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Biometals

, Volume 18, Issue 5, pp 541–551 | Cite as

Early Histological and Functional Effects of Chronic Copper Exposure in Rat Liver

  • Felipe A. Cisternas
  • Gladys Tapia
  • Miguel Arredondo
  • Denise Cartier-Ugarte
  • Pamela Romanque
  • Walter D. Sierralta
  • María T. Vial
  • Luis A. Videla
  • Magdalena Araya
Article

Abstract

Cu is an essential trace element capable of producing toxic effects in animals and man when ingested acutely or chronically in excess. Although chronic Cu exposure is increasingly recognized as a public health issue, its early effects remain largely unknown. We approached the significance of a moderate chronic Cu load in young rats to correlate early hepatic histopathological changes with functional alterations of liver cells. For this purpose, supplementation with 1200 ppm of Cu in rat food for 16 weeks was chosen. In these conditions, Cu load elicited a significant decrease in growth curves. There were mild light microscopy alterations in Cu-treated rats, although increasing intracellular Cu storage was correlated with longer Cu exposure both by histological and biochemical measurements. Ultrastructural alterations included lysosomal inclusions as well as mitochondrial and nuclear changes. Liver perfusion studies revealed higher rates of basal O2 consumption and colloidal carbon-induced O2 uptake in Cu-treated rats, with enhanced carbon-induced O2/carbon uptake ratios and NF-κB DNA binding activity. These changes were time-dependent and returned to control values after 12 or16 weeks. It is concluded that subchronic Cu loading in young rats induces early hepatic morphological changes, with enhancement in Küpffer cell-dependent respiratory burst activity and NF-κB DNA binding, cellular responses that may prevent or alleviate the hepatotoxicity of the metal.

