Role of apoptosis in copper deficiency-induced pancreatic involution in the rat

Rats maintained on a copper-deficient diet supplemented with a copper-chelating agent, triethylenetetramine tetrahydrochloride, for 8 to 10 weeks show marked involution of pancreatic acinar tissue. The present study deals with the possible mechanism of pancreatic acinar cell involution during copper deficiency. Sequential light and electron microscopic observations during the copper-depletion regimen, suggest that apoptosis is the main cause of progressive loss of acinar cells. At 4 weeks of copper deficiency, the apoptotic index was 2 +/- 0.6/1,000 cells. By 6 weeks, the apoptotic index reached a maximum of 95 +/- 25/1,000. By 8 weeks, there was almost total loss of acinar cells. The earliest change of apoptosis was characterized by condensation and margination of chromatin against nuclear membrane. Subsequently, several apoptotic bodies displayed pyknotic nucleus and eosinophilic cytoplasmic condensation. Apoptotic bodies were extruded into the interstitium or phagocytosed by unaffected acinar cells. No associated pancreatic inflammation was present. These results indicate that apoptosis is the process involved in pancreatic involution caused by copper deficiency. The molecular mechanism(s) by which copper deficiency causes apoptosis remain unclear.