Cadmium stimulates mouse skin fibroblast apoptosis by affecting intracellular homeostasis

Abstract

Context: Cadmium (Cd2+) is an important industrial and environmental pollutant and has been shown to induce apoptosis in a variety of cell types and tissues. Objective: To assess the specific effects of low-dose Cd2+ on the skin. This organ is easily exposed to Cd2+, but how it damages cells is not fully understood. Materials and methods: Mouse skin fibroblasts were treated with low doses of Cd2+ (0.4, 0.8 or 1.6 μM) for 12–48 h, and we observed cell morphological alterations, measured DNA damage and quantified cell viability changes. Results: Cd2+-treated fibroblasts exhibited morphological changes and evidence of DNA damage, as well as higher numbers of apoptotic and necrotic cells. There were increased caspase −3, −8 and −9 activities when fibroblasts were treated with 0.4, 0.8 and 1.6 μM CdCl2 for 24 h. Higher intracellular calcium (Ca2+) and reactive oxygen species (ROS) levels, and enhanced efflux of extracellular Ca2+ and potassium (K+). The mitochondrial membrane potential was lowered in treated cells, and the cell cycle arrested in the G0/G1 phase. Bax and Fas gene expression increased and Bcl-2 gene expression decreased. Discussion: The results demonstrate that Cd2+ exerts typical apoptotic effects in mouse skin fibroblasts. It strongly inhibited proliferation and induced apoptosis in a dose- and duration-dependent manner. Ca2+ homeostasis was disturbed by oxidative stress, mitochondrial dysfunction and caspase-mediated apoptosis. Conclusion: K+ efflux and Bax, Bcl-2 and Fas gene expression regulation play important roles in Cd2+-induced dysfunction by disrupting intracellular homeostasis in mouse skin fibroblasts.