丙烯酰胺对神经丝磷酸化有关的蛋白激酶及相关蛋白的影响
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摘要
目的
丙烯酰胺(ACR)是一种用途广泛的工业毒物。它是一种神经毒性物质和人类可能致癌物,它的神经毒性主要表现为中枢-周围性远端轴索病,临床表现为共济失调、骨骼肌无力,其病理特征是远端轴突肿胀、变性、神经丝(neurofilament,NF)聚集：我们前面的研究发现,ACR中毒大鼠坐骨神经组织中NFs(包括NF-L、NF-M和NF-H)的含量均是下降的。但其神经毒性的作用机制仍未完全阐明。
基于ACR中毒NFs及其超微结构的改变,为进一步探讨ACR中毒性外周神经病变发生的分子机制,我们建立了ACR亚慢性中毒大鼠模型,测定了坐骨神经中与NFs磷酸化有关的三种蛋白激酶：蛋白激酶A(PKA)、蛋白激酶C(PKC)和细胞周期依赖性蛋白激酶5 (CDK5),及其相关蛋白包括钙调蛋白(CaM)、环磷腺苷(cAMP)、CDK5的两个激活因子P35和P25的变化。此外还对血清PKA和PKC的含量进行了分析,以期为ACR神经损伤生物标志物的探索提供依据。
方法
1.成年雄性Wistar大鼠随机分为对照组、低剂量组和高剂量组。低、高剂量组分别以20 mg/kg体重和40 mg/kg体重剂量腹腔注射ACR染毒,每周3次,连续8周；对照组腹腔注射等体积双蒸水。
2.神经行为的改变和步态评分密切观察各组大鼠的一般状况和神经行为的改变,测量大鼠体重,给出步态评分。
3.分离坐骨神经组织,匀浆后超速离心,取上清-80℃保存备用。用SDS-PAGE和Western Blotting方法测定PKA、PKC、CDK、P35和P25蛋白含量；用ELISA试剂盒测定CaM和cAMP的含量。
4.取大鼠坐骨神经组织匀浆上清,利用放射性同位素技术研究ACR染毒对大鼠神经组织中PKA和PKC活性的影响。
5.断头取血,常规分离血清,利用SDS-PAGE和Western Blotting方法测定血清中PKA和PKC的含量。
结果
1.体重结果与中毒表现：与对照组相比,ACR染毒组大鼠体重减轻,高剂量组第5-8周体重下降(P<0.05)。高剂量组大鼠在染毒第8周后肢完全瘫痪,走路时后肢后拖,足背着地,无法支撑身体,步态得分增高；染毒终止时,低、高剂量组分别呈轻度和重度受损步态。与对照组比较,ACR染毒组大鼠步态评分增高,低剂量组第8周出现增高(P<0.01),高剂量组第4-8周出现增高(P<0.01)。
2.蛋白测定结果：与对照组相比,低剂量组和高剂量组坐骨神经中的蛋白激酶及其相关蛋白都发生了不同程度的变化。
(1)坐骨神经中CaM含量的变化：与对照组相比,低剂量组无明显变化,高剂量组增高了50%(P<0.01)；与低剂量组相比,高剂量组升高了50%(P<0.01)。
(2)坐骨神经中cAMP含量的变化：cAMP蛋白含量在ACR亚慢性中毒大鼠坐骨神经中明显降低,与对照相比,cAMP在低剂量组降低了11%,在高剂量组降低了95%(P<0.01)；与低剂量组相比,cAMP在高剂量组降低了94%(P<0.01)。
(3)坐骨神经中PKA和PKC的含量及活性的变化：与对照组相比,PKA和PKC的含量在低剂量组分别升高了18%和21%,在高剂量组分别增高了73%(P<0.01)和170%(P<0.01)；与低剂量组相比,这两者的含量在高剂量组分别升高了46%(P<0.01)和125%(P<0.01)。PKA活性与对照组相比,低剂量组增高了60%(P<0.01),高剂量组降低了50%(P<0.01)；与低剂量组相比,高剂量组降低了220%(P<0.01)。PKC活性与对照组相比,低剂量组增高了50%,高剂量组增高了6倍(P<0.01)；与低剂量组相比,高剂量组增高了3倍(P<0.01)。
(4)坐骨神经中CDK5、P25和P35含量的变化：与对照组相比,CDK5在低剂量组降低了51%(P<0.01),高剂量组降低了22%(P<0.05)；与低剂量组相比,高剂量组升高了59%(P<0.01)。P25和P35含量与对照组相比,低剂量组分别降低了10%和21%(P<0.01),高剂量组分别降低了77%(P<0.01)和82%(P<0.01)；与低剂量组相比,高剂量组分别降低了74%(P<0.01)和77%(P<0.01)。
(5)血清中PKC和PKA的含量与对照组相比,低剂量组分别升高了6%和6%,高剂量组分别升高了45%(P<0.01)和55%(P<0.01)；与低剂量组相比,高剂量组分别升高了37%(P<0.01)和47%(P<0.01)。
结论
1.ACR亚慢性染毒可以引起神经系统损伤,表现为大鼠步态评分异常。
2.ACR染毒可明显升高坐骨神经组织中CaM含量,说明ACR可明显增加细胞内Ca2+浓度。
3.坐骨神经中蛋白激酶的变化可能与ACR的周围神经毒性有关,表现为ACR亚慢染毒可明显改变坐骨神经中cAMP、PKA、PKC、CDK5、P35和P25蛋白的含量以及PKA和PKC的活性,从而导致NFs磷酸化状态变化。
4.血清中PKC和PKA有可能作为ACR神经病变的生物效应标志物,表现为ACR亚慢性染毒可引起大鼠血清中PKC和PKA相对含量改变。
5.ACR的周围神经毒性作用机制可能与上述蛋白的变化相关。
Objective
Acrylamide (ACR) is a kind of widely-used industrial material. It is regarded as a neurotoxicant and human potential carcinogen through the studies of more than thirty years. ACR is known to produce central-peripheral distal axonopathy, which is characterized by ataxia and distal skeletal muscle weakness. The major pathological hallmarks are distal swellings and secondary degeneration both in experimental animals and human companioning excessive accumulation of neurofilaments (NFs) in the distal swollen axon. However, the exact mechanism of action of its neurotoxicity has not been completely clear until now.
