Regional Susceptibility to ER Stress and Protection by Salubrinal Following a Single Exposure to Deltamethrin
Regional Susceptibility to ER Stress and Protection by Salubrinal Following a Single Exposure to Deltamethrin
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DOI：
10.1093/toxsci/kfy238
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发表时间：
2019-01-01
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.;Sivaram, Ganeshraj;Richardson, Jason R.
内质网应激是神经退行性变和认知功能障碍的重要因素。最近，我们报道了反复暴露于拟除虫菊酯杀虫剂溴氰菊酯导致成年小鼠海马区内质网应激，并伴有学习障碍(Hossain等人，2015)。在这里，我们研究了局部对内质网应激的敏感性，以及单次口服溴氰菊酯(6 mg/kg)后，内质网应激抑制剂Salubrine减少细胞凋亡的能力。与年龄匹配的对照组相比，溴氰菊酯在24和48h显著增加了海马区ER应激标志物C/EBP同源蛋白(CHOP)的表达148%。相比之下，溴氰菊酯暴露后48h，额叶皮质CHOP增加了146%。同样，GRP-78在海马区24和48h分别增加314%和262%，而额叶皮质在24 h和48 h分别增加178%和139%。伴随着这些变化的是，两个脑区中激活的caspase-12、caspase-3和TUNEL阳性细胞水平增加，其中海马区表现出更强劲的反应。用eIF2抑制剂Salubrina预处理小鼠可阻止溴氰菊酯诱导的caspase-3激活，并减少TUNEL阳性细胞的数量。这些数据表明，成年动物的海马体似乎特别容易受到溴氰菊酯的影响，这可能有助于观察到溴氰菊酯对认知功能的影响。
Endoplasmic reticulum (ER) stress is a significant contributor to neurodegeneration and cognitive dysfunction. Recently, we reported that repeated exposure to the pyrethroid insecticide deltamethrin caused ER stress in the hippocampus of adult mice, which was accompanied by deficits in learning (Hossain et al., 2015). Here, we investigated regional susceptibility to ER stress and the ability of salubrinal, an inhibitor of ER stress, to reduce apoptosis following a single oral administration of deltamethrin (6 mg/kg). Deltamethrin significantly increased the ER stress marker C/EBP-homologous protein (CHOP) in the hippocampus by 148% at 24 and 48 h compared with age-matched controls. In contrast, CHOP was increased by 146% in the frontal cortex only at 48 h after deltamethrin exposure. Similarly, the level of GRP-78 was increased by 314% and 262% in the hippocampus at 24 and 48 h, whereas the same factors were increased by 178% at 24 h and 139% at 48 h in the frontal cortex. These changes were accompanied by increased levels of activated caspase-12, caspase-3, and TUNEL-positive cells in both brain regions, with the hippocampus showing a more robust response. Pre-treatment of mice with the eIf2 inhibitor salubrinal prevented deltamethrin-induced caspase-3 activation and attenuated the number of TUNEL-positive cells. These data demonstrate that the hippocampus appears to be particularly vulnerable to deltamethrin exposure in adult animals, which may contribute to observed effects of deltamethrin on cognitive function.