Cadmium-induced apoptosis in mouse liver.

Apoptosis is a process of active cell death, distinct from necrosis and characterized by specific morphological and biochemical features. Although the acute hepatotoxic effects of cadmium (Cd) are well described, little is known about the occurrence of apoptosis in Cd toxicity. Therefore, mice were injected with 5-60 mumol/kg i.p. of Cd and their livers were removed 1.5-48 h later and examined by light microscopy. Cd induced both a time- and dose-dependent increase in apoptotic index, severity of necrosis, and mitotic index. Apoptotic index peaked at 9-14 h after Cd administration and then decreased. The time course of apoptotic DNA fragmentation index, monitored by quantification of oligonucleosomal DNA fragments, correlated with the results obtained by histopathological analysis and a commercial in situ apoptotic DNA detection kit. Liver necrosis, as demonstrated by histology and serum alanine aminotransferase and sorbitol dehydrogenase assays, was most severe 14-48 h after Cd injection. Apoptosis was decreasing by 24 h while necrosis persisted. Replacement of liver tissue by blood lakes (peliosis hepatis) was observed after 14 h. The mitotic index increased gradually with time, indicating compensatory liver cell regeneration. There was a progressive increase in the severity of necrosis, apoptotic index, and mitotic index with increasing dose of Cd. These data demonstrate that apoptosis is a major mode of elimination of critically damaged cells in acute Cd hepatotoxicity in the mouse, and it precedes necrosis.