Based on the pathological alterations, we built ACR-intoxicated rats models and investigated the relative levels of proteins in the tissue of sciatic nerves (SN) to determine the molecular mechanisms. We detected the changes of three protein kinases and four relative proteins, include calmodulin (CAM), protein kinase C (PKC), protein kinase A (PKA), Cyclic Adenosine monophosphate (cAMP), cyclin dependent kinase 5 (CDK5) and CDK5-related factors (P35 and P25) in SN of ACR-treated rats. Moreover, the contents of PKA and PKC in the serum of rats were also tested, which will offer the cues and evidences for exploring the mechanism of ACR neurotoxicity and searching biomarkers.
Methods
1. Male Wistar rats weighing 180-220g were divided into three groups, each 9 animals. The rats in group 1 served as control, and received double distilled water (DDW). The animals in group 2 and 3 were given ACR dissolved in DDW(20、40 mg/kg i.p.3 days/week) for 8 weeks.
2. Neurobehavioral index were determined per week. The changes of general status, body weight of rats and neurobehavioral function were observed. In addition, we observed abnormal gait and got the gait score.
3. The excised nervous tissues of SN were homogenized in ice-cold homogenizing buffer and then centrifuged at a high speed. The supernatant was saved in-80℃.The relative levels of PKA, PKC, CDK5, P35 and P25 in the supernatant of SN were determined by SDS-PAGE and Western Blotting. The contents of CaM and cAMP in SN were determined by ELISA kits.
4. The activities of PKA and PKC were determined by using corresponding radioactivated 32P assay kits in corresponding cytosolic fractions of SN of control and experimental group rats.
5. The decapitated bloods were sampled, and the serum was separated routinely. The contents of PKA and PKC in the rat serum were investigated by SDS-PAGE and immunoblotting.
Results
1. The body weight and gait score
Compared with the control, the body weight of rats lost in the ACR-induced groups, i.e. the body weight of the 5th to 8th week decreased significantly (P<0.05) of high ACR group. Compared with the control, gait score increased remarkably at 8th week (P<0.01) of low ACR group and increased remarkably at 4th to 8th week (P<0.01) of high ACR group.
2. The changes of proteins
(1) The change of CaM contents in sciatic nerves:Compared with control, no significant changes observed in the low dose group and high dose group had increased 50%(P<0.01). Compared with the low dose group, CaM content increased by 50%(P<0.01) in the high dose group.
(2) The change of cAMP contents in sciatic nerves:The exposure to ACR resulted in a significant decrease in cAMP contents. Compared with the control, the level of cAMP decreased by 11% in the low dose group and by 95%(P<0.01) in the high dose group. Compared with the low dose group, cAMP content decreased by 94%(P<0.01) in the high dose group.
(3) The contents and activities of PKA and PKC in sciatic nerves:In comparison with the control rats, the levels of PKA and PKC increased respectively by 18%and 21% in low ACR group, by73% (P<0.01) and 170%(P<0.01) in high ACR group. Compared with the control group, PKA activity had increased 60% (P＜0.01) in low dose group but decreased 50%(P<0.01) in high dose group. While compared with the low dose group, it decreased 220%(P<0.01) in high dose group. Compared with the control, PKC activity was significantly increased in 20 (by 50%, P< 0.01) and 40 (6 folds, P< 0.01) mg/kg ACR group rats, respectively. Compared with the 20 mg/kg ACR group, PKC activity increased 3 folds (P<0.01).
(4) The exposure to ACR resulted in a significant decrease in CDK5, P25 and P35 contents in sciatic nerve. In comparison with the control rats, CDK5 in the low dose group decreased 51%(P<0.01), in the high dose group decreased 22%(P<0.05). Compared with the low dose group, CDK5 in the high dose group increased by 59%(P<0.01). In comparison with the control rats, the levels of P25 and P35 in the high dose group decreased respectively by 77%(P<0.01) and 82%(P<0.01). (5) The levels of PKA and PKC in serum significantly increased by 6% and 6%in 20mg/kg ACR rats,by 45%(P<0.01) and 55%(P<0.01)in 40 mg/kg ACR rats, respectively.
Conclusions
1. Subchronic intoxation of ACR can induce the injury of nerve system. It was showed that the gait abnormal.
2. ACR exposure could increase the content of CaM in sciatic nerve tissue, which indicates ACR significantly increased the intracellular Ca2+ concentration.
3. The changes of protein kinases in sciatic nerve may be related to ACR induced peripheral nerve toxicity. ACR exposure could significantly change the contents of cAMP, PKA, PKC, CDK5, P35 and P25, and, the activities of PKA and PKC in sciatic nerve. As a result, the phosphorylation state of NFs changed.
4. The contents of PKA and PKC were significantly increased in serum of ACR-treated rats, which suggested they might be served as some of the biomarkers of ACR-induced neuropathy for earlier diagnosis.