Keywords

copper Küpffer cells liver damage oxidative stress rats 

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References

  1. Aburto, EM, Cribb, AE, Fuentealba, IC,  et al. 2001Morphological and biochemical assessment of the liver response to excess dietary copper in Fischer 344 ratsCan J Vet Res6597103PubMedGoogle Scholar
  2. Araya, M, Koletzko, B, Uauy, R 2003Copper deficiency and excess in infancy: developing a research agendaJ Pediatr Gast Nutr37422429CrossRefGoogle Scholar
  3. Association of Official Analytical Chemist AOAC1997AOAC Official methods of analysisAOACWashington, DCGoogle Scholar
  4. Aust, SD, Morehouse, LA, Thomas, CE 1985Role of metals in oxygen radical reactionsFree Radical Bio Med1325CrossRefGoogle Scholar
  5. Bouwens, L, Baekeland, M, Zanger, R,  et al. 1986Quantification, tissue distribution, and proliferation kinetics of Küpffer cells in normal rat liverHepatology6718722PubMedCrossRefGoogle Scholar
  6. Bremner, I 1998Manifestations of copper excessAm J Clin Nutr671069S1073SPubMedGoogle Scholar
  7. Brewer, GJ, Yuzbasiyan-Gurkan, V 1992Wilson diseaseMedicine (Baltimore)71139164Google Scholar
  8. Bull, PC, Thomas, GR, Rommens, JM,  et al. 1993The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes geneNat Genet5327337CrossRefPubMedGoogle Scholar
  9. Cowper, KB, Currin, RT, Dawson, TL,  et al. 1990A new method to monitor Küpffer-cell function continuously in the perfused rat liverBiochem J226141147Google Scholar
  10. Decker, K 1990Biologically active products of stimulated liver macrophages (Küpffer cells)Eur J Biochem192245261CrossRefPubMedGoogle Scholar
  11. Deryckere, F, Gannon, F 1994A one-hour minipreparation technique for extraction of DNA-binding proteins from animal tissuesBioTechniques16405PubMedGoogle Scholar
  12. Evering, WE, Haywood, S, Elmes, ME,  et al. 1990Histochemical and immunocytochemical evaluation of copper and metallothionein in the liver and kidney of copper-loaded ratsJ Pathol160305312CrossRefPubMedGoogle Scholar
  13. Evering, WE, Haywood, S, Bremner, I 1991The protective role of metallothionein in copper overload: I. Differential distribution of immunoreactive metallothionein in copper-loaded rat liver and kidneyChem Biol Interact78283295PubMedCrossRefGoogle Scholar
  14. Freedman, JH, Ciriolo, MR, Peisach, J 1989The role of glutathione in copper metabolism and toxicityJ Biol Chem26455985605PubMedGoogle Scholar
  15. Fuentealba, IC, Haywood, S, Trafford, J 1987Evaluation of histochemical methods for the detection of copper overload in rat liverLiver7277282PubMedGoogle Scholar
  16. Fuentealba, I, Haywood, S 1988Cellular mechanisms of toxicity and tolerance in the copper-loaded rat. I. Ultrastructural changes in the liverLiver8372380PubMedGoogle Scholar
  17. Fuentealba, I, Haywood, S, Foster, J 1989Cellular mechanisms of toxicity and tolerance in the copper-loaded rat. II. Pathogenesis of copper toxicity in the liverExp Mol Pathol502637CrossRefPubMedGoogle Scholar
  18. Fuentealba, IC, Davis, RW, Elmes, ME,  et al. 1993Mechanisms of tolerance in the copper-loaded rat liverExp Mol Pathol597184CrossRefPubMedGoogle Scholar
  19. Fuentealba, IC, Mullins, JE, Aburto, EM,  et al. 2000Effect of age and sex on liver damage due to excess dietary copper in Fischer 344 ratsClin Toxicol38709717CrossRefGoogle Scholar
  20. Ganesh, L, Burstein, E, Guha-Niyogi, A,  et al. 2003The gene product Murr1 restricts HIV-1 replication in resting CD4+ lymphocytesNature426853857CrossRefPubMedGoogle Scholar
  21. Haywood, S, Loughran, M 1985Copper toxicosis and tolerance in the rat. II. Tolerance-a liver protective adaptationLiver5267275PubMedGoogle Scholar
  22. Haywood, S, Fuentealba, IC, Foster, J,  et al. 1996Pathobiology of copper-induced injury in Bedlington terriers: ultrastructural and microanalytical studiesAnal Cell Pathol10229241PubMedGoogle Scholar
  23. Hebert, CD, Elwell, MR, Travlos, GS,  et al. 1993Subchronic toxicity of cupric sulfate administered in drinking water and feed to rats and miceFund Appl Toxicol2146175CrossRefGoogle Scholar
  24. Jandl, RC, André-Schwartz, J, Borges-DuBois, L,  et al. 1978Termination of the respiratory burst in human neutrophilsJ Clin Invest6111761185PubMedCrossRefGoogle Scholar
  25. Klomp, AE, Sluis, B, Klomp, LW,  et al. 2003The ubiquitously expressed MURR1 protein is absent in canine copper toxicosisJ Hepatol39703709CrossRefPubMedGoogle Scholar
  26. Kudrin, AV 2000Trace elements in regulation of NF-kappaB activityJ Trace Elem Med Bio14129142CrossRefGoogle Scholar
  27. Kumaratilake, JS, Howell, JM 1989Lysosomes in the pathogenesis of liver injury in chronic copper poisoned sheep: an ultrastructural and morphometric studyJ Comp Pathol100381390CrossRefPubMedGoogle Scholar
