of the samples: SIMS analysis of theses samples show the localization of uranium soluble forms in the cell cytoplasm and nucleus with a more homogenous distribution when using cryopreparation probably due to the diffusible portion of uranium inside the cytoplasm.

Antioxidant status in rat kidneys after coexposure to uranium and gentamicin.

Uranium (U) accumulates and produces its toxic effects preferentially in the kidneys, especially in the proximal tubular structure. U disturbs the balance of pro-/antioxidants in the renal cortex after acute exposure. Other nephrotoxic agents, such as medications, also cause oxidative stress, but the effects of coexposure are not known. The aim of this study was to analyze the effect of chronic exposure to U and acute gentamicin treatment on the pro- and antioxidant status of the renal cortex of rats. Animals were chronically exposed (9 months) to a nonnephrotoxic level of U (40 mg/L) and then treated with daily injections of gentamicin at a range of doses (0, 5, 25, 100, and 150 mg/kg) during the last week of contamination. We studied changes in the gene expression, protein expression, and enzyme activity of key factors involved in the pro-/antioxidant balance in the renal cortex. At and above a dose of 100 mg/kg, gentamicin decreased the messenger RNA (mRNA) levels of catalase (CAT), copper/zinc superoxide dismutase (SOD) and increased the mRNA levels of heme oxygenase-1 in contaminated rats. This treatment decreased CAT activity, but did not significantly change the SOD protein level. Chronic exposure to U did not worsen these effects in our experimental conditions. In conclusion, gentamicin treatment disturbed the oxidative balance in our model's renal cortex, but the chronic exposure to U at this nonnephrotoxic level did not appear to reinforce these effects.

Chronic uranium exposure dose-dependently induces glutathione in rats without any nephrotoxicity.

Uranium is a heavy metal naturally found in the earth's crust that can contaminate the general public population when ingested. The acute effect and notably the uranium nephrotoxicity are well known but knowledge about the effect of chronic uranium exposure is less clear. In a dose-response study we sought to determine if a chronic exposure to uranium is toxic to the kidneys and the liver, and what the anti-oxidative system plays in these effects. Rats were contaminated for 3 or 9 months by uranium in drinking water at different concentrations (0, 1, 40, 120, 400, or 600 mg/L). Uranium tissue content in the liver, kidneys, and bones was linear and proportional to uranium intake after 3 and 9 months of contamination; it reached 6 µg per gram of kidney tissues for the highest uranium level in drinking water. Nevertheless, no histological lesions of the kidney were observed, nor any modification of kidney biomarkers such as creatinine or KIM-1. After 9 months of contamination at and above the 120-mg/L concentration of uranium, lipid peroxidation levels decreased in plasma, liver, and kidneys. Glutathione concentration increased in the liver for the 600-mg/L group, in the kidney it increased dose dependently, up to 10-fold, after 9 months of contamination. Conversely, chronic uranium exposure irregularly modified gene expression of antioxidant enzymes and activities in the liver and kidneys. In conclusion, chronic uranium exposure did not induce nephrotoxic effects under our experimental conditions, but instead reinforced the antioxidant system, especially by increasing glutathione levels in the kidneys.

Influence of environmental enrichment and depleted uranium on behaviour, cholesterol and acetylcholine in apolipoprotein E-deficient mice.

Alzheimer's disease is associated with genetic risk factors, of which the apolipoprotein E (ApoE) is the most prevalent, and is affected by environmental factors that include education early in life and exposure to metals. The industrial and military use of depleted uranium (DU) resulted in an increase of its deposition in some areas and led to a possible environmental factor. The present study aims to ascertain the effects on the behaviour and the metabolism of cholesterol and acetylcholine of ApoE-/- mice exposed to enriched environment (EE) and exposed to DU (20 mg/L) for 14 weeks. Here we show that ApoE-/- mice were unaffected by the EE and their learning and memory were similar to those of the non-enriched ApoE-/- mice. ApoE-/- mice showed a significant decrease in total (-16 %) and free (-16 %) cholesterol in the entorhinal cortex in comparison to control wild-type mice. Whatever the housing conditions, the exposure to DU of ApoE-/- mice impaired working memory, but had no effect on anxiety-like behaviour, in comparison to control ApoE-/- mice. The exposure of ApoE-/- mice to DU also induced a trend toward higher total cholesterol content in the cerebral cortex (+15 %) compared to control ApoE-/- mice. In conclusion, these results demonstrate that enriched environment does not ameliorate neurobehaviour in ApoE-/- mice and that ApoE mutation induced specific effects on the brain cholesterol. These findings also suggested that DU exposure could modify the pathology in this ApoE model, with no influence of housing conditions.