CADMIUM-INDUCED APOPTOSIS IN MOUSE-LIVER

Apoptosis is a process of active cell death, distinct from necrosis an d characterized by specific morphological and biochemical features. Al though the acute hepatotoxic effects of cadmium (Cd) are well describe d, little is known about the occurrence of apoptosis in Cd toxicity. T herefore, mice were injected with 5-60 mu mol/kg ip of Cd and their li vers were removed 1.5-48 h later and examined by light microscopy. Cd induced both a time-and dose-dependent increase in apoptotic index, se verity of necrosis, and mitotic index. Apoptotic index peaked at 9-14 h after Cd administration and then decreased. The time course of apopt otic DNA fragmentation index, monitored by quantification of oligonucl eosomal DNA fragments, correlated with the results obtained by histopa thological analysis and a commercial in situ apoptotic DNA detection k it. Liver necrosis, as demonstrated by histology and serum alanine ami notransferase 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 hepat is) was observed after 14 h. The mitotic index increased gradually wit h time, indicating compensatory liver cell regeneration. There was a p rogressive 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 i n acute Cd hepatotoxicity in the mouse, and it precedes necrosis. (C) 1998 Academic Press.