5. The peripheral nerve toxicity mechanism of ACR may be associated with the changes of the above-mentioned proteins.
丙烯酰胺(ACR)是一种用途广泛的工业毒物。它是一种神经毒性物质和人类可能致癌物,它的神经毒性主要表现为中枢-周围性远端轴索病,临床表现为共济失调、骨骼肌无力,其病理特征是远端轴突肿胀、变性、神经丝(neurofilament,NF)聚集：我们前面的研究发现,ACR中毒大鼠坐骨神经组织中NFs(包括NF-L、NF-M和NF-H)的含量均是下降的。但其神经毒性的作用机制仍未完全阐明。
基于ACR中毒NFs及其超微结构的改变,为进一步探讨ACR中毒性外周神经病变发生的分子机制,我们建立了ACR亚慢性中毒大鼠模型,测定了坐骨神经中与NFs磷酸化有关的三种蛋白激酶：蛋白激酶A(PKA)、蛋白激酶C(PKC)和细胞周期依赖性蛋白激酶5 (CDK5),及其相关蛋白包括钙调蛋白(CaM)、环磷腺苷(cAMP)、CDK5的两个激活因子P35和P25的变化。此外还对血清PKA和PKC的含量进行了分析,以期为ACR神经损伤生物标志物的探索提供依据。
方法
1.成年雄性Wistar大鼠随机分为对照组、低剂量组和高剂量组。低、高剂量组分别以20 mg/kg体重和40 mg/kg体重剂量腹腔注射ACR染毒,每周3次,连续8周；对照组腹腔注射等体积双蒸水。
2.神经行为的改变和步态评分密切观察各组大鼠的一般状况和神经行为的改变,测量大鼠体重,给出步态评分。
3.分离坐骨神经组织,匀浆后超速离心,取上清-80℃保存备用。用SDS-PAGE和Western Blotting方法测定PKA、PKC、CDK、P35和P25蛋白含量；用ELISA试剂盒测定CaM和cAMP的含量。
4.取大鼠坐骨神经组织匀浆上清,利用放射性同位素技术研究ACR染毒对大鼠神经组织中PKA和PKC活性的影响。
5.断头取血,常规分离血清,利用SDS-PAGE和Western Blotting方法测定血清中PKA和PKC的含量。
结果
1.体重结果与中毒表现：与对照组相比,ACR染毒组大鼠体重减轻,高剂量组第5-8周体重下降(P<0.05)。高剂量组大鼠在染毒第8周后肢完全瘫痪,走路时后肢后拖,足背着地,无法支撑身体,步态得分增高；染毒终止时,低、高剂量组分别呈轻度和重度受损步态。与对照组比较,ACR染毒组大鼠步态评分增高,低剂量组第8周出现增高(P<0.01),高剂量组第4-8周出现增高(P<0.01)。
2.蛋白测定结果：与对照组相比,低剂量组和高剂量组坐骨神经中的蛋白激酶及其相关蛋白都发生了不同程度的变化。
(1)坐骨神经中CaM含量的变化：与对照组相比,低剂量组无明显变化,高剂量组增高了50%(P<0.01)；与低剂量组相比,高剂量组升高了50%(P<0.01)。
(2)坐骨神经中cAMP含量的变化：cAMP蛋白含量在ACR亚慢性中毒大鼠坐骨神经中明显降低,与对照相比,cAMP在低剂量组降低了11%,在高剂量组降低了95%(P<0.01)；与低剂量组相比,cAMP在高剂量组降低了94%(P<0.01)。
(3)坐骨神经中PKA和PKC的含量及活性的变化：与对照组相比,PKA和PKC的含量在低剂量组分别升高了18%和21%,在高剂量组分别增高了73%(P<0.01)和170%(P<0.01)；与低剂量组相比,这两者的含量在高剂量组分别升高了46%(P<0.01)和125%(P<0.01)。PKA活性与对照组相比,低剂量组增高了60%(P<0.01),高剂量组降低了50%(P<0.01)；与低剂量组相比,高剂量组降低了220%(P<0.01)。PKC活性与对照组相比,低剂量组增高了50%,高剂量组增高了6倍(P<0.01)；与低剂量组相比,高剂量组增高了3倍(P<0.01)。
(4)坐骨神经中CDK5、P25和P35含量的变化：与对照组相比,CDK5在低剂量组降低了51%(P<0.01),高剂量组降低了22%(P<0.05)；与低剂量组相比,高剂量组升高了59%(P<0.01)。P25和P35含量与对照组相比,低剂量组分别降低了10%和21%(P<0.01),高剂量组分别降低了77%(P<0.01)和82%(P<0.01)；与低剂量组相比,高剂量组分别降低了74%(P<0.01)和77%(P<0.01)。
(5)血清中PKC和PKA的含量与对照组相比,低剂量组分别升高了6%和6%,高剂量组分别升高了45%(P<0.01)和55%(P<0.01)；与低剂量组相比,高剂量组分别升高了37%(P<0.01)和47%(P<0.01)。
结论
1.ACR亚慢性染毒可以引起神经系统损伤,表现为大鼠步态评分异常。
2.ACR染毒可明显升高坐骨神经组织中CaM含量,说明ACR可明显增加细胞内Ca2+浓度。
3.坐骨神经中蛋白激酶的变化可能与ACR的周围神经毒性有关,表现为ACR亚慢染毒可明显改变坐骨神经中cAMP、PKA、PKC、CDK5、P35和P25蛋白的含量以及PKA和PKC的活性,从而导致NFs磷酸化状态变化。
4.血清中PKC和PKA有可能作为ACR神经病变的生物效应标志物,表现为ACR亚慢性染毒可引起大鼠血清中PKC和PKA相对含量改变。
5.ACR的周围神经毒性作用机制可能与上述蛋白的变化相关。
Objective
Acrylamide (ACR) is a kind of widely-used industrial material. It is regarded as a neurotoxicant and human potential carcinogen through the studies of more than thirty years. ACR is known to produce central-peripheral distal axonopathy, which is characterized by ataxia and distal skeletal muscle weakness. The major pathological hallmarks are distal swellings and secondary degeneration both in experimental animals and human companioning excessive accumulation of neurofilaments (NFs) in the distal swollen axon. However, the exact mechanism of action of its neurotoxicity has not been completely clear until now.
Based on the pathological alterations, we built ACR-intoxicated rats models and investigated the relative levels of proteins in the tissue of sciatic nerves (SN) to determine the molecular mechanisms. We detected the changes of three protein kinases and four relative proteins, include calmodulin (CAM), protein kinase C (PKC), protein kinase A (PKA), Cyclic Adenosine monophosphate (cAMP), cyclin dependent kinase 5 (CDK5) and CDK5-related factors (P35 and P25) in SN of ACR-treated rats. Moreover, the contents of PKA and PKC in the serum of rats were also tested, which will offer the cues and evidences for exploring the mechanism of ACR neurotoxicity and searching biomarkers.
Methods
1. Male Wistar rats weighing 180-220g were divided into three groups, each 9 animals. The rats in group 1 served as control, and received double distilled water (DDW). The animals in group 2 and 3 were given ACR dissolved in DDW(20、40 mg/kg i.p.3 days/week) for 8 weeks.
2. Neurobehavioral index were determined per week. The changes of general status, body weight of rats and neurobehavioral function were observed. In addition, we observed abnormal gait and got the gait score.
3. The excised nervous tissues of SN were homogenized in ice-cold homogenizing buffer and then centrifuged at a high speed. The supernatant was saved in-80℃.The relative levels of PKA, PKC, CDK5, P35 and P25 in the supernatant of SN were determined by SDS-PAGE and Western Blotting. The contents of CaM and cAMP in SN were determined by ELISA kits.
