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Pathogenesis of chronic copper poisoning in sheep and the effects of thiomolybdate

Kumaratilake, Jaliya Sarah (1984) Pathogenesis of chronic copper poisoning in sheep and the effects of thiomolybdate. PhD thesis, Murdoch University.

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This project was carried out to determine the pathogenesis of chronic copper (Cu) poisoning and the effects of intravenously (I/V) administered thiomolybdate (TM) in sheep.. Biochemical≫ histopathological, histochemical, electron microscopic, morphometric and subcellular fractionation techniques were used,in order to study the changes occurring in liver, blood, kidney, muscle, brain, eye, bone and wool. The results revealed that the deposition of Cu starts in hepatocytes of the centrilobular zones of the sheep liver and that the Cu moves in to the cytosol and lysosomes. With Cu loading, increases were observed in the number and size of Cu containing lysosomes and in the number of hepatocytes containing such organelles. However, the uptake of Cu between hepatocytes was different and some hepatocytes became packed with Cu containing lysosomes. The predominant change was degeneration and necrosis of isolated Cu loaded hepatocytes. It seems probable that necrosis of these cells was due to a reduction in the uptake of Cu by lysosomes resulting in an accumulation of Cu in cytosol, thereby leading to lipid peroxidation of membranes, cellular injury and death. Necrosis of isolated hepatocytes was associated with elevations of plasma Cu and serum acid phosphatase (AP) activity. Haemolysis was associated with a marked increase in the number of necrotic isolated hepatocytes, which liberated Cu and lysosomal hydrolases in to the blood stream. Marked elevations of Cu and lysosomal hydrolases in the blood may have caused lipid peroxidation of red blood cell (RBC) membranes which may have been responsible for the influx of Cu in to RBC which immediately preceeded haemolysis.

It is suggested that the elevated levels of Cu and lysosomal hydrolases in blood may have acted on muscle causing the elevations of creatine kinase activity which were observed during the pre-haemolytic, haemolytic and post-haemolytic phases. It is also suggested that the observed marked elevations of the levels of Cu and AP in blood immediately prior to haemolysis may have caused the development of kidney damage which was seen during haemolysis.

Intravenous administration of 100 mg of TM at 24 hour intervals, commencing at the onset and with a maximum of 3 doses, during haemolysis was effective in the treatment of haemolytic episodes in chronic Cu poisoned sheep. Furthermore, I/V administration of 50 mg of TM twice weekly was effective in the prevention of the development of haemolysis, and also in the reduction of liver Cu in Cu loaded sheep as well as in sheep that recovered from haemolysis. The primary effect of TM was to remove Cu from Cu loaded hepatocytes and thereby to reduce the necrosis of liver cells. Thiomolybdate appeared to enter in to hepatocytes and remove Cu from cytosol and lysosomes.

Increased Cu levels were seen in the bones of Cu loaded sheep with and without TM administration. Furthermore, in Cu loaded sheep there was early closure of the distal epiphyseal plates of the femur. Copper loading to sheep did not increase the wool Cu levels.

Item Type: Thesis (PhD)
Murdoch Affiliation(s): School of Veterinary Studies
Notes: Note to the author: If you would like to make your thesis openly available on Murdoch University Library's Research Repository, please contact: Thank you.
Supervisor(s): Howell, John McC.
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