丙烯酰胺对大鼠神经组织和血清抗氧化系统及坐骨神经电生理的影响
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摘要
目的
本实验建立丙烯酰胺(acrylamide，ACR)亚慢性中毒大鼠模型，测定坐骨神经干电生理指标、神经组织和血清中氧化抗氧化指标随染毒时间的变化以及ACR染毒并用谷胱甘肽(glutathione，GSH)干预后的原代神经细胞β-actin含量，以阐明机体氧化抗氧化系统在ACR所致周围性神经病中的作用，为探讨ACR引起的中毒性周围神经病的发病机制以及预防治疗提供依据。
方法
一、动物模型及动物行为观察
健康雄性Wistar大鼠随机分为两部分，一部分用作研究ACR对神经组织及血清氧化抗氧化系统的影响，另一部分用作研究ACR对坐骨神经电生理指标的影响。每部分随机分为0、2、4、6、10周对照组和染毒组。染毒组按40mg／kg腹腔注射ACR的生理盐水溶液(2ml／kg体重)，每周3次，使动物瘫痪。对照组同种方式注射生理盐水。氧化抗氧化各组大鼠于设定时间断头处死，留取大脑、脊髓、坐骨神经组织和血清，用作测定氧化抗氧化指标。电生理各组大鼠于设定时间麻醉，迅速取出坐骨神经测定电生理指标。密切观察大鼠一般状况的变化，每周测量体重，观察其步态的变化并做评分。
二、电生理测定方法
控制室温于23℃，大鼠以4％戊巴比妥钠腹腔注射麻醉，小心剪开皮肤肌肉分离坐骨神经干，迅速取出使其自然伸展置于测定盒内，刺激神经，记录结果。
三、酶生物化学方法
分别取出大脑、脊髓和坐骨神经，匀浆，离心(血液直接离心出血清)，以生化试剂盒测定其GSH、丙二醛(malondialdehyde，MDA)、抗活性氧(reactive oxygen
OBJECTS
Acrylamide is an important industrial chemical, but at the same time it can induce the peripheral neuropathy. To determine the effect of the antioxidant system in the acrylamide-induced peripheral neuropathy, we measured the time-depended changes in (1)the sciatic nerve electrophsiological indexes,(2)the indexes of nerve tissues, serum antioxidant system,(3)the β -actin levels in the rat brain cells treated with acrylamide and those treated with both acrylamide and glutathione. The determination of the effects of antioxidant system can give some proof for the mechanism research, the prevention and the therapy of the acrylamide-induced peripheral neuropathy.
METHODS
1. ANIMAL MODEL AND EVALUATION OF ANIMAL BEHAVIOUR Healthy Wistar rats were randomly divided into two parts: one was for the research of electrophysiology; the other was for the antioxidation. Each part was randomly divided into 10 groups (0, 2, 4, 6, 10 weeks treatment groups and the corresponding control groups). The treatment groups were administered acrylamide dissolved in normal saline via intraperitoneal injection (40 mg/kg/dose, 3 times/week). The control group was administered normal saline in the same way. Rats in antioxidation study groups were sacrificed at the preset time and nerve tissues (cerebrums, spinal cords, sciatic nerves) and serum for antioxidation determination
本实验建立丙烯酰胺(acrylamide，ACR)亚慢性中毒大鼠模型，测定坐骨神经干电生理指标、神经组织和血清中氧化抗氧化指标随染毒时间的变化以及ACR染毒并用谷胱甘肽(glutathione，GSH)干预后的原代神经细胞β-actin含量，以阐明机体氧化抗氧化系统在ACR所致周围性神经病中的作用，为探讨ACR引起的中毒性周围神经病的发病机制以及预防治疗提供依据。
方法
一、动物模型及动物行为观察
健康雄性Wistar大鼠随机分为两部分，一部分用作研究ACR对神经组织及血清氧化抗氧化系统的影响，另一部分用作研究ACR对坐骨神经电生理指标的影响。每部分随机分为0、2、4、6、10周对照组和染毒组。染毒组按40mg／kg腹腔注射ACR的生理盐水溶液(2ml／kg体重)，每周3次，使动物瘫痪。对照组同种方式注射生理盐水。氧化抗氧化各组大鼠于设定时间断头处死，留取大脑、脊髓、坐骨神经组织和血清，用作测定氧化抗氧化指标。电生理各组大鼠于设定时间麻醉，迅速取出坐骨神经测定电生理指标。密切观察大鼠一般状况的变化，每周测量体重，观察其步态的变化并做评分。
二、电生理测定方法
控制室温于23℃，大鼠以4％戊巴比妥钠腹腔注射麻醉，小心剪开皮肤肌肉分离坐骨神经干，迅速取出使其自然伸展置于测定盒内，刺激神经，记录结果。
三、酶生物化学方法
分别取出大脑、脊髓和坐骨神经，匀浆，离心(血液直接离心出血清)，以生化试剂盒测定其GSH、丙二醛(malondialdehyde，MDA)、抗活性氧(reactive oxygen
OBJECTS
Acrylamide is an important industrial chemical, but at the same time it can induce the peripheral neuropathy. To determine the effect of the antioxidant system in the acrylamide-induced peripheral neuropathy, we measured the time-depended changes in (1)the sciatic nerve electrophsiological indexes,(2)the indexes of nerve tissues, serum antioxidant system,(3)the β -actin levels in the rat brain cells treated with acrylamide and those treated with both acrylamide and glutathione. The determination of the effects of antioxidant system can give some proof for the mechanism research, the prevention and the therapy of the acrylamide-induced peripheral neuropathy.