4. The activities of PKA and PKC were determined by using corresponding radioactivated 32P assay kits in corresponding cytosolic fractions of SN of control and experimental group rats.
5. The decapitated bloods were sampled, and the serum was separated routinely. The contents of PKA and PKC in the rat serum were investigated by SDS-PAGE and immunoblotting.
Results
1. The body weight and gait score
Compared with the control, the body weight of rats lost in the ACR-induced groups, i.e. the body weight of the 5th to 8th week decreased significantly (P<0.05) of high ACR group. Compared with the control, gait score increased remarkably at 8th week (P<0.01) of low ACR group and increased remarkably at 4th to 8th week (P<0.01) of high ACR group.
2. The changes of proteins
(1) The change of CaM contents in sciatic nerves:Compared with control, no significant changes observed in the low dose group and high dose group had increased 50%(P<0.01). Compared with the low dose group, CaM content increased by 50%(P<0.01) in the high dose group.
(2) The change of cAMP contents in sciatic nerves:The exposure to ACR resulted in a significant decrease in cAMP contents. Compared with the control, the level of cAMP decreased by 11% in the low dose group and by 95%(P<0.01) in the high dose group. Compared with the low dose group, cAMP content decreased by 94%(P<0.01) in the high dose group.
(3) The contents and activities of PKA and PKC in sciatic nerves:In comparison with the control rats, the levels of PKA and PKC increased respectively by 18%and 21% in low ACR group, by73% (P<0.01) and 170%(P<0.01) in high ACR group. Compared with the control group, PKA activity had increased 60% (P＜0.01) in low dose group but decreased 50%(P<0.01) in high dose group. While compared with the low dose group, it decreased 220%(P<0.01) in high dose group. Compared with the control, PKC activity was significantly increased in 20 (by 50%, P< 0.01) and 40 (6 folds, P< 0.01) mg/kg ACR group rats, respectively. Compared with the 20 mg/kg ACR group, PKC activity increased 3 folds (P<0.01).
(4) The exposure to ACR resulted in a significant decrease in CDK5, P25 and P35 contents in sciatic nerve. In comparison with the control rats, CDK5 in the low dose group decreased 51%(P<0.01), in the high dose group decreased 22%(P<0.05). Compared with the low dose group, CDK5 in the high dose group increased by 59%(P<0.01). In comparison with the control rats, the levels of P25 and P35 in the high dose group decreased respectively by 77%(P<0.01) and 82%(P<0.01). (5) The levels of PKA and PKC in serum significantly increased by 6% and 6%in 20mg/kg ACR rats,by 45%(P<0.01) and 55%(P<0.01)in 40 mg/kg ACR rats, respectively.
Conclusions
1. Subchronic intoxation of ACR can induce the injury of nerve system. It was showed that the gait abnormal.
2. ACR exposure could increase the content of CaM in sciatic nerve tissue, which indicates ACR significantly increased the intracellular Ca2+ concentration.
3. The changes of protein kinases in sciatic nerve may be related to ACR induced peripheral nerve toxicity. ACR exposure could significantly change the contents of cAMP, PKA, PKC, CDK5, P35 and P25, and, the activities of PKA and PKC in sciatic nerve. As a result, the phosphorylation state of NFs changed.
4. The contents of PKA and PKC were significantly increased in serum of ACR-treated rats, which suggested they might be served as some of the biomarkers of ACR-induced neuropathy for earlier diagnosis.
5. The peripheral nerve toxicity mechanism of ACR may be associated with the changes of the above-mentioned proteins.
引文
1. Anonymous:Acrylamide, NICNAS:Priority existing chemical assessment report. 2002,23(61):174.
2.王爱红.丙烯酰胺危害健康的研究进展[J].中国公共卫生,2003,19(21)：1534-1535.
3.贾文英,程琳,史弘道.医用聚丙烯酰胺水凝胶(奥美定)细胞毒性研究[J].实用美容整形外科杂志,2001,12(2)：75-76.
4. Tareke E, Rydberg P, Karlsson P, et al. Acrylamide:A cooking carcinogent[J]. Chem Res Toxicol,2002,13(2):517-522.
5.张寿林,何凤生,王玉萍等.41例丙烯酞胺作业工人临床分析[J].中国工业医学杂志,1992,5(2)：193.
6.邓海,焦小云,何凤生等.丙烯酞胺和环氧丙烯酞胺的神经毒性研究[J].中华预防医学杂志,1997,31(4)：202-207.
7. Tareke E, Rydberg P, Karlsson P, et al. Analysis of acrylamide, a carcinogen formed in heated foodstuffs[J]. J. Agric. Food Chem.,2002,50(2):4998-5006.
8.王慧兰,聂兴田,李风玲.丙烯酰胺中毒原因的分析[J].中华劳动卫生职业病杂志,1997,15(5)：265-267.
9.李闪霞,崔宁,张翠丽等.大鼠亚慢性丙烯酞胺中毒神经行为功能的改变[J].中国公共卫生,2004,20(12)：1458—1459.
10. LoPachin RM, Balaban CD, Ross JF. Acrylamide axonopathy revisited[J]. Toxicol Appl Pharmacol,2003,188(2):135-53.
11. Spencer PS, Schaumburg HH. A review of acrylamide neurotoxicity. Part Ⅰ. Properties, uses and human exposure[J]. Can J Neurol Sci,1974a,1(2):151-169.
12. Spencer PS, Schaumburg HH. A review of acrylamide neurotoxicity. Part Ⅱ. Experimental animal neurotoxicity and pathologic mechanisms[J]. Can J Neurol Sci,1974b,1(2):170-192.
13. Deng H., He S., Zhang S. Quantitative measurements of vibration threshold in health adults and acrylamide workers[J]. Int. Arch. Occup. Environ. Health,1993, 65(2):53-56.
14. LoPachin RM. The changing view of acrylamide neurotoxicity[J]. NeuroToxicology,2004,25(2):617-630.
15. LoPachin RM. The role of fast axonal transport in acrylamide pathophysiology: Mechanism or epiphenomenon?[J]. Neurotoxicology,2002,23(2):253-257.
