Abstract：
Microcystins (MCs) are toxic to the central nervous system of mammals. However, the direct toxicity of MCs on mammalian brain cells and the involved molecular mechanisms are not fully elucidated. Here, we incubated primary astrocytes, the major glial cell-type in the brain, with 0-12.5 μM concentrations of MC-LR for 48 h, and the impairment was evaluated. We found that MC-LR caused significant increases in the cell viability at the range of 0.05-1 μM concentrations with the highest density at 0.1 μM concentration. Treatment with 0.1 μM MC-LR induced YAP nuclear translocation and decreased the ratio of p-YAP to YAP. It also decreased mRNA levels of the upstream regulator (AMOT), and enhanced expressions of YAP interacted genes (Egfr, Tead1, and Ctgf) in primary astrocytes. Overexpression of AMOT significantly attenuated the increase of MC-LR-induced astrocyte proliferation and the expression of YAP downstream genes. These results indicate that Hippo signaling contributed to MC-LR-caused astrocyte proliferation. Further, reactive astrogliosis was observed in the mice brain after MC-LR exposure to environmentally relevant concentrations (20 or 100 μg/L) through drinking water for 16 weeks. Pathological observations revealed that 100 μg/L MC-LR exposure caused neuronal damages with characteristics of shrunken or vacuolation in the region of the cerebral cortex, striatum and cerebellum. These results were accompanied with increased oxidative stress and inflammatory response. Our data reveal the potential astrocytic mechanisms in MC-induced neurotoxicity and raise an alarm for neurodegenerative disease risk following daily exposure to MC-LR.
摘要：
微囊藻毒素(MCs)对哺乳动物的中枢神经系统具有毒性。然而,MCs对哺乳动物脑细胞的直接毒性及其相关分子机制尚未完全阐明。这里,我们培养了原代星形胶质细胞，大脑中主要的神经胶质细胞类型，用0-12.5μM浓度的MC-LR持续48小时，并对减值进行了评估。我们发现MC-LR在0.05-1μM浓度范围内引起细胞活力的显着增加，在0.1μM浓度下密度最高。用0.1μMMC-LR治疗可诱导YAP核易位，并降低p-YAP与YAP的比率。它还降低了上游调节因子（AMOT）的mRNA水平，和YAP相互作用基因的表达增强(Egfr，Tead1和Ctgf）在原代星形胶质细胞中。AMOT的过表达显著减弱MC-LR诱导的星形胶质细胞增殖的增加和YAP下游基因的表达。这些结果表明Hippo信号传导有助于MC-LR引起的星形胶质细胞增殖。Further,MC-LR通过饮用水暴露于环境相关浓度(20或100μg/L)16周后,在小鼠脑中观察到反应性星形胶质增生.病理观察表明，100μg/LMC-LR暴露导致大脑皮层区域神经元损伤，具有萎缩或空泡化的特征，纹状体和小脑.这些结果伴随着增加的氧化应激和炎症反应。我们的数据揭示了MC诱导的神经毒性的潜在星形细胞机制，并在每天暴露于MC-LR后引发了神经退行性疾病风险的警报。
