|
Sign In to gain access to subscriptions and/or personal tools.
|
Histopathological Evaluation of Liver, Pancreas, Spleen, and Heart from Iron-Overloaded Sprague-Dawley Rats*1,2
Paul Whittaker
Center for Food Safety and Applied Nutrition, Food and Drug Administration, Washington, D.C. 20204
Fred A. Hines
Center for Food Safety and Applied Nutrition, Food and Drug Administration, Washington, D.C. 20204
Martin G. Robl
Center for Food Safety and Applied Nutrition, Food and Drug Administration, Washington, D.C. 20204
Virginia C. Dunkel
Center for Food Safety and Applied Nutrition, Food and Drug Administration, Washington, D.C. 20204
The effects of increasing dietary levels of Fe on the histopathology of liver, pancreas, spleen, and heart were examined in a rat model for iron overload. Sprague-Dawley rats were fed diets containing 35, 350, 3,500, or 20,000 µg Fe/g, and, after 12 wk, there was a direct correlation between increased liver nonheme Fe and lipid peroxidation measured by the lipid-conjugated diene assay. Histopathological examination of tissues revealed the following: (a) hepatocellular hemosiderosis in all groups of rats, with a dose-related accumulation of cytoplasmic Fe-positive material predominantly in hepatocytes located in the periportal region (Zone 1), (b) myocardial degeneration and necrosis (cardiomyopathy) with hemosiderin in interstitial macrophages or in myocardial fibers of animals with heart damage, (c) splenic lymphoid atrophy affecting the marginal zone of the white pulp and hemosiderin deposition in the sinusoidal macrophages, and (d) pancreatic atrophy with loss of both the endocrine and exocrine pancreatic tissue in those animals receiving 3,500 and 20,000 µg Fe/g of diet. The toxic effects of Fe overload in this rat model include cellular apoptosis or necrosis in heart, spleen, and pancreas and, when coupled with the findings on lipid peroxidation, suggests that oxidative stress is involved in the pathogenesis of the lesions.
Key Words: Iron toxicity • hepatocellular hemosiderosis • pancreatic atrophy • cardiotoxicity • splenic atrophy • apoptosis
- ABstat (1993). Abstat User Manual, version 6.04. Anderson-Bell, Parker, Colorado.
- Alt ER, Sternlieb I., and Goldfischer S. (1990). The cytopathology of metal overload. Int. Rev. Exp. Pathol. 31: 165-188.[Medline]
[Order article via Infotrieve]
- Bonkovsky HL (1991). Iron and the liver. Am. J. Med. Sci. 301: 32-43.[Web of Science][Medline]
[Order article via Infotrieve]
- Cotran RS, Kumar V, and Robbins SL (eds) ( 1989). The liver and biliary tract. In: Robbins Pathologic Basis of Disease. W. B. Saunders, Philadelphia, pp. 950-953.
- Desousa, M. (1992). T lymphocytes and iron overload: Novel correlations of possible significance to the biology of the immunological system. Mem. Inst. Oswaldo Cruz 87: 23-29.[Web of Science][Medline]
[Order article via Infotrieve]
- Dixon D., Heider K., and Elwell MR (1995). Incidence of nonneoplastic lesions in historical control male and female Fischer-344 rats from 90-day toxicity studies. Toxicol. Pathol. 23: 338-348.[Abstract/Free Full Text]
- Folch J., Lees M., and Sloane GH (1957). A simple method for the isolation and purification of total lipids from animal tissues. J. Biol. Chem. 226: 497-509.[Free Full Text]
- Iancu TC, Ward RJ, and Peters TJ (1990). Ultrastructural changes in the pancreas of carbonyl iron-fed rats. J. Pediatr. Gastroenterol. Nutr. 10: 95-101.[Web of Science][Medline]
[Order article via Infotrieve]
- Jacobs A. (1977). Iron overload-Clinical and pathological aspects. Sem. Hematol. 14: 89-113.[Web of Science][Medline]
[Order article via Infotrieve]
- Keenan KP, Soper KA, Hertzog PR, Gumprecht LA, Smith PF, Mattson BA, Ballam GC, and Clark RL (1995). Diet, overfeeding, and moderate dietary restriction in control Sprague-Dawley rats: II. Effects on age-related proliferative and degenerative lesions. Toxicol. Pathol. 23: 287-302.[Abstract/Free Full Text]
- Luna LG (1968). Manual of Histologic Staining Methods of the Armed Forces Institute of Pathology, 3rd ed. McGraw-Hill, New York.
- Majno G. and Joris I. (1995). Apoptosis, oncosis, and necrosis: An overview of cell death. Am. J. Pathol. 146: 3-15.[Abstract]
- O'Connell MJ, Ward RJ, Baum H., and Peters TJ (1985). The role of iron in ferritin and haemosiderin-mediated lipid peroxidation in lysosomes. Biochem. J. 229: 135-139.[Web of Science][Medline]
[Order article via Infotrieve]
- Olson LJ, Edwards WD, McCall JT, Ilstrup DM, and Gersh BJ (1987). Cardiac iron deposition in idiopathic hemochromatosis: Histologic and analytic assessment of 14 hearts from autopsy. J. Am. Coll. Cardiol. 10: 1239-1243.[Abstract]
- Park CH, Bacon BR, Brittenham GM, and Tavill AS (1987). Pathology of dietary carbonyl iron overload in rats. Lab. Invest. 57: 555-563.[Web of Science][Medline]
[Order article via Infotrieve]
- Powell LW and Isselbacher KJ (1987). Hemochromatoisis. In: Harrison's Principles of Internal Medicine, 11th ed., E Braunwald, KJ Isselbacher, RG Peterdorf, JD Wilson, JB Martin, and AS Fauci (eds). McGraw-Hill, New York, pp. 1632-1635.