16. Sickles DW, Stone JD, Friedman MA. Fast axonal transport: A site of acrylamide neurotoxicity[J]. Neurotoxicolog,2002,23(2):223-251.
17.韩漫夫,赫秋月,冯加纯.丙烯酰胺对脑能量代谢的影响及意义[J].中风与神经疾病杂志,2000,17(3)：142-143.
18. Tanii H, Hashimoto K. Effect of acrylamide and related compounds on glycolytic enzymes of rat brain[J]. Toxicol Lett,1985,26(1):79-84.
19. Sakamoto J, Hashimoto K. Effect of acrylamide and related compounds on glycolytic enzymes in rat sciatic nerve in vivo[J]. Arch Toxicol,1985,57(4): 282-284.
20. Schmuck G, Ahr HJ, Schluter G. Rat cortical neuron cultures:an in vitro model for differentiating mechanisms of chemically induced neurotoxicity[J].In Vitr Mol Toxicol,2000,13(1):37-50.
21. Lapadula DM, Bowe M, Carrington CD, et al. In vitro binding of [14C] acrylamide to neurofilament and microtubule proteins of rats[J]. Brain Res.1989,481 (1): 157-61.
22. Sickles DW, Pearson JK, Beall A, et al. Toxic axonal degeneration occurs independent of neurofilament accumulation[J]. Neurosci Res,1994,39(3): 347-354.
23. Takahashi A, Mizutani M, Itakura C. Acrylamide-induced peripheral neuropathy in normal and neurofilament-deficient Japanese quails[J]. Acta Neuropathol (Berl), 1995,89(1):17-22.
24. Spencer PS, Schaumburg HH. Nerotoxic chemicals as probs of cellular michenisms neuromuscular disease.in: Current topics in nerve and musele research[J]. Can J Neurol Sci,1978,2(1):274-281.
25.赫秋月,饶明俐.丙烯酰胺中毒后大鼠神经组织离子的改变[J].中国工业医学杂志,2000,13(5)：265-267.
26. LoPachin RM, Castiglia CM, Lehning E, et al. effects of acrylamide on subcellular distribution of elements in rat sciatic nerve myelinated axons and Schwann cells[J]. Brain Res,1993,608:238-246.
27. LoPachin RM, Lehning EJ, Castiglia CM, et al. acrylamide disrupts elemental composition and water content of rat tibial nerve[J]. Toxicol Appl Pharmacol, 1993,122(1):54-60.
28. Tanii H, Hayashi M, Hashimoto K. Neurofilament degradation in the nervous system of rats intoxicated with acrylamide, related compounds or 2,5-hexanedione[J]. Arch Toxicol,1988,62(1):70-75.
29. Gupta RP, Abou-Donia MB. Alterations in the neutral proteinase activities of central and peripheral nervous systems of acrylamide-, carbon disulfide-, or 2,5-hexanedione-treated rats[J]. Mol Chem Neuropathol,1996,29(1):53-66.
30. LoPachin RM. Evidence suggests that acrylamide (ACR) neurotoxicity is mediated by decreased presynaptic neurotransmitter release[J]. Toxicolo Sci,2006, 89 (1):224-234.
31. LoPachin RM, Ross JF, Lehning EJ. Nerve terminals as the primary site of acrylamide action:a hypothesis[J]. Neurotoxicology,2002,23:43-60.
32. Simpson PB, Russell JT. Role of mitochondrial Ca2+ regulation in neuronal and glial cell signalling[J]. Brain Res Brain Res Rev,1998,26(1):72-81.
33. Bofill-Cardona E, Kudlacek O, Yang Q, et al. Binding of calmodulin to the D2-dopamine receptor reduces receptor signaling by arresting the G protein activation switch[J]. J Biol Chem,2000,275(42):32672-32680.
34. Drum CL, Yan SZ, Sarac R, et al. An extended conformation of calmodulin induces interactions between the structural domains of adenylyl cyclase from Bacillus anthracis to promote catalysis[J]. J Biol Chem,2000,275(46): 36334-36340.
35. Shen Y, Zhukovskaya NL, Guo Q, et al. Calcium-independent calmodulin binding and two-metal-ion catalytic mechanism of anthrax edema factor[J]. EMBO J, 2005,24(5):929-941.
36. Hollander BA, Bennett GS, Shaw G. Localization of sites in the tail domain of the middle molecular mass neurofilament subunit phosphorylated by a neurofilament-associated kinase and by casein kinase I[J]. Neurochem,1996, 66(1):412-420.
37. Darios F, Muriel MP, Khondiker ME, et al. Neurotoxic calcium transfer from endoplasmic reticulum to mitochondria is regulated by cyclin-dependent kinase 5-dependent phosphorylation of tau[J]. Neurosci,2005,25(16):4159-4168.
38.鲁吉波,黄金祥,张寿林等.二硫化碳对大鼠神经细胞内游离钙离子、蛋白激酶C和细胞骨架的影响[J].职业卫生与应急救援,1996,14(4)：4-6.
39.孙鹂.铅对细胞内钙离子及钙调蛋白影响的研究进展[J].国外医学卫生学分册,2002,29(6)：328-330.
40.王英鹏,宋俊峰,饶志仁.CDK5与神经退行性疾病[J].生理科学进展,2004,35(1)：45-48.
41. Borshi R, Giliberto L, Assim A, et al. Increase of cdk5 is related to neurofibrillary pathology in progressive supranuclearpalsy[J]. Neurology,2002,58(4):589-592.
42. LoPachin RM, Ross JF, Reid ML, et al. Neurological evaluation of toxic axonopathies in rats:acrylamide and 2-5-hexanedione[J]. Neurotoxicology,2002, 23(2):95-110.
43. Hahn K, DeBiasio R, Taylor DL. Patterns of elevated free calcium and calmodulin activation in living cells[J]. Nature,1992,359(6397):736-738.
44. Fukui Y, De Lozanne A, Spudich JA. Structure and function of the cytoskeleton of a Dictyostelium myosin-defective mutant[J]. J Cell Biol,1990,110(2):367-378.
45. Hahn K, DeBiasio R, Taylor DL. Patterns of elevated free calcium and calmodulin activation in living cells[J]. Nature,1992,359(6397):736-738.
