纳米氧化钛诱导仔鼠海马神经元细胞自噬作用的分子机制

摘要：诸多研究已证明纳米TiO2母体暴露可穿越胎盘屏障在子代动物积累并导致神经毒性如学习记忆下降，但这种神经毒性机制尚不明确。本文分别用1。25、2。5和5 mg/kg BW的纳米TiO2对母鼠从妊娠第7d至断乳期(产后21 d)持续灌胃后，探讨对仔鼠海马神经元树突发育的影响及是否涉及神经元细胞的过度自噬作用及其分子机制。实验观察到纳米TiO2母体暴露后仔鼠海马神经元树突丝长度明显低于对照，并发生过度自噬作用。进一步研究表明仔鼠海马神经元活性氧自由基(ROS)大量积累，丙二醛(MDA)增加，线粒体膜电位和ATP含量下降；同时凋亡和自噬相关分子如H2AX、cytc、caspase-3、PI3K3C、Beclin 1、c-Jun、LC3Ⅰ、LC3Ⅱ、JNK和 p-JNK的表达上调及其LC3Ⅱ/ LC3Ⅰ比值增加，而Bcl-2表达下调。因此，纳米TiO2母体暴露可抑制仔鼠海马神经元树突发育并与过度自噬作用发生有关，而过度自噬作用的发生又与严重的氧化应激、凋亡及自噬相关分子的表达改变相关。这些发现对于深入了解纳米TiO2神经发育毒性机制至关重要。78282

毕业论文关键词：纳米TiO2；母体暴露；仔鼠；海马神经元；自噬作用；树突发育

Abstract: Numerous studies have demonstrated that maternal exposure to nano-TiO2 can cross the placental barrier and accumulate in offspring animals and cause neurotoxicity such as reductions of learning and memory。 However, the neurotoxic mechanisms are not fully understood。 The present study was therefore undertaken to determine effect of nano-TiO2 on development of the dendrites of offspring mice hippocampal neurons and to determine whether nano-TiO2 induces the role of excessive autophagy as well as its molecular mechanism in offspring mice hippocampal neurons in female mice from 7d to weaning during pregnancy (21 d postpartum) by consecutive intragastric administrations with 1。25, 2。5, and 5 mg/kg body weight nano-TiO2。 It was observed that the length of the dendrites of the hippocampal neurons was lower than that of the control group, and excessive autophagy of the hippocampal neurons occurred in offspring mice caused by nano TiO2。 Furthermore, maternal exposure to nano-TiO2 can cause over reactive oxygen species production, malondialdehyde increase, reductions of mitochondrial membrane potential and ATP contents, upregulation of apoptosis- or autophagy-related factors including H2AX, cytc, caspase-3, PI3K3C, Beclin 1, c-Jun, LC3 I, LC3Ⅱ, JNK和 p-JNK expression and increase of LC3Ⅱ/ LC3 I as well as downregulation of Bcl-2 expression in the hippocampal neurons of offspring mice。 Taken together, maternal exposure to nano-TiO2 can inhibit dendritic development of hippocampal neurons in offspring mice which is associated with excessive autophagy of the neurons; the excessive autophagy is related to severe oxidative stress, alterations of apoptosis- or autophagy-related factor expression due to exposure to nano-TiO2。 Our findings are crucial for understanding the mechanisms of the neural development toxicity caused by nano-TiO2。

Key words: Nano-sized TiO2; Maternal exposure; Offspring mice; Hippocampal neurons; Autophagy; Dendritic development

第一部分：研究背景 5

1 纳米材料的特征及应用 5

2 纳米颗粒进入神经中枢系统的途径 6

2。1 纳米颗粒跨越血脑屏障 6

2。2 鼻腔黏膜摄入纳米颗粒至嗅球, 经嗅神经转运 7

2。3 经感觉神经末梢直接摄入及神经转运 7

3 纳米TiO2的神经毒性 7

3。1 纳米TiO2的体内神经毒性研究纳米氧化钛诱导仔鼠海马神经元细胞自噬作用的分子机制:http://www.youerw.com/shengwu/lunwen_90187.html