Morphological and biochemical assessment of the liver response to excess dietary copper in Fischer 344 rats

The aim of this study was to determine the amount of excess dietary copper (Cu) necessary to experimentally induce liver lesions characteristic of Cu- associated disease in Fischer 344 rats. Male weanling Fischer 344 rats of u niform age were divided into 6 groups (n = 5) and fed a rodent diet contain ing 18 (control), 750, 1000, 1250, 1500, and 2000 mug/g Cu added as CuSO4. Rats were euthanized after 3 months on the experimental diets and their liv ers processed for histology, histochemistry, Cu analysis (by atomic absorpt ion spectrophotometry), and quantification of malondialdehyde (MDA) by the thiobarbituric acid reaction. Hepatic Cu levels were significantly higher ( P < 0.01) in rats receiving over 1000 <mu>g/g Cu compared to the controls ( means for each diet: control = 4.8 mug/g, 750 mug/g Cu = 39.6 mug/g, 1000 m ug/g Cu = 111.2 mug/g, 1250 mug/g Cu = 389 mug/g, 1500 mug/g Cu 509.4 mug/g , and 2000 mug/g Cu = 766 mug/g). Histological lesions increased gradually according to the level of dietary Cu. Significant morphologic changes (necr osis, portal inflammation, hyaline remnants) and reduced growth rate occurr ed in rats receiving over 1250 mug/g Cu. However, no significant difference s were found for MDA levels between groups. The present study demonstrates that compared to other species, very high levels of excess dietary Cu are n eeded to induce significant liver injury in Fischer 344 rats. Increased MDA content was not detected in rats with morphologic evidence of liver damage , suggesting that lipid peroxidation may not play a major role in this mode l of Cu toxicity.