46. Craske M, Takeo T, Gerasimenko O, et al. Hormone-induced secretory and nuclear translocation of calmodulin: oscillations of calmodulin concentration with the nucleus as an integrator[J]. Proc Natl Acad Sci USA,1999,96(8):4426-4431.
47. D.M. Kuhn, W. Lovenberg, Role of calmodulin in the activation of tryptophan hydroxylase[J]. Fed. Proc,1982,41:2258-2264.
48. Fujisawa H, Yamauchi T, Nakata H, et al. Role of calmodulin in neurotransmitter synthesis[J]. Fed. Proc,1984,43:3011-3014.
49. DeLorenzo RJ. Calmodulin in neurotransmitter release and synaptic function[J]. Fed. Proc,1982,41:2265-2272.
50. Marcum JM, Dedman JR, Brinkley BR, et al. Control of microtubule assembly-dissassembly by calcium- dependent regulator protein[J]. Proc. Natl. Acad. Sci,1978,75:3771-3775.
51. Hollander BA, Bennett GS, Shaw G. Localization Of sites in the tail domin of the middle molecular mass neurofilament subunit phosphorylated by a neurofilament-associated kinase and by casein kinase I[J]. Neurochem,1996,66: 412-420.
52. Kishimoto A, Mikawa K, Hashimoto K, et al. Limited proteolysis of protein kinase C subspecies by calcium-dependent neutral protease (calpain)[J]. Bio Chem,1989,264(7):4088-4092.
53. Zhang GY, Wang JH, Scharma RK. Purification and characterization of bovine brain calmodulin-dependent protein kinase. Ⅱ. The significance of autophosphorylation in the regulation of 63 kDa calmodulin-dependent cyclic nucleotide phosphodiesterase isozyme[J]. Mol Cell Biochem,1993,122(2): 159-169.
54. Gonda Y, Nishizawa K, Ando S, et al. Involvement of protein kinase C in the regulation of assembly-disassembly of neurofilaments in vitro[J]. Biochem Biophys Res Commun,1990,167(3):1316-1325.
55. Bressler J, Kim KA, Chakraborti T, et al. Molecular mechanisms of lead neurotoxicity[J]. Neurochem Res.1999,24(4):595-600.
56. Kaur A, Gill KD. Disruption of neuronal calcium homeostasis after chronic aluminium toxicity in rats[J]. Basic Clin Pharmacol Toxicol,2005,96(2): 118-122.
57. Hisanaga S, Gonda Y, Inagaki M, et al. Effects of phosphorylation of the neurofilament L protein on filamentous structures[J]. Cell Regul,1990,1(2): 237-248.
58.孙莉,刘声远.王建枝等.蛋白激酶A与阿尔茨海默病[J].生命的化学,2002,22(1)：45-47.
59. Connell-Crowley L, Le Gall M, Vo DJ, et al. The cyclin-dependent kinase CDK5 control multiple aspects of axon patterning in vivo[J]. Curr Biol,2000,10(10): 599-602.
60. Tsai LH, Delalle I, Caviness VS Jr, et al. p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5[J]. Nature,1994,371(6496):419-423.
61. Humbert S, Dhavan R, Tsai L. p39 activates cdk5 in neurons, and is associated with the actin cytoskeleton[J]. Cell Sci,2000,113(6):975-983.
62. Cruz JC, Tseng HC, Goldman JA, et al. Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles[J]. Neuron,2003,40(3):471-483.
63. Sharma M. Sharma P, Pant HC. CDK-5-mediated neurofilament phosphorylation in SHSY5Y human neuroblastoma cells[J]. Neurochem,1999,73(1):79-86.
64. Patzke H. Tsai LH. CDK5 sinks into ALs[J]. rrends Neuresci,2002,25:8-10.
65. Nakalnura S, Kawamoto Y, Nakan o S, et al. p35 and cyclin-dependent kinase 5 colocalize in Lewy bodies of brains witll Parkinsong disease[J]. Acta Neuropathol, 1997,94:153-157.
66. Borshi R, Giliberto L, Assim A, et al. Increase of cdk5 is related to neurofibrillary pathology in progressive supranuclear palsy[J]. Neurology,2002,58:589-592.
67. Chae T, Kwon YT, Bronson R, et al. Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality[J]. Neuron,1997,18:29-42.
68. Ohshima T, Ward JM, Huh CG, et al. Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death[J]. Proc. Natl Acad. Sci,1996,93:11173-11178.
69. Janice L, Hallows, Ken Chen, et al. Decreased Cyclin-Dependent Kinase 5 (cdk5) Activity Is Accompanied by Redistribution of cdk5 and Cytoskeletal Proteins and Increased Cytoskeletal Protein Phosphorylation in p35 Null Mice[J].The Journal of Neuroscience,2003,23(33):10633-10644.
70. Wilson KM, Balter K, Adami HO, et al. Acrylamide exposure measured by food frequency questionnaire and hemoglobin adduct levels and prostate cancer risk in the Cancer of the Prostate in Sweden Study[J]. Int J Cancer,2009,124(10): 2384-2390.
71. Yi C, Xie KQ, Song FY, et al. The Changes of Cytoskeletal Proteins in Plasma of Acrylamide-Induced Rats[J]. Neurochem Res,2006,31:751-757.
2.王爱红.丙烯酰胺危害健康的研究进展[J].中国公共卫生,2003,19(21)：1534-1535.
3.贾文英,程琳,史弘道.医用聚丙烯酰胺水凝胶(奥美定)细胞毒性研究[J].实用美容整形外科杂志,2001,12(2)：75-76.
4. Tareke E, Rydberg P, Karlsson P, et al. Acrylamide:A cooking carcinogent[J]. Chem Res Toxicol,2002,13(2):517-522.
5.张寿林,何凤生,王玉萍等.41例丙烯酞胺作业工人临床分析[J].中国工业医学杂志,1992,5(2)：193.
6.邓海,焦小云,何凤生等.丙烯酞胺和环氧丙烯酞胺的神经毒性研究[J].中华预防医学杂志,1997,31(4)：202-207.
7. Tareke E, Rydberg P, Karlsson P, et al. Analysis of acrylamide, a carcinogen formed in heated foodstuffs[J]. J. Agric. Food Chem.,2002,50(2):4998-5006.
