Uranyl Nitrate—Induced Proximal Tubule Alterations in Rabbits: A Quantitative Analysis

Abstract

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 anlysis 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.

Keywords

Kidney renal ultrastructure morphometry renotoxic metal

References

Bencosme SA , Stone RS , Latta H. , and Madden SC (1960). Acute tubular and glomerular lesions in rat kidneys after uranium injury. Arch. Pathol. 69: 470-476.

Berlin M. and Rudell B. (1986). Uranium. In: Handbook on the Toxicology of Metals, 2nd ed., L Friberg , GF Nordberg , and VB Vouk (eds). Elsevier/ North-Holland Biomedical Press, Amsterdam, pp. 623-637.

Blantz RC and Konnen K. (1975). The mechanism of acute renal failure after uranyl nitrate. J. Clin. Invest. 55: 621-635.

Blantz RC , Pelayo JC , Gushwa LC , Myers RR , and Evan AP (1985). Functional basis for the glomerular alterations in uranyl nitrate acute renal failure. Kidney Int. 28: 733-743.

Brady HR , Kone BC , Brenner RM , and Gullans SR (1988). Uranyl nitrate (UN) inhibits cellular respiration before increasing plasma membrane K+ permeability in rabbit proximal tubule segments (PTS). Kidney Int. 33: 441.

Cothern CR , Lapenbusch WL , and Cotruvo JA (1983). Health effects guidance for uranium in drinking water. Health Phys. 44(suppl.1): 377-384.

Dunnill MS (1985). Some statistical aspects of sampling in morphometry . Anal. Quant. Cytol. Histol. 7(4): 250-255.

Fawcett DW (1986). The cell. In: A Textbook of Histology . W. B. Saunders, Philadelphia , pp. 50-53.

Finn WF (1983). Environmental toxins and renal disease. J. Clin. Pharmacol. 23: 461-472.

10.

Fowler BA , Mistry P. , and Goering PL (1987). Mechanism of metal-induced nephrotoxicity. In: Nephrotoxicity in the Experimental and Clinical Situation, Pt. 2, PH Bach and EA Lock (eds). Martinus Nijhoff, Dordrecht, pp. 659-681.

11.

Fukuda S. and Kopple JD (1980). Chronic uremia syndrome in dogs induced with uranyl nitrate. Nephron 25: 139-143.

12.

Gilman AP , Moss MA , Villeneuve DC , Secours VE , Yagminas AP , Tracy BL , Quinn JM , Long BL , and Valli VE (1996). Uranyl nitrate: 91-Day exposure and recovery studies in the male New Zealand White rabbit. Fund. Appl. Toxicol. (in press).

13.

Gilman AP , Villeneuve DC , Secours VE , Yagminas AP , Tracy BL , Quinn JM , Valli VE , and Moss MA (1996). Uranyl nitrate: 91-Day toxicity studies in the New Zealand White rabbit. Fund. Appl. Toxicol. (in press).

14.

Gilman AP , Villeneuve DC , Secours VE , Yagminas AP , Tracy BL , Quinn JM , Valli VE , Willes RJ , and Moss MA (1996). Uranyl nitrate: 28-Day and 91-day toxicity studies in the Sprague-Dawley rat. Fund. Appl. Toxicol. (in press).

15.

Goel KA , Garg VK , and Garg V. (1980). Histopathology of kidney of albino rats poisoned with uranyl nitrate. Bull. Environ. Contam. Toxicol. 24: 9-12.

16.

Guglielmotti MB , Ubios AM , and Cabrini RL (1985). Alveolar wound healing alteration under uranyl nitrate intoxication. J. Oral Pathol . 14: 565-572.

17.

Haley DP (1982). Morphologic changes in uranyl nitrate-induced acute renal failure in saline- and water-drinking rats. Lab. Invest. 46(2): 196-207.

18.

Haley DP , Bulger RE , and Dobyan DC (1982). The long-term effects of uranyl nitrate on the structure and function of the rat kidney. Virchows Arch. B: Cell Pathol. 41: 181-192.

19.

Harvey RB , Kubena LF , Phillips TD , and Heilelbaugh ND (1986). Validation of impaired renal function chick model with uranyl nitrate. Bull. Environ. Contam. Toxicol. 36: 67-72.

20.

La Touche YD , Willis DL , and Dawydiak OI (1987). Absorption and biokinetics of U in rats following an oral administration of uranyl nitrate solution. Health Phys. 53(2): 147-162.

21.

McDonald-Taylor CK , Bhatnagar MK , Gilman A. , Yagminas A. , and Singh A. (1992). Uranyl nitrate-induced glomerular basement membrane alterations in rabbits: A quantitative analysis . Bull. Environ. Contam. Toxicol. 48: 367-373.

22.

Mollenhauer HH , Harvey RB , Kubena LF , Droleskey RE , and Davis R. (1986). Distribution and form of uranium-containing deposits in chickens treated with uranyl nitrate. Vet. Pathol. 23: 706-711.

23.

Moss MA , McCurdy RF , Dooley KC , Givner ML , Dymond LC , Slayler JM , and Courneya MM (1983) Uranium in drinking water-Report on clinical studies in Nova Scotia. In: Chemical Toxicity and Clinical Chemistry of Metals. Proceeding of 2nd International Conference , SS Brown and J Savory (eds). Academic Press, London, pp. 149-152.

24.

Nielsen JT and Christensen EI (1983). Ultrastructure of isolated perfused proximal tubules from rabbit kidney: A comparison with proximal tubules fixed by perfusion in vivo. Lab. Invest. 49(4): 400-411.

25.

Stone RS , Bencosme SA , Latta H. , and Madden SC (1961). Renal tubular fine structure studied during reaction to acute uranium injury. Arch. Pathol. 71: 160-174.

26.

Tracy BL , Quinn JM , Lahey J. , Gilman AP , Mancuso K. , Yagminas AP , and Villeneuve DC (1992). Absorption and retention of uranium from drinking water by rats and rabbits. Health Phys. 62(1): 65-73.

27.

Weibel ER (1979). Elementary introduction to stereological principles . In: Stereological Methods, Vol. 1. Practical Methods for Biological Morphometry. Academic Press, London, pp. 44-45.

28.

Weiss L. (1987). The cell. In: Histology, 5th ed., L Weiss and RO Greep (eds). McGraw-Hill , New York, pp. 1-90.