Cadmium induces apoptosis of human granulosa cell line KGN via mitochondrial dysfunction-mediated pathways

Cadmium (Cd) is an important industrial and environmental pollutant, which is closely correlated with female infertility. Although Cd-induced developmental disorders of human ovarian follicles have been widely reported, the underlying mechanisms remain not fully elucidated. In this study, we explored the mechanism underlying Cd-triggered apoptosis in granulosa cells. Following the treatment with various levels of Cd (0, 0.625, 1.25, 2.5 and 5 μM), we found that Cd triggered the death of KGN cells (a human granulosa-like tumor cell line) in a dose- as well as time-dependent manner. The levels of expressions of Bax and Bak were significantly increased, whereas the expression levels of Mcl-1 and Bcl-2 were considerably decreased after being treated with high levels of Cd. We showed that Cd exposure remarkably triggered mitochondrial dysfunction, including increased intracellular ROS and free Ca2+ levels, and decreased ATP generation and mitochondrial membrane potential. Furthermore, we found that mitochondrial dysfunction, especially excessive ROS production and intracellular Ca2+ overload, serve a vital role in Cd-triggered apoptosis of KGN cells. After using inhibitors to block the corresponding signaling cascades, Cd-mediated apoptosis was markedly repressed by ASK1 and p38 inhibitors in contrast with the control group. This suggests the activation of downstream pathways triggered by mitochondrial dysfunction participates in granulosa cell death and may cause female reproductive toxicity after Cd exposure.