8.王慧兰,聂兴田,李风玲.丙烯酰胺中毒原因的分析[J].中华劳动卫生职业病杂志,1997,15(5)：265-267.
9.李闪霞,崔宁,张翠丽等.大鼠亚慢性丙烯酞胺中毒神经行为功能的改变[J].中国公共卫生,2004,20(12)：1458—1459.
10. LoPachin RM, Balaban CD, Ross JF. Acrylamide axonopathy revisited[J]. Toxicol Appl Pharmacol,2003,188(2):135-53.
11. Spencer PS, Schaumburg HH. A review of acrylamide neurotoxicity. Part Ⅰ. Properties, uses and human exposure[J]. Can J Neurol Sci,1974a,1(2):151-169.
12. Spencer PS, Schaumburg HH. A review of acrylamide neurotoxicity. Part Ⅱ. Experimental animal neurotoxicity and pathologic mechanisms[J]. Can J Neurol Sci,1974b,1(2):170-192.
13. Deng H., He S., Zhang S. Quantitative measurements of vibration threshold in health adults and acrylamide workers[J]. Int. Arch. Occup. Environ. Health,1993, 65(2):53-56.
14. LoPachin RM. The changing view of acrylamide neurotoxicity[J]. NeuroToxicology,2004,25(2):617-630.
15. LoPachin RM. The role of fast axonal transport in acrylamide pathophysiology: Mechanism or epiphenomenon?[J]. Neurotoxicology,2002,23(2):253-257.
16. Sickles DW, Stone JD, Friedman MA. Fast axonal transport: A site of acrylamide neurotoxicity[J]. Neurotoxicolog,2002,23(2):223-251.
17.韩漫夫,赫秋月,冯加纯.丙烯酰胺对脑能量代谢的影响及意义[J].中风与神经疾病杂志,2000,17(3)：142-143.
18. Tanii H, Hashimoto K. Effect of acrylamide and related compounds on glycolytic enzymes of rat brain[J]. Toxicol Lett,1985,26(1):79-84.
19. Sakamoto J, Hashimoto K. Effect of acrylamide and related compounds on glycolytic enzymes in rat sciatic nerve in vivo[J]. Arch Toxicol,1985,57(4): 282-284.
20. Schmuck G, Ahr HJ, Schluter G. Rat cortical neuron cultures:an in vitro model for differentiating mechanisms of chemically induced neurotoxicity[J].In Vitr Mol Toxicol,2000,13(1):37-50.
21. Lapadula DM, Bowe M, Carrington CD, et al. In vitro binding of [14C] acrylamide to neurofilament and microtubule proteins of rats[J]. Brain Res.1989,481 (1): 157-61.
22. Sickles DW, Pearson JK, Beall A, et al. Toxic axonal degeneration occurs independent of neurofilament accumulation[J]. Neurosci Res,1994,39(3): 347-354.
23. Takahashi A, Mizutani M, Itakura C. Acrylamide-induced peripheral neuropathy in normal and neurofilament-deficient Japanese quails[J]. Acta Neuropathol (Berl), 1995,89(1):17-22.
24. Spencer PS, Schaumburg HH. Nerotoxic chemicals as probs of cellular michenisms neuromuscular disease.in: Current topics in nerve and musele research[J]. Can J Neurol Sci,1978,2(1):274-281.
25.赫秋月,饶明俐.丙烯酰胺中毒后大鼠神经组织离子的改变[J].中国工业医学杂志,2000,13(5)：265-267.
26. LoPachin RM, Castiglia CM, Lehning E, et al. effects of acrylamide on subcellular distribution of elements in rat sciatic nerve myelinated axons and Schwann cells[J]. Brain Res,1993,608:238-246.
27. LoPachin RM, Lehning EJ, Castiglia CM, et al. acrylamide disrupts elemental composition and water content of rat tibial nerve[J]. Toxicol Appl Pharmacol, 1993,122(1):54-60.
28. Tanii H, Hayashi M, Hashimoto K. Neurofilament degradation in the nervous system of rats intoxicated with acrylamide, related compounds or 2,5-hexanedione[J]. Arch Toxicol,1988,62(1):70-75.
29. Gupta RP, Abou-Donia MB. Alterations in the neutral proteinase activities of central and peripheral nervous systems of acrylamide-, carbon disulfide-, or 2,5-hexanedione-treated rats[J]. Mol Chem Neuropathol,1996,29(1):53-66.
30. LoPachin RM. Evidence suggests that acrylamide (ACR) neurotoxicity is mediated by decreased presynaptic neurotransmitter release[J]. Toxicolo Sci,2006, 89 (1):224-234.
31. LoPachin RM, Ross JF, Lehning EJ. Nerve terminals as the primary site of acrylamide action:a hypothesis[J]. Neurotoxicology,2002,23:43-60.
32. Simpson PB, Russell JT. Role of mitochondrial Ca2+ regulation in neuronal and glial cell signalling[J]. Brain Res Brain Res Rev,1998,26(1):72-81.
33. Bofill-Cardona E, Kudlacek O, Yang Q, et al. Binding of calmodulin to the D2-dopamine receptor reduces receptor signaling by arresting the G protein activation switch[J]. J Biol Chem,2000,275(42):32672-32680.
34. Drum CL, Yan SZ, Sarac R, et al. An extended conformation of calmodulin induces interactions between the structural domains of adenylyl cyclase from Bacillus anthracis to promote catalysis[J]. J Biol Chem,2000,275(46): 36334-36340.
35. Shen Y, Zhukovskaya NL, Guo Q, et al. Calcium-independent calmodulin binding and two-metal-ion catalytic mechanism of anthrax edema factor[J]. EMBO J, 2005,24(5):929-941.
36. Hollander BA, Bennett GS, Shaw G. Localization of sites in the tail domain of the middle molecular mass neurofilament subunit phosphorylated by a neurofilament-associated kinase and by casein kinase I[J]. Neurochem,1996, 66(1):412-420.
37. Darios F, Muriel MP, Khondiker ME, et al. Neurotoxic calcium transfer from endoplasmic reticulum to mitochondria is regulated by cyclin-dependent kinase 5-dependent phosphorylation of tau[J]. Neurosci,2005,25(16):4159-4168.