METHODS
1. ANIMAL MODEL AND EVALUATION OF ANIMAL BEHAVIOUR Healthy Wistar rats were randomly divided into two parts: one was for the research of electrophysiology; the other was for the antioxidation. Each part was randomly divided into 10 groups (0, 2, 4, 6, 10 weeks treatment groups and the corresponding control groups). The treatment groups were administered acrylamide dissolved in normal saline via intraperitoneal injection (40 mg/kg/dose, 3 times/week). The control group was administered normal saline in the same way. Rats in antioxidation study groups were sacrificed at the preset time and nerve tissues (cerebrums, spinal cords, sciatic nerves) and serum for antioxidation determination
引文
[1] 张寿林，何凤生，王玉萍等．41例丙烯酰胺作业工人临床分析．中国工业医学杂志．1992，5(2)：193．
[2] 邓海，焦小云，何凤生，等．丙烯酰胺和环氧丙烯酰胺的神经毒性研究．中华预防医学杂志．1997，31(4)：202-205．
[3] 李闪霞，崔宁，张翠丽，等．大鼠亚慢性丙烯酰胺中毒神经行为功能的改变．中国公共卫生．2004，20(12)：1458-1459．
[4] Burek JD, Albee RR, Beyer JE, Bell TJ, Carreon RM, Morden DC, Wade CE, Hermann EA, Gorzinski SJ. Subchronic toxicity of acrylamide administered to rats in the drinking water followed by up to 144 days of recover, J.Environ.Pathol.Toxicol. 1980, 4(5-6): 157-182.
[5] Godin AC, Bengtsson B, Niskanen R, Tareke E, Tornqvist M, Forslund K. Acrylamide and N-methylolacrylamide poisoning in a herd of Charolais crossbreed cattle.Vet.Rec.2002, 151 (24): 724-728.
[6] LoPachin RM, Balaban CD and Ross JF, Acrylamide axonopathy revisited, Toxicol. Appl. Pharmacol.2003, 188 (3): 135-153.
[7] Abou-Donia MB, Ibrahim SM, Corcoran JJ, Lack L, Friedman MA and Lapadula DM. Neurotoxicity of glycidamide, an acrylamide metabolite, following intraperitoneal injections in rats, J. Environ. Pathol. Toxicol. 1993, 39 (4): 447-464.
[8] LoPachin RM Jr, Lehning EJ. Acrylamide-induced distal axon degeneration: a proposed mechanism of action. Neurotoxicology. 1994,15 (2): 47-59.
[9] 范志涛．丙烯酰胺染毒小鼠的神经病理改变．中国职业医学．2002，29(4)：58．
[10] 陈在射．丙烯酰胺的毒性．国外医学卫生学分册．1983，(4)：211-214．
[11] Kuperman AS.Effects of acrylamide on the Central nervous system of the cat .J pharmecol and experiment theraneutics. 1958,123(3): 180-192.
[12] 潘金城等．丙烯酰胺中毒4例报告．职业医学．1986，13(5)：28-30．
[13] 李涛，程建军．丙烯酰胺中毒16例临床分析．中华劳动卫生职业病杂志．2003(21)：152．
[14] 沈国柱，符展明，洪文轲，等．26例丙烯酰胺中毒的临床研究．华西医学．1997(12)3：322-323．
[15] 李纲，何凤生．丙烯酰胺中毒的电生理研究．国外医学卫生学分册．1989，(1)：8-11．
[16] Sickles DW, Stone JD, Friedman MA.Fast Axonal Transport: A Site of Acrylamide Neurotoxicity? Neurotoxicology.2002, 23:223-251.
