Hippocampal ER Stress and Learning Deficits Following Repeated Pyrethroid Exposure
Hippocampal ER Stress and Learning Deficits Following Repeated Pyrethroid Exposure
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DOI：
10.1093/toxsci/kfu226
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发表时间：
2015-01-01
影响因子：
3.8
通讯作者：
Richardson, Jason R.
中科院分区：
文献类型：
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作者：
Hossain, Muhammad M.;DiCicco-Bloom, Emanuel;Richardson, Jason R.
内质网（ER）应激是神经退行性变和认知功能障碍的重要因素。以前，我们报道了广泛使用的拟除虫菊酯杀虫剂溴氰菊酯导致ER应激介导的SK-N-AS神经母细胞瘤细胞凋亡。这种情况是否在体内发生仍不清楚。在这里，我们证明了重复的溴氰菊酯暴露（3毫克/公斤，每3天60天）导致海马ER应激和学习缺陷的成年小鼠。重复暴露于溴氰菊酯导致海马中的ER应激，表现为C/EBP同源蛋白（131%）和葡萄糖调节蛋白78（96%）水平升高。这伴随着caspase-12（110%）和活化caspase-3（50%）水平的增加。为了确定这些影响是否导致学习缺陷，使用Morris水迷宫评估了海马依赖性学习。溴氰菊酯治疗的动物表现出深刻的缺陷，在收购的学习。我们还发现，溴氰菊酯暴露导致海马齿状回BrdU阳性细胞减少（37%），表明海马神经发生可能受损。总之，这些结果表明，重复溴氰菊酯暴露导致ER应激、海马中的凋亡细胞死亡和海马前体增殖缺陷，这与学习缺陷相关。
Endoplasmic reticulum (ER) stress is implicated as a significant contributor to neurodegeneration and cognitive dysfunction. Previously, we reported that the widely used pyrethroid pesticide deltamethrin causes ER stress-mediated apoptosis in SK-N-AS neuroblastoma cells. Whether or not this occurs in vivo remains unknown. Here, we demonstrate that repeated deltamethrin exposure (3 mg/kg every 3 days for 60 days) causes hippocampal ER stress and learning deficits in adult mice. Repeated exposure to deltamethrin caused ER stress in the hippocampus as indicated by increased levels of C/EBP-homologous protein (131%) and glucose-regulated protein 78 (96%). This was accompanied by increased levels of caspase-12 (110%) and activated caspase-3 (50%). To determine whether these effects resulted in learning deficits, hippocampal-dependent learning was evaluated using the Morris water maze. Deltamethrin-treated animals exhibited profound deficits in the acquisition of learning. We also found that deltamethrin exposure resulted in decreased BrdU-positive cells (37%) in the dentate gyrus of the hippocampus, suggesting potential impairment of hippocampal neurogenesis. Collectively, these results demonstrate that repeated deltamethrin exposure leads to ER stress, apoptotic cell death in the hippocampus, and deficits in hippocampal precursor proliferation, which is associated with learning deficits.