Modifications of Inflammatory Pathways in Rat Intestine Following Chronic Ingestion of Depleted Uranium

Abstract

The environmental contamination by dispersion of depleted uranium (DU) might result in its chronic ingestion of DU by local populations. The aim of this study was to determine if chronic ingestion of DU at low doses induces inflammatory reactions in intestine, first biological system exposed to uranium after ingestion. Experiments were performed with rats receiving uranium in drinking water (40 mg/l) during 3, 6, or 9 months. Several parameters referring to prostaglandin, histamine, cytokine, and nitric oxide (NO) pathways were assessed in ileum. Concerning the prostaglandin pathway, a twofold increase in gene expression of cyclooxygenase of type 2 was noted after 6 months, with no changes in prostaglandins levels. At the same time, a decrease in mast cell number was observed without any changes in histamine levels. Experiments on cytokines showed increased gene expression of interleukin (IL)-1beta and IL-10 at 6 months, and decreased messenger RNA level of CCL-2. This change was associated with decreased macrophage density. An opposite effect of DU was induced on neutrophils, since increased number was observed at 3 (x1.7) and 9 months (x3). The results obtained on NO pathway seemed to indicate that DU exposure inhibited this pathway (decreased endothelial NO synthase messenger RNA, inductive NO synthase activity and NO(2)(-)/NO(3)(-) levels) at 6 months. In conclusion, this study demonstrated that chronic ingestion of DU-induced time-dependent modifications of inflammatory pathways, notably in terms of immune cell content. The ultimate effects of DU contamination might be pathogenic by suppressing defense mechanisms or inducing hypersensitivity. Further experiments should be thus performed to determine real consequences on intestinal response to oral antigens.

Unexpected Lack of Deleterious Effects of Uranium on Physiological Systems following a Chronic Oral Intake in Adult Rat

“…However, these variations should not be considered adverse effects, given that the number of immune cells in the intestinal mucosa did not change significantly. The only change was a nonsignificant 50% diminution of macrophages, as mentioned previously [20]. Biological effects of uranium on the brain were estimated by investigating the cholinergic pathway and oxidative stress.…”

“…Animals were contaminated for 9 months with drinking water containing uranium (uranyl nitrate hexahydrate (UO 2 (NO 3 ) 2 ·6H 2 O)) dissolved in mineral water for final concentration at 0.2, 2, 5, 10, 20, 40, or 120 mg/L (AREVA, France) (10 rats per group). The group of 40 mg/L was added in this study to serve as the reference group, as several studies have been published with this uranium level in drinking water [20, 23, 30, 31]. Control animals drunk uncontaminated mineral water (which contains naturally uranium at 1.42  μ g/L).…”

“…Determination of immune cells was also performed in terminal ileum by immunohistochemistry or histochemistry as previously reported in [20]. The tissue neutrophil infiltration was estimated on paraffin sections incubated with rabbit antibody directed against rat myeloperoxidase (IMG antibody, d = 1/ x 00, Clinisciences, Nanterre, France) and LSAB2 HRP kit (Dako, Trappes, France).…”

“…Considering the previous guideline of WHO [3], the value of 15  μ g/L was derived from a single study of subchronic renal effects of uranium when administered to rats in drinking water for 3 months [19]. Moreover, several authors have since shown that the kidneys are not the only biological target of chronic exposure to low levels of uranium; for examples changes have been reported in the gastrointestinal system [20], in the central nervous system [21, 22], or in the liver [23]. …”

Uranyl Nitrate Induced Histological Changes in Lung Tissue

“…For these reasons dust inhalation is considered the most important route of exposure. It may also be due to an inflammatory response of the lung tissue that begins to retard absorption after a few days ( 20) .Whatever the mechanism, inhaled DU appears to have a pulmonary half-life of about 4 years (21). There is human research indicating that inhalation of insoluble uranium dioxide is associated with general damage to pulmonary structure, usually non-cancerous damage to alveolar epithelium.…”