[17] RM Jr, Lehning EJ.Acrylamide-induced distal axon degeneration: a proposed mechanism of action. Neurotoxicology. 1994 15(2): 247-259.
[18] Howland RD, Vyas IL, Lowndes HE.The etiology of acrylamide neuropathy: possible involvement of neuron specific enolase. Brain Res. 1980, 190(2):529-535.
[19] Husain R, Srivastava S, Srivastava SP, Seth PK. Effect of acrylamide on energy-linked functions in rat brain. Bull Environ Contain Toxicol. 1986, 37(3): 427-432.
[20] Lapin EP et al. The sensitivities of creatine and adenylate kinases to the neurotoxins acrylamide and methyl n-butyl ketone. Environ Res. 1982,28:21-31.
[21] Sickles DW. Neural specificity of acrylamide action upon enzymes associated with oxidative energy-producing pathways. I. Histochemical analysis of NADH-tetrazolium reductase activity. Neurotoxicology. 1987,8:623-630.
[22] Souyri F et al. Acrylamide-induced' neuropathy and impairment of axonal transport of proteins. I. Multifocal retention of fast transported proteins at the periphery of axons as revealed by light microscope radioautography. Brain Res. 1981, 205:1-13.
[23] Ali.SF et al. Effect of acrylamide on neurotransmitter metabolism and neuropeptide levels in several brain regions and upon circulating hormones. Arch Toxico. 1983,52:35-43.
[24] Sakamoto J et al. Effect of acrylamide and related compounds on glycolytic enzymes in mouse brain in vitro. Arch Toxicol. 1985, 57:276-281.
[25] Howland RD. The etiology of acrylamide neuropathy: enolase, phosphofructokinase, and glyceraldehyde-3-phosphate dehydrogenase activities in peripheral nerve, spinal cord, brain, and skeletal muscle of acrylamide-intoxicated cats. Toxicol Appl Pharmacol. 1981,60:324-333.
[26] Ernest Hodgson, Robert C.Smart, 1999, Oxidative stress, In: Introduction to Biochemical Toxicology. 235-237.
[27] 李云波，刘世杰．细胞内活性氧系统和化学毒物对其影响的研究概况(续)．卫生毒理学杂志．1990，4(2)：107-112．
[28] Srivastava S, Sabri MI, Agrawal AK, Seth PK. Effect of single and repeated doses of acrylamide and bis-acrylamide on glutathione-S-transferase and dopamine receptors in rat brain. Brain Res. 1986, 371(2): 319-23.
[29] 崔群，刘志敏，范志涛，等．丙烯酰胺对小鼠抗氧化能力和免疫功能的影响．中国工业医学杂志．2004，17(3)：188-189
[30] 陈瑗，周玫．自由基医学基础与病理生理．北京：人民卫生出版社，2002，157．
[31] 孙凤样，翟筱，崔群．丙烯酰胺对染毒小鼠血清生化指标的影响．潍坊医学院学报．2002，24(1)：64-65．
[32] LoPachin RM, Ross JF, Reid ML, et al. Neurological Evaluation of Toxic Axonopathies in Rats: Acrylamide and 2,5-Hexanedione. NeuroToxicology. 2002,23:95-110.
[33] Broxup B, Robinson K, Losos G, et al. Correlation between behavioral and pathological changes in the evaluation of neurotoxicity. Toxicol Appl Pharmacol. 1989,101(3): 510-20.
[34] 李六一，宋新光，申风琴，等．丙烯酰胺致多发性神经病的神经肌电图分析(附21例报告)．中原医刊．1996，23(2)：40-41．
[35] 李涛，程建军．丙烯酰胺中毒16例临床分析．中华劳动卫生职业病杂志．2003，21(2)：152．
[36] 崔淑君．丙烯酰胺中毒22例神经肌电图变化．中国误诊学杂志．2003，3(2)241-242．
[37] 姜开生，季德宽，尹桂玉，等．丙烯酰胺作业者神经肌电图测定临床价值．化工劳动保护(工业卫生与职业病分册)．1995，16(1)：6-8．
[38] 贺锡雯，邓海，何风生，等．丙烯酰胺及其代谢产物神经毒理的研究．卫生毒理学杂志．1992，6(2)：71．
[39] 李纲，何凤生．丙烯酰胺中毒的电生理研究．国外医学卫生学分册．1989，1：8-11．
[40] Lehning E J, Jortner BS, Fox JH, et al. al.γ-Diketone peripheral neuropathy. I .Quality morphometric analyses of axonal atrophy and swelling.Toxicol.2000, 165:127-140.
