Effects of cadmium on cellular calcium and proto-oncogene expression.

Effects of the carcinogenic metal cadmium on cellular calcium signalling and proto-oncogene expression were studied in mammalian cells. Cadmium ions interfered with bradykinin- and adenosinetriphosphate (ATP)-stimulated calcium transients in rat pheocromocytoma PC12 cells, but Cd2+ as such did not evoke intracellular Ca2+ spikes. At variance, cadmium ions caused a sustained elevation of intracellular free Ca2+ by inhibition of active calcium transport systems in various cell types. Problems of mutual interference of Ca2+ and Cd2+ analysis with the fluorescent probe Fura-2 could be overcome by the use of the fluorine 19 nuclear magnetic resonance (19F-NMR) probe acetoxymethyl ester of 1,2-bis(2-amino-5-fluorophenoxy)ethane-N,N,N'N'-tetraacetic acid (5F-BAPTA), which allows the measurement of free intracellular Ca2+, Cd2+ and other metal ions concurrently. Furthermore, the induction of the cellular protooncogenes c-fos and c-jun by Cd2+ was studied in PC12 cells. A dose of 0.5 microM Ca2+ sufficed to induce the c-Fos and c-Jun proteins within 30 min. These results support a model which suggests that cadmium stimulates cell proliferation by interference with intracellular calcium and induction of immediate early genes.