Signaling pathways of bisphenol A-induced apoptosis in hippocampal neuronal cells:: Role of calcium-induced reactive oxygen species, mitogen-activated protein kinases, and nuclear factor-κB

In the present study, we investigated the neurotoxicity of bisphenol A [BPA; 2,2-bis-(4 hydroxyphenyl) propane] and the underlying mechanisms of action in mouse hippocampal HT-22 cells. BPA, known to be a xenoestrogen, is used in the production of water bottles, cans, and teeth suture materials. BPA-treated HT-22 cells showed lower cell viability than did controls at concentrations of BPA over 100 mu M. BPA induced apoptotic cell death as indicated by staining with Hoechst 33258, costaining with Annexin V/propidium iodide, and activation of caspase 3. BPA regulated the generation of reactive oxygen species (ROS) by increasing intracellular calcium. BPA activated phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), and nuclear translocation of nuclear factor (NF)-kappa B. Pretreatment with specific inhibitors for calcium, ROS, ERK, and JNK decreased BPA-induced cell death; however, inhibitor for NF-kappa B increased BPA-induced cell death. The results suggest that calcium, ROS, ERK, and JNK are involved in BPA-induced apoptotic cell death in HT-22 cells. In contrast, an NF-kappa B cascade was activated for survival signaling after BPA treatment. (C) 2008 Wiley-Liss, Inc.