[41] 赫秋月，韩漫夫，饶明俐．丙烯酰胺对变异Ola鼠和正常6J鼠轴突影响的实验研究．白求恩医科大学学报，2000，26(6)：573-576．
[42] 鲁洁波，黄金祥，丁茂柏．轴浆运输与中毒性周围神经病．国外医学卫生学分册，1996，23(5)：257-260．
[43] 崔群，刘志敏，范志涛，等．丙烯酰胺对小鼠抗氧化能力和免疫功能的影响．中国工业医学杂志，2004，17(3)：188-189．
[44] 赫秋月，韩漫夫，饶明俐．丙烯酰胺中毒后6J鼠神经组织离子的改变．中国工业医学杂志，2000，13(5)：265-267．
[45] 张桥．卫生毒理学基础．人民卫生出版社．58-63．
[46] 李云波，刘世杰．细胞内活性氧系统和化学毒物对其影响的研究概况．卫生毒理学杂志．1990；4(2)：107-112．
[47] 谢克勤，赵丽，于丽华，等．氯丙烯对大鼠神经组织抗氧化系统的影响．卫生毒理学杂志．2002；16(3)：178-180．
[48] 赵丽，谢克勤，张曼，等．氯丙烯对神经细胞NO、MDA含量和NOS、SOD、GSH-PX活性的影响．山东医科大学学报．2001，39(2)：176-178．
[49] Shukla G S, et al. Possible role of regional superoxide dismutase activity and lipid peroxide levels in cadmium neurotoxicity: in vivo and in vitro studies in growing rats. Life Sci. 1987,41:2215.
[50] 王桂兰，刘双军，侯玉春，等．铅对大鼠脑细胞膜脂质过氧化及超氧化物歧化酶活性的影响．卫生毒理学杂志．1995，9(3)：175-176．
[51] 逯晓波，陈葆春，于丽华，等．铅致新生大鼠氧化损伤及细胞凋亡的某些改变．中国职业医学．2002，29(3)：34-35．
[52] 任春兰，陆荣柱，殷若元．氰戊菊酯对小鼠脑组织脂质过氧化及抗过氧化能力的影响．劳动医学．1995，12(2)：4-6．
[53] Srivastava SP, Das M, Seth PK.Enhancement of lipid peroxidation in rat liver on acute exposure to styrene and acrylamide a consequence of glutathione depletion. Chem Biol Interact. 1983,45(3): 373-380.
[54] Dixit R, Das M, Seth PK, Mukhtar H. Interaction of acrylamide with glutathione in rat erythrocytes. Toxicol Lett. 1984, 23(3): 291-298.
[55] Park J, Kamendulis LM, Friedman MA, Klaunig JE. Acrylamide-induced cellular transformation. Toxicol Sci. 2002,65(2): 177-183.
[56] Turrens J F, et al. Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria. Biochem J. 1980, 191: 421-427.
[57] Shi X L, et al. ESR evidence for the hydroxyl radical formation in aqueous suspension of quartz particles and its possible significance to lipid peroxidation in silicosis. J Toxicol Environ Health. 1988, 25: 237-245.
[58] Kehrer J P, et al. Systematically applied chemicals that damage lung tissue. Toxicology. 1985, 35: 251-293.
[59] Horton A A, et al. Lipid peroxidation and mechanisms of toxicity. Crit Rev Toxicol. 1987, 18: 27-79.
[60] Ruch R J, et al. Inhibition of mouse hepatocyte intercellular communication by paraquat-generated oxygen free radicals. Toxicol Appl Pharmacol. 1988, 94: 427-436.
[61] 李云波，刘世杰．细胞内活性氧系统和化学毒物对其影响的研究概况．卫生毒理学杂志．1990，4(2)：107-112．
[62] Moutaery K, Morais C, Biary N, A1 Deeb S, Tariq M.Effect of acrylamide on neurological recovery following spinal cord injury in rats. Acta Neurochir (Wien). 1999, 141 (9): 989-998.
[63] 贺锡雯，邓海，何凤生，等．丙烯酰胺及其代谢产物神经毒理的研究，卫生毒理学杂志．1992，6(2)：71．
[64] Abou-Donia MB, Ibrahim SM, Corcoran JJ, Lack L, Friedman MA, Lapadula DM. Neurotoxicity of glycidamide, an acrylamide metabolite, following intraperitoneal injections in rats. J Toxicol Environ Health. 1993, 39 (4): 447-464.
