Critical role of calcium overloading in cadmium-induced apoptosis in mouse thymocytes.
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 (Ca2+) elevation, followed by caspase-3 activation and PARP cleavage, all of which preceded the characteristic DNA fragmentation. BAPTA-AM, a specific intracellular Ca2+ chelator, abolished Cd-induced Ca2+ overloading and subsequently inhibited caspase-3 activation, PARP cleavage, and apoptosis. It is believed that intracellular Ca2+ elevation may trigger caspase-3 activation either through mitochondria or through activation of Ca2+-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.
Shen
H M
HM
Centre for Environmental and Occupational Health, Department of Community, Occupational and Family Medicine, MD3, Faculty of Medicine, National University of Singapore, 16 Medical Drive, Singapore, 117597, Republic of Singapore.
Dong
S Y
SY
Ong
C N
CN
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002104:Cadmium / Q000633:toxicity*; D002118:Calcium / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000502:physiology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects*
D002104:Cadmium; D004533:Egtazic Acid; D011065:Poly(ADP-ribose) Polymerases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium