title: Neurotoxic effects of bisphenol AF on calcium-induced ROS and MAPKs.
abstract: 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.
authors.affiliation: CMRI, Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea.
authors.forename: Soyoung
authors.initials: S
authors.lastname: Lee
authors.forename: Yoo Kyeong
authors.initials: YK
authors.lastname: Kim
authors.forename: Tae-Yong
authors.initials: TY
authors.lastname: Shin
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001559:Benzhydryl Compounds / Q000737:chemistry / Q000633:toxicity*; D020013:Calcium Signaling / Q000187:drug effects*; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D018920:Coculture Techniques; D004789:Enzyme Activation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010636:Phenols / Q000737:chemistry / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D005466:Fluorocarbons; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D009569:Nitric Oxide; D010636:Phenols; D017382:Reactive Oxygen Species; C583074:bisphenol AF; D005466:Fluorocarbons; D000098826:Bisphenol A Compounds