Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China.
Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
J Hazard Mater. 2019 Jul 5;373:504-518. doi: 10.1016/j.jhazmat.2019.03.106. Epub 2019 Mar 26.
Previous studies have demonstrated that toxins produced by toxic cyanobacterial blooms are hazardous materials. Although microcystin-LR (MC-LR) has been revealed to inflict damage to the brain, the mechanisms underlying its neurotoxicity as a result of chronic exposure to MC-LR are not fully described. In this study, the mice were exposed to MC-LR dissolved in drinking water at doses of 1, 7.5, 15, or 30 μg/L for 180 days. MC-LR accumulated mostly in the mouse hippocampus (55 ng/g dry weight) followed by cortex (28 ng/g dry weight) after exposure to MC-LR at 30 μg/L. MC-LR exposure at this concentration induced dysfunction of learning and memory, accompanied with apoptosis of neuronal cells (with 10% reduction of the neurons in the CA1 region and 15% in the CA2 region), reduction of spine density, accumulation of β-amyloid plaques 1-42 (Aβ1-42), and enhanced phosphorylation of tau (p-tau) in the brain, which is characteristic of Alzheimer's disease (AD). These data indicate that MC-LR may induce AD-like pathology. Following prolonged exposure, MC-LR significantly upregulated the ratio of proBDNF to BDNF by downregulating the tPA levels, thereby activating downstream signaling pathways to improve the expression of p-JNK, and c-Jun while to inhibit the expression of p-Creb and p-PKC. This study uncovered new molecular mechanisms that account for neurotoxicity after chronic exposure to MC-LR, which has wide-ranging implications for public health.
先前的研究表明，有毒蓝藻水华产生的毒素是危险物质。虽然已证实微囊藻毒素-LR（MC-LR）会损害大脑，但 MC-LR 慢性暴露导致其神经毒性的机制尚未完全描述。在这项研究中，小鼠被暴露于以 1、7.5、15 或 30μg/L 的剂量溶解在饮用水中的 MC-LR 中，持续 180 天。MC-LR 暴露于 30μg/L 后，主要积聚在小鼠海马体（55ng/g 干重），其次是皮质（28ng/g 干重）。在该浓度下，MC-LR 暴露会导致学习和记忆功能障碍，伴随着神经元细胞凋亡（CA1 区减少 10%，CA2 区减少 15%），棘突密度降低，β-淀粉样斑块 1-42（Aβ1-42）积聚，以及脑中 tau 蛋白磷酸化（p-tau）增强，这是阿尔茨海默病（AD）的特征。这些数据表明，MC-LR 可能会诱导 AD 样病理。长期暴露后，MC-LR 通过下调 tPA 水平，显著上调 proBDNF 与 BDNF 的比值，从而激活下游信号通路，提高 p-JNK 和 c-Jun 的表达，同时抑制 p-Creb 和 p-PKC 的表达。本研究揭示了慢性 MC-LR 暴露后导致神经毒性的新分子机制，这对公共卫生具有广泛的意义。