[65] Nagano M, Yamamoto H, Haradaet al. Comparative study of modification and degradation of neurofilament proteins in rats subchronically treated with allyl chloride, acrylamide or 2, 5-hexanedione. Environmental Research .1993, 63: 229-240.
[66] Nagano M, Hitoshi T, Futatsuka M et al. Neurotoxicity of allyl chloride in rats: Dose-effect relationship following long-term exposure. Jpn. J. Ind. Health. 1991, 33:73-80.
[67] 郑玉新，梁友信．化学毒物的神经毒性效应及其毒理学评价．卫生毒理学杂志．1995，9(3)：189-192．
[68] 赫秋月，韩漫夫，饶明俐．丙烯酰胺中毒后6J鼠神经组织离子的改变．中国工业医学杂志．2000，13(5)：265-267
[69] Cardoso SM, et al. Biochem Biophys Res Comm. 1998, 246 (3): 703-710.
[70] Miester A, Anderso ME. Glutathion. Annu. Rev. Biochem. 1991, 52:711-722
[71] Smith CV, Jones DP, Guenthner TM, Lash LH, Lauterburg BH. Compartmentation of glutathione: implications for the study of toxicity and disease. Toxicol Appl Pharmacol. 1996, 140 (1): 1-12.
[72] 张铣，刘毓谷．毒理学．北京：北京医科大学中国协和医科大学联合出版社．1997：136-153．
[73] Rowley, et al. FEBS Lett. 1982, 138: 143.
[74] Friedman, M, Cavins, JF and Wall, JS. Relative nucleophilic reactivities of amino groups and mercaptide ions in addition reactions with alpha, beta-unsaturated compounds. J. Am. Chem. Soc. 1965,87: 3672-3682.
[75] Tong GC, Cornwell WK, Means GE.Reactions of acrylamide with glutathione and serum albumin. Toxicol Lett. 2004, 147(2):127-31.
[76] Kemplay S, Cavanagh JB.Effects of acrylamide and some other sulfhydryl reagents on spontaneous and pathologically induced terminal sprouting from motor end-plates. Muscle Nerve. 1984, 7(2): 101-109.
[77] Selective modulation of glutathione in mouse brain regions and its effect on acrylamide-induced neurotoxicity. Shivakumar BR, Ravindranath V. Biochem Pharmacol. 1992, 43(2):263-269.
[78] Stunner SC, Williams CC, Snyder RW, Krol WL, Asgharian B, Fennell TR. Acrylamide: a comparison of metabolism and hemoglobin adducts in rodents following dermal, intraperitoneal, oral, or inhalation exposure. Toxicol Sci. 2003, 75 (2): 260-70.
[79] Sumner SC, Selvaraj L, Nauhaus SK, Fennell TR.Urinary metabolites from F344 rats and B6C3F1 mice coadministered acrylamide and acrylonitrile for 1 or 5 days. Chem Res Toxicol. 1997,10 (10): 1152-1160.
[80] Rachel Perdn-Nadif, Guyauburtin, Msrtine busch, et al. Blood Antioxdant Enzymes as Markers of Exposure or Effect in Coal Miners. Occup.and Euciron. Med. 1996, 53: 41-134.
[81] 王镜岩，朱圣庚，朱长法．生物化学．北京：高等教育出版社．2002，103
[82] Callahan B.G. Can hormesis be a default for dose-response? Hum Exp Toxicol. 2005, 24 (5): 271-273.
[83] Lopachin RM Jr, Lehning EJ Acrylamide-induced distal axon degeneration: a proposed mechanism of action. Neurotoxicology. 1994, 15 (2): 247-259.
[84] 赫秋月，韩漫夫，饶明俐．丙烯酰胺中毒后小鼠周围神经逆行性坏死的实验病理研究．中华劳动卫生职业病杂志．2001，19(6)：436-438．
[85] Schulze GE, Boysen BG. A neurotoxicity screening battery for use in safety evaluation: effects of acrylamide and 3', 3'-iminodipropionitrile. Fundam Appl Toxicol. 1991, 16 (3): 602-615.
[86] Tanii H, Hashimoto K. Neurotoxicity of acrylamide and related compounds in rats. Effects on rotarod performance, morphology of nerves and neurotubulin. Arch Toxicol. 1983, 54 (3): 203-213.
[87] Howland RD, Vyas IL, Lowndes HE. The etiology of acrylamide neuropathy: possible involvement of neuron specific enolase. Brain Res. 1980, 190 (2): 529-535.
[88] Schaumburg HH, Wisniewski HM, Spencer PS. Ultrastructural studies of the dying-back process. I. Peripheral nerve terminal and axon degeneration in systemic acrylamide intoxication. J Neuropathol Exp Neurol. 1974, 33 (2): 260-284.
[89] 蔡文琴，李海标等．发育神经生物学．科学出版社．2001，76-82．
[90] Alberts, Bruce; Bray, Dennis; Lewis, Julian; Raff, Martin; Roberts, Keith; Watson, James D. Molecular Biology of the Cell. 3rd ed. New York and London: Garland Publishing; 1994
[91] Lodish, Harvey; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Damell, James E. Molecular Cell Biology. 4th ed New York: W H Freeman &Co; 2000.
[92] Dau J, Wenthold RJ. Immuno-cytochemical localization of neuro-filament subunits in the spiral ganglion of normal and neomycin-treated guinea pigs. Hear Res. 1989, 42 (2-3): 253-263.
[93] Halpain S. Actin in a supporting role. Nat Neurosci. 2003, 6 (2): 101-102.
[94] Vandekerckhove J, Weber K. At least six diferent actins are expressed in a higher mammal: an analysis based on the amino acid sequence of the amino-terminal tryptic peptide. J Mol Biol.1978, 126(4): 783-802.
[95] Bassell GJ, Zhang H, Byrd AL, Femino AM, Singer RH, Taneja KL, Lifshitz LM, Herman IM, Kosik KS. Sorting of beta-actin mRNA and protein to neurites and growth cones in culture. The Journal of Neuroscience. 1998, 18(1): 251-265.
[96] Sase I, Miyata H, Ishiwata S, Kinosita K Jr. Axial rotation of sliding actin filaments revealed by single-fluorophore imaging-Proc Natl Acad Sci U S A. 1997,94(11): 5646-5650.
[97] Kuznetsov SA, Langford GM, Weiss DG. Actin-dependent organelle movement in squid axoplasm. Nature. 1992,356(6371): 722-725.
[98] Bearer EL, DeGiorgis JA, Bodner RA, Kao AW, Reese TS. Evidence for myosin motors on organelles in squid axoplasm. Proc Natl Acad Sci U S A. 1993,90(23): 11252-11256.
[99] Evans LL, Bridgman PC. Particles move along actin filament bundles in nerve growth cones. Proc Natl Acad Sci USA. 1995, 92 (24): 10954-10958.
[100] Gozes I, Walker MD, Kaye AM, Littauer UZ. Synthesis of tubulin and actin by neuronal and glial nuclear preparations from devloping rat brain. J Biol Chem. 1977, 252 (5): 1819-1825.
[101] Hou L, Lanni F, Luby-Phelps K. Tracer diffusion in F-actin and Ficoll mixtures. Toward a model for cytoplasm. Biophys J. 1990, 58 (1): 31-43.
[102] Provance DW Jr, McDowall A, Marko M, Luby-Phelps K. Cytoarchitecture of size-excluding compartments in living cells. J Cell Sci. 1993, 106 (2): 565-577.
[103] 李岩，谢克勤，赵丽，张忠彬，段化伟．氯丙烯对原代培养的大鼠大脑神经 细胞G蛋白的影响．卫生毒理学杂志．2003，17：6-9
[104] 陈诗书，汤雪明主编．膜受体介导的信使作用，医学细胞与分子生物学，上海医科大学出版社，1999；333-338．
[105] 于素芳，谢克勤，赵秀兰．丙烯酰胺中毒对大鼠脊髓细胞骨架蛋白表达的影响毒理学杂志，2005，19(3)增刊：L221．
[106] Cooper JA. The role of actin polymerization in cell motility. Annu Rev Physiol 1991, 53:585-605
[107] Ivan V. Maly and Gary G. Borisy. Self-organization of a propulsive actin network as an evolutionary process. Proc. Natl. Acad. Sci. USA. 2001 98 (20): 11324-11329
[108] Dominique Didry, Made-France Carlier, and Dominique Pantaloni. Synergy between actin depolymerizing factor/cofilin and profilin in increasing actin Filament Turnover. J. Biol. Chem., 1998; 273:25602-25611.
[109] Kinosian HJ, Newman J, Lincoln B, Selden LA, Gershman LC, Estes JE.Ca2+ regulation of gelsolin activity: binding and severing of F-actin. Biophys J. 1998, 75 (6): 3101-3109.
