College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, South Korea.
Neurochem Int. 2011 Oct;59(5):582-90. doi: 10.1016/j.neuint.2011.04.006. Epub 2011 Jun 13.
Because estrogen plays important neurotrophic and neuroprotective roles in the brain by activating estrogen receptors (ERs), disruption of normal estrogen signaling can leave neurons vulnerable to a variety of insults, including β-amyloid peptide (Aβ). Aroclor1254 (A1254) belongs to the endocrine-disrupting chemical (EDC) polychlorinated biphenyls and has anti-estrogenic properties. In the present study, we evaluated the effect of A1254 on the protective activity of estrogen against Aβ toxicity in differentiated cholinergic SN56 cells. Aged Aβ25-35 causes apoptotic cell death in differentiated SN56 cells, and the cytotoxic evidences are effectively rescued by estrogen. We found that A1254 abolishes the neuroprotective activity of estrogen against Aβ toxicity, and attenuates the suppressive effect of estrogen on Aβ-induced tau phosphorylation and JNK activation. The effects of A1254 on the neuroprotective effects of estrogen in Aβ toxicity are very similar to the effects of the estrogen receptor antagonist ICI182,780. Thus, exposure to EDCs that have anti-estrogenic activity might interfere with normal estrogen-activated neuroprotective signaling events and leave neurons more vulnerable to dangerous stimuli. Our present results provide new understanding of the mechanisms contributing to the harmful effects of EDCs on the function and viability of neurons, and the possible relevance of EDCs in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease.
因为雌激素通过激活雌激素受体（ER）在大脑中发挥重要的神经营养和神经保护作用，所以正常雌激素信号的中断会使神经元容易受到各种刺激的影响，包括β-淀粉样肽（Aβ）。多氯联苯（PCBs）中的 Aroclor1254（A1254）属于内分泌干扰化学物质（EDC），具有抗雌激素特性。在本研究中，我们评估了 A1254 对雌激素对分化的胆碱能 SN56 细胞中 Aβ毒性的保护活性的影响。老化的 Aβ25-35 会导致分化的 SN56 细胞发生凋亡性细胞死亡，而雌激素可以有效地挽救细胞毒性证据。我们发现，A1254 会破坏雌激素对 Aβ毒性的神经保护活性，并减弱雌激素对 Aβ诱导的 tau 磷酸化和 JNK 激活的抑制作用。A1254 对雌激素在 Aβ毒性中神经保护作用的影响与雌激素受体拮抗剂 ICI182780 的影响非常相似。因此，暴露于具有抗雌激素活性的 EDC 可能会干扰正常的雌激素激活的神经保护信号事件，并使神经元更容易受到危险刺激的影响。我们目前的研究结果为 EDC 对神经元功能和活力的有害影响的机制提供了新的认识，并且 EDC 可能与阿尔茨海默病等神经退行性疾病的发病机制有关。
