Cellular mechanisms of toxicity and tolerance in the copper-loaded rat. I. Ultrastructural changes in the liver

Ultrastructural changes have been studied in the copper-loaded livers of rats in order to clarify the pathogenesis of damage induced by the metal and the subsequent recovery. Male rats fed a high copper diet (1500 ppm) for 16 weeks were killed at intervals. Their livers were removed and portions fixed in 4% paraformaldehyde and 2% glutaraldehyde for transmission electron microscopy and analysed for copper by AA spectrophotometry. Increasing copper concentrations were associated with an increase in the numbers and diversity of lysosomes, swelling of smooth endoplasmic reticulum, mitochondria and canalicular microvilli and fragmentation of rough endoplasmic reticulum. Nuclear degeneration occurred early, culminating in lysis. Subsequent changes included a decline in liver copper, extrusion of apoptotic bodies and the recovery of remaining hepatocytes with retention of inert remnants (Mallory body-like structures). Excess copper is associated primarily with irreversible nuclear damage and does not appear to cause disruption of lysosomes. The mechanism of cellular adaptation remains unclear.