[110] Schindelholz B, Reber BF. L-type Ca2+ channels and purinergic P2X2 cation channels participate in calcium-tyrosine kinase-mediated PC 12 growth cone arrest. Eur J Neurosci. 2000, 12 (1): 194-204
[2] 邓海，焦小云，何凤生，等．丙烯酰胺和环氧丙烯酰胺的神经毒性研究．中华预防医学杂志．1997，31(4)：202-205．
[3] 李闪霞，崔宁，张翠丽，等．大鼠亚慢性丙烯酰胺中毒神经行为功能的改变．中国公共卫生．2004，20(12)：1458-1459．
[4] Burek JD, Albee RR, Beyer JE, Bell TJ, Carreon RM, Morden DC, Wade CE, Hermann EA, Gorzinski SJ. Subchronic toxicity of acrylamide administered to rats in the drinking water followed by up to 144 days of recover, J.Environ.Pathol.Toxicol. 1980, 4(5-6): 157-182.
[5] Godin AC, Bengtsson B, Niskanen R, Tareke E, Tornqvist M, Forslund K. Acrylamide and N-methylolacrylamide poisoning in a herd of Charolais crossbreed cattle.Vet.Rec.2002, 151 (24): 724-728.
[6] LoPachin RM, Balaban CD and Ross JF, Acrylamide axonopathy revisited, Toxicol. Appl. Pharmacol.2003, 188 (3): 135-153.
[7] Abou-Donia MB, Ibrahim SM, Corcoran JJ, Lack L, Friedman MA and Lapadula DM. Neurotoxicity of glycidamide, an acrylamide metabolite, following intraperitoneal injections in rats, J. Environ. Pathol. Toxicol. 1993, 39 (4): 447-464.
[8] LoPachin RM Jr, Lehning EJ. Acrylamide-induced distal axon degeneration: a proposed mechanism of action. Neurotoxicology. 1994,15 (2): 47-59.
[9] 范志涛．丙烯酰胺染毒小鼠的神经病理改变．中国职业医学．2002，29(4)：58．
[10] 陈在射．丙烯酰胺的毒性．国外医学卫生学分册．1983，(4)：211-214．
[11] Kuperman AS.Effects of acrylamide on the Central nervous system of the cat .J pharmecol and experiment theraneutics. 1958,123(3): 180-192.
[12] 潘金城等．丙烯酰胺中毒4例报告．职业医学．1986，13(5)：28-30．
[13] 李涛，程建军．丙烯酰胺中毒16例临床分析．中华劳动卫生职业病杂志．2003(21)：152．
[14] 沈国柱，符展明，洪文轲，等．26例丙烯酰胺中毒的临床研究．华西医学．1997(12)3：322-323．
[15] 李纲，何凤生．丙烯酰胺中毒的电生理研究．国外医学卫生学分册．1989，(1)：8-11．
[16] Sickles DW, Stone JD, Friedman MA.Fast Axonal Transport: A Site of Acrylamide Neurotoxicity? Neurotoxicology.2002, 23:223-251.
[17] RM Jr, Lehning EJ.Acrylamide-induced distal axon degeneration: a proposed mechanism of action. Neurotoxicology. 1994 15(2): 247-259.
[18] Howland RD, Vyas IL, Lowndes HE.The etiology of acrylamide neuropathy: possible involvement of neuron specific enolase. Brain Res. 1980, 190(2):529-535.
[19] Husain R, Srivastava S, Srivastava SP, Seth PK. Effect of acrylamide on energy-linked functions in rat brain. Bull Environ Contain Toxicol. 1986, 37(3): 427-432.
[20] Lapin EP et al. The sensitivities of creatine and adenylate kinases to the neurotoxins acrylamide and methyl n-butyl ketone. Environ Res. 1982,28:21-31.
[21] Sickles DW. Neural specificity of acrylamide action upon enzymes associated with oxidative energy-producing pathways. I. Histochemical analysis of NADH-tetrazolium reductase activity. Neurotoxicology. 1987,8:623-630.
[22] Souyri F et al. Acrylamide-induced' neuropathy and impairment of axonal transport of proteins. I. Multifocal retention of fast transported proteins at the periphery of axons as revealed by light microscope radioautography. Brain Res. 1981, 205:1-13.
[23] Ali.SF et al. Effect of acrylamide on neurotransmitter metabolism and neuropeptide levels in several brain regions and upon circulating hormones. Arch Toxico. 1983,52:35-43.
[24] Sakamoto J et al. Effect of acrylamide and related compounds on glycolytic enzymes in mouse brain in vitro. Arch Toxicol. 1985, 57:276-281.
[25] Howland RD. The etiology of acrylamide neuropathy: enolase, phosphofructokinase, and glyceraldehyde-3-phosphate dehydrogenase activities in peripheral nerve, spinal cord, brain, and skeletal muscle of acrylamide-intoxicated cats. Toxicol Appl Pharmacol. 1981,60:324-333.
