Uranyl nitrate-induced proximal tubule alterations in rabbits: a quantitative analysis

Naturally occurring uranium in drinking water is a significant health concern in several areas of North America. Because the kidney is a known target organ to examine the effects of uranium or its compounds, the objective of this study was to determine whether kidney repair occurs after exposure to, and withdrawal of, uranyl nitrate (UN). This work, part of a larger study to establish safe levels of uranium in drinking water supplies, examined the ultrastructural changes in proximal tubule cells of New Zealand white rabbits following subchronic exposure to UN in water and for 91 days after exposure ended. The rabbit was chosen as the experimental animal because of its high sensitivity to uranium. Animals were exposed to 24 or 600 mg UN per liter (UN/L) in drinking water for 91 days, with no recovery or recovery periods of 45 or 91 days. Ultrastructural changes, quantified by a stereological image analysis system based on point counting, were observed in renal proximal tubules (PTs). Each electron micrograph was statistically considered an experimental unit. The severity of lesions was directly proportional to the dose. Animals exposed to 600 mg UN/L had the most severe lesions; nevertheless, alterations were remarkable in animals exposed to the low dose. At both recovery periods, the lesions were significantly more severe than those in animals of the no-recovery group, which may result from the kidney's ability to store uranium. The PT cells had increased lysosomal and vacuolar mass as well as variations in mitochondrial mass. In addition, there was epithelial cell degeneration with a focal loss of brush borders, thickening and splitting of tubular basement membrane, and occasionally cell necrosis. Interstitial fibrosis of the renal cortex persisted as the recovery period increased in the animals of UN-dosed groups. Alterations may be due to disturbed fluid transport across the PT and other cells and decreased cell respiration resulting from damaged cell constituents. Cell damage caused by UN in drinking water persisted throughout the 91-day recovery period. By eventually determining the no observable effect level for the kidney by UN, this study may assist in devising a model to ascertain the safe levels of uranium in water.