Critical role of calcium overloading in cadmium-induced apoptosis in mouse thymocytes

Abstract

Cadmium (Cd) is a well-known environmental carcinogen and immunotoxin. Currently the direct cytotoxic effects of Cd on thymocytes are largely unexplored. The main objective of the present study was to investigate the apoptogenic property of Cd and the mechanisms involved, using primary cultured mouse thymocytes as a model. Cd-induced apoptosis in thymocytes was studied by TdT-mediated dUTP nick end-labeling assay and DNA gel electrophoresis. The results showed that Cd was able to cause apoptosis in mouse thymocytes in a time- and dose-dependent manner. Moreover, Cd exposure led to a rapid and sustained intracellular calcium (Ca 2+) elevation, followed by caspase-3 activation and PARP cleavage, all of which preceded the characteristic DNA fragmentation. BAPTA-AM, a specific intracellular Ca 2+ chelator, abolished Cd-induced Ca 2+ overloading and subsequently inhibited caspase-3 activation, PARP cleavage, and apoptosis. It is believed that intracellular Ca 2+ elevation may trigger caspase-3 activation either through mitochondria or through activation of Ca 2+-dependent protease in Cd-treated thymocytes. Results from this study thus provide new information for a better understanding of the immunotoxic and immunomodulatory effects of Cd. © 2001 Academic Press.