Neurotoxic Effects of Bisphenol AF on Calcium-Induced ROS and MAPKs

• DOI: 10.1007/s12640-012-9353-4
• Publication Date: 2012-09-20T03:54:51Z
• Authors: Soyoung Lee; Yoo Kyeong Kim; Tae-Yong Shin; Sang-Hyun Kim
• Keywords: Neurons; 0301 basic medicine; Molecular Structure; MAP Kinase Signaling System; NF-kappa B; Apoptosis; Nerve Tissue Proteins; Nitric Oxide; Hippocampus; Coculture Techniques; Cell Line; 3. Good health; Enzyme Activation; Mice; Neuroblastoma; 03 medical and health sciences; Cell Line, Tumor; Animals; Calcium Signaling; Microglia; Benzhydryl Compounds; Mitogen-Activated Protein Kinases; Cells, Cultured

Bisphenol AF (BPAF), a newly introduced chemical structurally related to bisphenol A, is used extensively in fluoroelastomers and polyesters, and has been known to induce estrogen-dependent responses. However, the toxicity of BPAF is largely unknown except for its endocrine-related effects. In this study, we investigated the neurotoxicity of BPAF and underlying mechanisms of action using hippocampal cell line (HT-22) and mouse primary neuronal cells. We found that BPAF induced apoptosis in both HT-22 and primary neuronal cells. In order to clarify the underlying mechanisms of BPAF-induced apoptosis, various signaling molecules were evaluated. BPAF increased the level of intracellular calcium, followed by the generation of reactive oxygen species (ROS). BPAF upregulated the phosphorylation of mitogen-activated protein kinase: extracellular signal-regulated kinase, p38 and c-Jun N-terminal kinase (JNK), and nuclear translocation of nuclear factor-κB. Using specific inhibitors, we confirmed that calcium, ROS, p38, and JNK mediated the BPAF-induced apoptosis. In addition, BPAF inhibited microglial activation in a microglia/neuroblastoma coculture model by the reduction of nitric oxide production. We found that BPAF interrupted the normal physiologic functions of microglia at non-toxic levels. Taken together, our results suggest that BPAF, the substitute of BPA, also have neurotoxic properties.