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

Abstract

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 μM. 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)-κB. Pretreatment with specific inhibitors for calcium, ROS, ERK, and JNK decreased BPA-induced cell death; however, inhibitor for NF-κB 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-κB cascade was activated for survival signaling after BPA treatment.