- Rahier J., Loozen S., Goebbels RM, and Abrahem M. (1987). The haemochromatic human pancreas: A quantitative immunohistochemical and ultrastructural study. Diabetologia 30: 5-12.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Reunanen A., Takkunen H., Knekt P., Seppanen R., and Aromaa A. (1995). Body iron stores, dietary iron intake and coronary heart disease mortality. J. Intern. Med. 238: 223-230.[Web of Science][Medline]
[Order article via Infotrieve]
- Salonen JT, Nyyssönen K., Kirpela H., Tuomilehto J., Seppänen R., and Salonen R. (1992). High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation 86: 803-811.[Abstract/Free Full Text]
- Selden C., Owen M., Hopkins JMP, and Peters TJ (1985). Studies on the concentration and intracellular localization of iron proteins in liver biopsy specimens from patients with iron overload with special reference to their role in lysosomal disruption. Br. J. Haematol. 44: 593-603.[CrossRef]
- Sempos CT, Looker AC, Gillum RF, and Makuc DM (1994). Body iron stores and the risk of coronary heart disease. N. Engl. J. Med. 330: 1119-1124.[Abstract/Free Full Text]
- Seymour CA and Peters TJ (1978). Organelle pathology in primary and secondary haemochromatosis with special reference to lysosomal changes. Br. J. Haematol. 40: 239-253.[CrossRef]
- Skikne BS, Whittaker P., Cooke A., and Cook JD (1995). Ferritin excretion and iron balance in humans. Br. J. Haematol. 90: 681-687.[CrossRef]
- Snedecor GW and Cochran WG (1980). Statistical Methods. Iowa State University Press, Ames, pp. 175-193, 215-237.
- Thompson SW and Hunt RD (1966). Selected Histochemical and Histopathological Methods. Charles C Thomas, Springfield, Illinois.
- Watson BD, Busto R., Goldberg WJ, Santiso M., Yoshida S., and Ginsberg MD (1984). Lipid peroxidation in vivo induced by reversible global ischemia in rat brain. J. Neurochem. 42: 268-274.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Whittaker P., Chanderbhan R., Calvert R., and Dunkel V. (1994). Cellular and molecular responses in the Sprague-Dawley rat to chronic iron overload. J. Trace Elem. Exp. Med. 7: 19-31.
- Whittaker P., Skikne BS, Covell AM, Flowers C., Cooke A., Lynch SR, and Cook JD (1989). Duodenal iron proteins in idiopathic hemochromatosis. J. Clin. Invest. 83: 261-267.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Whittaker P., Wamer W., and Calvert RJ (1992). Effect of chronic iron overload on iron status, lipid peroxidation, cell proliferation, and DNA damage. J. Trace Elem. Exp. Med. 5: 227-236.
Toxicologic Pathology, Vol. 24, No. 5,
558-563 (1996)
DOI: 10.1177/019262339602400504
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter What's this?
This article has been cited by other articles:
|
|
|
|
 
J. H. Kramer, S. B. Murthi, R. M. Wise, I-T. Mak, and W. B. Weglicki
Antioxidant and lysosomotropic properties of acute d-propranolol underlies its cardioprotection of postischemic hearts from moderate iron-overloaded rats.
Experimental Biology and Medicine,
April 1, 2006;
231(4):
473 - 484.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. K. Yeung, L. Zhu, R. P. Glahn, and D. D. Miller
Iron Absorption from NaFeEDTA Is Downregulated in Iron-Loaded Rats
J. Nutr.,
September 1, 2004;
134(9):
2270 - 2274.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Narama, K. Ozaki, S. Matsushima, and T. Matsuura
Eosinophilic Gastroenterocolitis in Iron Lactate-Overloaded Rats
Toxicol Pathol,
May 1, 1999;
27(3):
318 - 324.
[Abstract]
[PDF]
|
|
|
|
|
|
|
M. A. Breider, H. M. Ulloa, D. G. Pegg, and A. W. Gough
Nitro-Imidazole Radiosensitizer-Induced Toxicity in Cynomolgus Monkeys
Toxicol Pathol,
September 1, 1998;
26(5):
651 - 656.
[Abstract]
[PDF]
|
|
|
|
|
|
|
P. Whittaker, V. C. Dunkel, T. J. Bucci, D. F Kusewitt, J. D. Thurman, A. Warbritton, and G. L. Wolff
Genome-Linked Toxic Responses to Dietary Iron Overload
Toxicol Pathol,
November 1, 1997;
25(6):
556 - 564.
[Abstract]
[PDF]
|
|
|
|
|
