CMRI, Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea.
Neurotox Res. 2013 Apr;23(3):249-59. doi: 10.1007/s12640-012-9353-4. Epub 2012 Sep 21.
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.
双酚 AF（BPAF）是一种与双酚 A 结构相关的新型化学物质，广泛用于氟弹性体和聚酯中，已知会引起雌激素依赖性反应。然而，除了与内分泌相关的影响外，BPAF 的毒性在很大程度上尚不清楚。在这项研究中，我们使用海马细胞系（HT-22）和小鼠原代神经元细胞研究了 BPAF 的神经毒性及其作用机制。我们发现 BPAF 可诱导 HT-22 和原代神经元细胞凋亡。为了阐明 BPAF 诱导凋亡的潜在机制，评估了各种信号分子。BPAF 增加了细胞内钙的水平，随后产生了活性氧（ROS）。BPAF 上调了丝裂原活化蛋白激酶：细胞外信号调节激酶、p38 和 c-Jun N-末端激酶（JNK）的磷酸化水平，并使核因子-κB 核转位。使用特异性抑制剂，我们证实钙、ROS、p38 和 JNK 介导了 BPAF 诱导的细胞凋亡。此外，BPAF 通过减少一氧化氮的产生抑制了小胶质细胞/神经母细胞瘤共培养模型中的小胶质细胞激活。我们发现 BPAF 在非毒性水平中断了小胶质细胞的正常生理功能。总之，我们的结果表明，BPA 的替代品 BPAF 也具有神经毒性。