  28. Linder, MC, Hazegh-Azam, M 1996Copper biochemistry and molecular biologyAm J Clin Nutr63797811Google Scholar
  29. Mullins, JE, Fuentealba, IC 1998Immunohistochemical detection of metallothionein in liver, duodenum and kidney after dietary copper-overload in ratsHistol Histopathol13627633PubMedGoogle Scholar
  30. Nederbragt, H 1985Strain- and sex-dependent differences in response to a single high dose of copper in the ratComp Biochem Phys C81425431CrossRefGoogle Scholar
  31. Okayasu, T, Tochimaru, H, Hyuga, T,  et al. 1992Inherited copper toxicity in Long-Evans cinnamon rats exhibiting spontaneous hepatitis: a model of Wilson’s diseasePediatr Res31253257PubMedCrossRefGoogle Scholar
  32. Pan, Q, Kleer, CG, Golen, KL,  et al. 2002Copper deficiency induced by tetrathiomolybdate suppresses tumor growth and angiogenesisCancer Res6248544859PubMedGoogle Scholar
  33. Plane, F, Wigmore, S, Angelini, GD,  et al. 1997Effect of copper on nitric oxide synthase and guanylyl cyclase activity in the rat isolated aortaBrit J Pharmacol121345350CrossRefGoogle Scholar
  34. Qu, W, Zhong, Z, Goto, M,  et al. 1996Küpffer cell prostaglandin E2 stimulates parenchymal cell O2 consumption: alcohol and cell-cell communicationAm J Physiol270G574G580PubMedGoogle Scholar
  35. Rowley, DA, Halliwell, B 1983Superoxide-dependent and ascorbate-dependent formation of hydroxyl radicals in the presence of copper salts: a physiologically significant reaction?Arch Biochem Biophys225279284CrossRefPubMedGoogle Scholar
  36. Samuni, A, Chevion, M, Czapski, G 1981Unusual copper-induced sensitization of the biological damage due to superoxide radicalsJ Biol Chem2561263212635PubMedGoogle Scholar
  37. Sans, J, Aguilera, A, Faundez, P,  et al. 1999Influence of copper-(II) on colloidal carbon-induced Küpffer cell-dependent oxygen uptake in rat liver: relation to hepatotoxicityFree Radical Res30489498CrossRefGoogle Scholar
  38. Sen, CK, Packer, L 1996Antioxidant and redox regulation of gene transcriptionFASEB J10709720PubMedGoogle Scholar
  39. Sierralta, WD 2001Immunoelectron microscopy in embryosMethods246169CrossRefPubMedGoogle Scholar
  40. Suska, F, Gretzer, C, Esposito, M,  et al. 2005 In vivo cytokine secretion and NF-kappaB activation around titanium and copper implantsBiomaterials26519527PubMedCrossRefGoogle Scholar
  41. Tapia, G, Pepper, I, Smok, G,  et al. 1997Küpffer cell function in thyroid hormone-induced liver oxidative stress in the ratFree Radical Res26267279CrossRefGoogle Scholar
  42. Tapia, G, Troncoso, P, Galleano, M,  et al. 1998Time course study of the influence of acute iron overload on Küpffer cell functioning and hepatotoxicity assessed in the isolated perfused rat liverHepatology2713111316CrossRefPubMedGoogle Scholar
  43. Tsukamoto, H, Lin, M 1997The role of Küpffer cells in liver injuryWisse, EKnook, DLBalabaud, C eds. Cells of the hepatic sinusoidThe Küpffer Cell FoundationLeiden, Netherlands244250Google Scholar
  44. Leeuwen, HJ, Bruggen, T, Asbeck, BS,  et al. 2001Effect of corticosteriods on nuclear factor-κB activation and hemodynamics in late septic shockCrit Care Med2910741077PubMedCrossRefGoogle Scholar
  45. Varada, KR, Harper, RG, Wapnir, RA 1993Development of copper intestinal absorption in the ratBiochem Med Metab Biol50277283CrossRefPubMedGoogle Scholar
  46. Viarengo, A, Burlando, B, Ceratto, N,  et al. 2000Antioxidant role of metallothioneins: a comparative overviewCell Mol Biol46407417PubMedGoogle Scholar
  47. Videla, LA, Fernández, V, Tapia, G,  et al. 2003Oxidative stress-mediated hepatotoxicity of iron and copper: role of Küpffer cellsBioMetals16103111CrossRefPubMedGoogle Scholar
  48. Wang, JF, Komarov, P, Groot, H 1993Luminol chemiluminescence in rat macrophages and granulocytes: the role of NO, O 2 /H2O2, and HOClArch Biochem Biophys304189196PubMedCrossRefGoogle Scholar
  49. Wong, HR, Ryan, M, Wispé, JR 1997Stress response decreases NF-κB nuclear translocation and increases IκBα expression in A549 cellsJ Clin Invest9924232428PubMedCrossRefGoogle Scholar
  50. Wu, J, Forbes, JR, Chen, HS,  et al. 1994The LEC rat has a deletion in the copper transporting ATPase gene homologous to the Wilson disease geneNat Genet7541545PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Felipe A. Cisternas
    • 1
  • Gladys Tapia
    • 2
  • Miguel Arredondo
    • 1
  • Denise Cartier-Ugarte
    • 2
  • Pamela Romanque
    • 2
  • Walter D. Sierralta
    • 1
  • María T. Vial
    • 3
  • Luis A. Videla
    • 2
  • Magdalena Araya
    • 1
  1. 1.Instituto de Nutrición y Tecnología de los AlimentosUniversidad de ChileMacul, SantiagoChile
  2. 2.Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Facultad de MedicinaUniversidad de ChileChile
  3. 3.Unidad de Anatomía PatológicaHospital San Borja ArriaránSantiagoChile

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