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目的研究氯化镧(lanthanum chloride,LaCl3)对大鼠海马细胞凋亡和内质网应激凋亡途径的影响,探讨LaCl3对海马产生毒性作用的机制。方法 40只Wistar雌性成年大鼠随机分成对照和低、中、高剂量LaCl3组,低、中、高剂量LaCl3组孕鼠产仔后分别饮用0.25%、0.50%、1.00%LaCl3溶液,对照孕鼠产仔后饮用蒸馏水。LaCl3组子代大鼠在断乳前吸吮母乳染镧,断乳后自行饮用0.25%、0.50%、1.00%LaCl3溶液1个月。取子代大鼠的海马,采用流式细胞仪测定海马细胞凋亡率,采用免疫印迹(Western blotting)法检测海马葡萄糖调节蛋白(glucose-regulated protein 78,GRP78)、磷酸化的PKR样内质网调节激酶(phosphorylated PKR-like endoplasmic reticulum-resident kinase,p-PERK)、C/EBP同源性蛋白(C/EBPhomologous protein,CHOP)、磷酸化的纤维醇需求酶-1(phosphorylated inositol-requiring enzyme 1,p-IRE-1)、磷酸化的cJun氨基末端激酶(phosphorylated c-Jun NH2-terminal kinases,p-JNK)、caspase-12、caspase-3和多聚(ADP-核糖)聚合酶(poly ADP-ribose polymerase,PARP)的蛋白表达水平。结果各LaCl3组子代大鼠海马细胞凋亡率显著高于对照组,且具有一定的剂量-反应关系。0.25%LaCl3组子代大鼠海马GRP-78、p-IRE-1、p-JNK、caspase-12、caspase-3和PARP蛋白表达水平显著高于对照组,0.50%LaCl3组子代大鼠海马GRP-78、p-PERK、CHOP、caspase-12、caspase-3和PARP蛋白表达水平显著高于对照组和0.25%LaCl3组,1.00%LaCl3组子代大鼠海马GRP-78、p-PERK、CHOP、p-IRE-1、p-JNK、caspase-12、caspase-3和PARP蛋白表达水平显著高于对照组和0.25%、0.50%LaCl3组。结论 LaCl3染毒造成大鼠海马细胞凋亡过度的机制可能涉及内质网应激凋亡途径表达增强。
Objective To investigate the effects of lanthanum chloride (LaCl3) on the apoptosis of hippocampus and the apoptotic pathway of endoplasmic reticulum (ER) in rats, and to explore the mechanism of LaCl3 toxicity on the hippocampus. Methods 40 Wistar female adult rats were randomly divided into control and low, medium and high doses of LaCl3 group, low, medium and high doses of LaCl3 group of pregnant rats were drank 0.25%, 0.50%, 1.00% LaCl3 solution, control pregnant rats After litter drinking distilled water. LaCl3 offspring rats suck breast milk with lanthanum before weaning, and drink 0.25%, 0.50% and 1.00% LaCl3 solution for 1 month after weaning. The hippocampus of the offspring rats were sacrificed and the hippocampal apoptosis rate was determined by flow cytometry. The expression of glucose-regulated protein 78 (GRP78), phosphorylated PKR-like endoplasmic reticulum Phosphorylated PKR-like endoplasmic reticulum-resident kinase (p-PERK), C / EBP homologous protein (CHOP), phosphorylated inositol- requiring enzyme 1, p-IRE-1), phosphorylated c-Jun NH2-terminal kinases (p-JNK), caspase- 12, caspase-3 and poly ADP-ribose polymerase, PARP) protein expression levels. Results The apoptotic rate of hippocampus in each LaCl3 group was significantly higher than that in control group, and had a dose-response relationship. The expression of GRP-78, p-IRE-1, p-JNK, caspase-12, caspase-3 and PARP in the hippocampus of the offspring of 0.25% LaCl3 group were significantly higher than those of the control group The expression of GRP-78, p-PERK, CHOP, caspase-12, caspase-3 and PARP in hippocampus of hippocampus were significantly higher than those in control group, 0.25% LaCl3 group and 1.00% LaCl3 group The expression levels of CHOP, p-IRE-1, p-JNK, caspase-12, caspase-3 and PARP were significantly higher than those in the control group and 0.25% and 0.50% LaCl3 groups, respectively. Conclusions The mechanism of over-apoptosis of hippocampal cells induced by LaCl3 may be related to the enhancement of ER stress-induced apoptosis pathway.