title: The greater susceptibility of North Ronaldsay sheep compared with Cambridge sheep to copper-induced oxidative stress, mitochondrial damage and hepatic stellate cell activation.
abstract: Sheep of the semi-feral North Ronaldsay (copper-sensitive) and domesticated Cambridge (copper-tolerant) breeds were compared in respect of pathological changes and protein expression in the liver as a result of excessive dietary copper. Acute mitochondrial damage and hepatic stellate cell (HSC) activation with collagen synthesis occurred in response to moderate copper overload in North Ronaldsay but not in Cambridge sheep. Mitochondrial degradative changes occurred either as ballooning degeneration and rupture with subsequent autophagic degradation or as mitochondrial matrical condensation (pyknosis). In North Ronaldsay sheep prolonged exposure to copper produced mitochondrial hyperplasia and hypertrophy, and nuclear damage with necrosis. Cytosolic isocitrate dehydrogenase (IDH), an enzyme responsive to oxidative stress, was induced in the liver of Cambridge sheep receiving a Cu-supplemented diet but was undetectable in the non-supplemented control sheep. Conversely, IDH was detected at similar levels in both control and copper-supplemented North Ronaldsay sheep, indicating a lower threshold response, and an enhanced susceptibility, to oxidative stress. "Upregulation" of mitochondrial thioredoxin-dependent peroxidase reductase (antioxidant protein-1) in the hepatic cytosol of the North Ronaldsay (but not Cambridge) sheep affirmed the increased susceptibility of the mitochondria to Cu-induced oxidative stress in this breed. Likewise the upregulation of cathepsin-D indicated increased lysosomal activity and HSC activation. The findings may be relevant to copper toxicosis in human infants.
authors.affiliation: Department of Veterinary Pathology, Faculty of Veterinary Science, University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: S
authors.initials: S
authors.lastname: Haywood
authors.forename: D M
authors.initials: DM
authors.lastname: Simpson
authors.forename: G
authors.initials: G
authors.lastname: Ross
authors.forename: R J
authors.initials: RJ
authors.lastname: Beynon
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology; D003300:Copper / Q000032:analysis / Q000633:toxicity*; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D004032:Diet; D004198:Disease Susceptibility; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000648:ultrastructure; D007521:Isocitrate Dehydrogenase / Q000096:biosynthesis; D007728:Kupffer Cells / Q000187:drug effects* / Q000648:ultrastructure; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000648:ultrastructure; D008933:Mitochondrial Swelling / Q000187:drug effects; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects*; D040901:Proteomics; D012756:Sheep; D012757:Sheep Diseases / Q000139:chemically induced* / Q000473:pathology; D013045:Species Specificity; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D009363:Neoplasm Proteins; D003300:Copper; D007521:Isocitrate Dehydrogenase