Abstract
Pathogenesis of liver injury in chronic copper poisoning of sheep was investigated using two experiments. Test sheep were dosed orally with a 0.2 % solution of CuSO4.5H2O at the rate of 10 ml/Kg body weight on five days of the week, until first day of the haemolytic crisis (HC). Liver samples were taken during the prehaemolytic period and on the first or second day of the HC, liver changes were evaluated using trace element, histochemical, subcellular fractionation, ultrastructural and morphometric methods. Copper concentrations in liver samples increased at a steady linear rate of 10.35 µg/g liver wet weight per day; uptake of copper among hepatocytes, among Kupffer cells and between zones of liver lobules was unequal. Individual hepatocytes became packed with copper loaded lysosomes and underwent degeneration and necrosis. Excess copper in liver cells was sequestered by the lysosomes leading to linear increases in volume density, numerical density and mean volume during the pre-haemolytic period. On the first day of HC, numerical density reduced, volume density remained unchanged and the mean volume increased. Linear increase in liver copper concentration indicates that copper absorption from the gut; excretion into bile and release into sinusoids by hepatocytes occur at linear steady rates. Thus, copper homeostasis in sheep is different to that of the humans and rats. In hepatocytes packed with copper loaded lysosomes, synthesis of new lysosomes reduced, causing decreased uptake of excess copper leading to accumulation of ionic copper in the cytoplasm, resulting in the degeneration and necrosis of the hepatocytes.
Highlights
Copper (Cu) is a trace nutrient and exists in the animal body in stable oxidized Cu II or unstable reduced Cu I states
The diastase resistant Periodic Acid-Schiff stained (DPAS) and Rubeanic acid (RA) positive granules seen in hepatocytes, Kupffer cells and macrophages of portal triads in liver samples taken from the sheep of Experiment 1 (Table 3 and Fig. 1) represent the lysosomes that are loaded with Cu (Goldfischer and Sternlieb, 1968; Ishmael et al, 1971; Kumaratilake, 1984; Gross et al, 1989)
Rats, pigs and humans absorption of copper has been identified to occur via the high affinity Cu importer, CTR1 protein located on the apical membrane of the enterocytes (Petris et al, 2003; Guo et al, 2004; Molloy and Kaplan, 2009; Nose et al, 2010) and in sheep too, the CTR1 protein may be involved in the absorption of Cu
Summary
Copper (Cu) is a trace nutrient and exists in the animal body in stable oxidized Cu II or unstable reduced Cu I states. It has the ability to cycle between the two forms, is used by enzymes involved in redox reactions that are essential in biological processes, such as mitochondrial oxidative phosphorylation, iron metabolism, pigmentation, neurotransmitter synthesis, crosslinking of collagen and elastin, and free radical detoxification (Camakaris et al, 1999; Puig et al, 2002; Petris et al, 2003; Andreini et al, 2008; Nose et al, 2010). Imbalances in Cu content of the body could lead to either Cu toxicity 1-22 sheep) (Mendel et al, 2007; Wang et al, 2011) or deficiency (Eg. Menkes disease in humans) (Wang et al, 2011; Vonk et al, 2012)
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