Effect of age and sex on liver damage due to excess dietary copper in Fischer 344 rats.
OBJECTIVE
The aim of this study was to investigate the morphologic and biochemical effects of excess dietary copper in young and adult rats of different sex.


METHODS
Adult Fischer 344 male and female rats were given a diet containing 1500 ppm copper for 18 weeks. Young male and female rats were fed a similar copper-loaded diet from birth until 16 weeks of age. Age- and sex-matched control rats were fed a normal rodent diet (<10 ppm copper). Serum liver enzyme activity was determined in all rats. Livers were sampled for histology, histochemistry (rhodanine), immunohistochemical detection of metallothionein and copper analysis by atomic absorption spectrophotometry. Hepatic metallothionein and zinc concentrations were measured in adult rats.


RESULTS
Excess dietary copper caused substantial liver injury, as evidenced by morphologic changes and increased activity of serum ALT, GGT, and SDH. All copper-loaded rats had significantly (p< 0.05) increased hepatic copper concentrations compared to controls. However, young copper-loaded rats accumulated more hepatic copper, had more severe liver changes, and had higher serum liver enzyme activities than adult rats. Histologic changes in copper-loaded rats consisted of multifocal hepatitis and widespread single-cell necrosis. Cytoplasmic copper was detected histochemically in centroacinar zone 1 (portal) and mid-zone in copper-loaded rats. Immunoreactivity for metallothionein was prominent in necrotic hepatocytes and within inflammatory foci in copper-loaded rats. However, differences in hepatic metallothionein concentrations were not detected between adult copper-loaded and control rats.


CONCLUSIONS
Young Fischer 344 rats are more susceptible than adults to copper-induced liver injury.
Fuentealba
I C
IC
Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Canada. cfuentealba@upei.ca
Mullins
J E
JE
Aburto
E M
EM
Lau
J C
JC
Cherian
G M
GM
D000375:Aging; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001663:Bilirubin / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology*; D003300:Copper / Q000008:administration & dosage / Q000032:analysis / Q000633:toxicity*; D004032:Diet; D005260:Female; D007064:L-Iditol 2-Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008297:Male; D008668:Metallothionein / Q000032:analysis; D009336:Necrosis; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D012727:Sex Characteristics; D015032:Zinc / Q000032:analysis; D005722:gamma-Glutamylcyclotransferase / Q000378:metabolism
D003300:Copper; D008668:Metallothionein; D007064:L-Iditol 2-Dehydrogenase; D000410:Alanine Transaminase; D005722:gamma-Glutamylcyclotransferase; D015032:Zinc; D001663:Bilirubin