38.鲁吉波,黄金祥,张寿林等.二硫化碳对大鼠神经细胞内游离钙离子、蛋白激酶C和细胞骨架的影响[J].职业卫生与应急救援,1996,14(4)：4-6.
39.孙鹂.铅对细胞内钙离子及钙调蛋白影响的研究进展[J].国外医学卫生学分册,2002,29(6)：328-330.
40.王英鹏,宋俊峰,饶志仁.CDK5与神经退行性疾病[J].生理科学进展,2004,35(1)：45-48.
41. Borshi R, Giliberto L, Assim A, et al. Increase of cdk5 is related to neurofibrillary pathology in progressive supranuclearpalsy[J]. Neurology,2002,58(4):589-592.
42. LoPachin RM, Ross JF, Reid ML, et al. Neurological evaluation of toxic axonopathies in rats:acrylamide and 2-5-hexanedione[J]. Neurotoxicology,2002, 23(2):95-110.
43. Hahn K, DeBiasio R, Taylor DL. Patterns of elevated free calcium and calmodulin activation in living cells[J]. Nature,1992,359(6397):736-738.
44. Fukui Y, De Lozanne A, Spudich JA. Structure and function of the cytoskeleton of a Dictyostelium myosin-defective mutant[J]. J Cell Biol,1990,110(2):367-378.
45. Hahn K, DeBiasio R, Taylor DL. Patterns of elevated free calcium and calmodulin activation in living cells[J]. Nature,1992,359(6397):736-738.
46. Craske M, Takeo T, Gerasimenko O, et al. Hormone-induced secretory and nuclear translocation of calmodulin: oscillations of calmodulin concentration with the nucleus as an integrator[J]. Proc Natl Acad Sci USA,1999,96(8):4426-4431.
47. D.M. Kuhn, W. Lovenberg, Role of calmodulin in the activation of tryptophan hydroxylase[J]. Fed. Proc,1982,41:2258-2264.
48. Fujisawa H, Yamauchi T, Nakata H, et al. Role of calmodulin in neurotransmitter synthesis[J]. Fed. Proc,1984,43:3011-3014.
49. DeLorenzo RJ. Calmodulin in neurotransmitter release and synaptic function[J]. Fed. Proc,1982,41:2265-2272.
50. Marcum JM, Dedman JR, Brinkley BR, et al. Control of microtubule assembly-dissassembly by calcium- dependent regulator protein[J]. Proc. Natl. Acad. Sci,1978,75:3771-3775.
51. Hollander BA, Bennett GS, Shaw G. Localization Of sites in the tail domin of the middle molecular mass neurofilament subunit phosphorylated by a neurofilament-associated kinase and by casein kinase I[J]. Neurochem,1996,66: 412-420.
52. Kishimoto A, Mikawa K, Hashimoto K, et al. Limited proteolysis of protein kinase C subspecies by calcium-dependent neutral protease (calpain)[J]. Bio Chem,1989,264(7):4088-4092.
53. Zhang GY, Wang JH, Scharma RK. Purification and characterization of bovine brain calmodulin-dependent protein kinase. Ⅱ. The significance of autophosphorylation in the regulation of 63 kDa calmodulin-dependent cyclic nucleotide phosphodiesterase isozyme[J]. Mol Cell Biochem,1993,122(2): 159-169.
54. Gonda Y, Nishizawa K, Ando S, et al. Involvement of protein kinase C in the regulation of assembly-disassembly of neurofilaments in vitro[J]. Biochem Biophys Res Commun,1990,167(3):1316-1325.
55. Bressler J, Kim KA, Chakraborti T, et al. Molecular mechanisms of lead neurotoxicity[J]. Neurochem Res.1999,24(4):595-600.
56. Kaur A, Gill KD. Disruption of neuronal calcium homeostasis after chronic aluminium toxicity in rats[J]. Basic Clin Pharmacol Toxicol,2005,96(2): 118-122.
57. Hisanaga S, Gonda Y, Inagaki M, et al. Effects of phosphorylation of the neurofilament L protein on filamentous structures[J]. Cell Regul,1990,1(2): 237-248.
58.孙莉,刘声远.王建枝等.蛋白激酶A与阿尔茨海默病[J].生命的化学,2002,22(1)：45-47.
59. Connell-Crowley L, Le Gall M, Vo DJ, et al. The cyclin-dependent kinase CDK5 control multiple aspects of axon patterning in vivo[J]. Curr Biol,2000,10(10): 599-602.
60. Tsai LH, Delalle I, Caviness VS Jr, et al. p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5[J]. Nature,1994,371(6496):419-423.
61. Humbert S, Dhavan R, Tsai L. p39 activates cdk5 in neurons, and is associated with the actin cytoskeleton[J]. Cell Sci,2000,113(6):975-983.
62. Cruz JC, Tseng HC, Goldman JA, et al. Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles[J]. Neuron,2003,40(3):471-483.
63. Sharma M. Sharma P, Pant HC. CDK-5-mediated neurofilament phosphorylation in SHSY5Y human neuroblastoma cells[J]. Neurochem,1999,73(1):79-86.
64. Patzke H. Tsai LH. CDK5 sinks into ALs[J]. rrends Neuresci,2002,25:8-10.
65. Nakalnura S, Kawamoto Y, Nakan o S, et al. p35 and cyclin-dependent kinase 5 colocalize in Lewy bodies of brains witll Parkinsong disease[J]. Acta Neuropathol, 1997,94:153-157.
66. Borshi R, Giliberto L, Assim A, et al. Increase of cdk5 is related to neurofibrillary pathology in progressive supranuclear palsy[J]. Neurology,2002,58:589-592.
67. Chae T, Kwon YT, Bronson R, et al. Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality[J]. Neuron,1997,18:29-42.
68. Ohshima T, Ward JM, Huh CG, et al. Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death[J]. Proc. Natl Acad. Sci,1996,93:11173-11178.
69. Janice L, Hallows, Ken Chen, et al. Decreased Cyclin-Dependent Kinase 5 (cdk5) Activity Is Accompanied by Redistribution of cdk5 and Cytoskeletal Proteins and Increased Cytoskeletal Protein Phosphorylation in p35 Null Mice[J].The Journal of Neuroscience,2003,23(33):10633-10644.
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