[26] Ernest Hodgson, Robert C.Smart, 1999, Oxidative stress, In: Introduction to Biochemical Toxicology. 235-237.
[27] 李云波，刘世杰．细胞内活性氧系统和化学毒物对其影响的研究概况(续)．卫生毒理学杂志．1990，4(2)：107-112．
[28] Srivastava S, Sabri MI, Agrawal AK, Seth PK. Effect of single and repeated doses of acrylamide and bis-acrylamide on glutathione-S-transferase and dopamine receptors in rat brain. Brain Res. 1986, 371(2): 319-23.
[29] 崔群，刘志敏，范志涛，等．丙烯酰胺对小鼠抗氧化能力和免疫功能的影响．中国工业医学杂志．2004，17(3)：188-189
[30] 陈瑗，周玫．自由基医学基础与病理生理．北京：人民卫生出版社，2002，157．
[31] 孙凤样，翟筱，崔群．丙烯酰胺对染毒小鼠血清生化指标的影响．潍坊医学院学报．2002，24(1)：64-65．
[32] LoPachin RM, Ross JF, Reid ML, et al. Neurological Evaluation of Toxic Axonopathies in Rats: Acrylamide and 2,5-Hexanedione. NeuroToxicology. 2002,23:95-110.
[33] Broxup B, Robinson K, Losos G, et al. Correlation between behavioral and pathological changes in the evaluation of neurotoxicity. Toxicol Appl Pharmacol. 1989,101(3): 510-20.
[34] 李六一，宋新光，申风琴，等．丙烯酰胺致多发性神经病的神经肌电图分析(附21例报告)．中原医刊．1996，23(2)：40-41．
[35] 李涛，程建军．丙烯酰胺中毒16例临床分析．中华劳动卫生职业病杂志．2003，21(2)：152．
[36] 崔淑君．丙烯酰胺中毒22例神经肌电图变化．中国误诊学杂志．2003，3(2)241-242．
[37] 姜开生，季德宽，尹桂玉，等．丙烯酰胺作业者神经肌电图测定临床价值．化工劳动保护(工业卫生与职业病分册)．1995，16(1)：6-8．
[38] 贺锡雯，邓海，何风生，等．丙烯酰胺及其代谢产物神经毒理的研究．卫生毒理学杂志．1992，6(2)：71．
[39] 李纲，何凤生．丙烯酰胺中毒的电生理研究．国外医学卫生学分册．1989，1：8-11．
[40] Lehning E J, Jortner BS, Fox JH, et al. al.γ-Diketone peripheral neuropathy. I .Quality morphometric analyses of axonal atrophy and swelling.Toxicol.2000, 165:127-140.
[41] 赫秋月，韩漫夫，饶明俐．丙烯酰胺对变异Ola鼠和正常6J鼠轴突影响的实验研究．白求恩医科大学学报，2000，26(6)：573-576．
[42] 鲁洁波，黄金祥，丁茂柏．轴浆运输与中毒性周围神经病．国外医学卫生学分册，1996，23(5)：257-260．
[43] 崔群，刘志敏，范志涛，等．丙烯酰胺对小鼠抗氧化能力和免疫功能的影响．中国工业医学杂志，2004，17(3)：188-189．
[44] 赫秋月，韩漫夫，饶明俐．丙烯酰胺中毒后6J鼠神经组织离子的改变．中国工业医学杂志，2000，13(5)：265-267．
[45] 张桥．卫生毒理学基础．人民卫生出版社．58-63．
[46] 李云波，刘世杰．细胞内活性氧系统和化学毒物对其影响的研究概况．卫生毒理学杂志．1990；4(2)：107-112．
[47] 谢克勤，赵丽，于丽华，等．氯丙烯对大鼠神经组织抗氧化系统的影响．卫生毒理学杂志．2002；16(3)：178-180．
[48] 赵丽，谢克勤，张曼，等．氯丙烯对神经细胞NO、MDA含量和NOS、SOD、GSH-PX活性的影响．山东医科大学学报．2001，39(2)：176-178．
[49] Shukla G S, et al. Possible role of regional superoxide dismutase activity and lipid peroxide levels in cadmium neurotoxicity: in vivo and in vitro studies in growing rats. Life Sci. 1987,41:2215.
[50] 王桂兰，刘双军，侯玉春，等．铅对大鼠脑细胞膜脂质过氧化及超氧化物歧化酶活性的影响．卫生毒理学杂志．1995，9(3)：175-176．
[51] 逯晓波，陈葆春，于丽华，等．铅致新生大鼠氧化损伤及细胞凋亡的某些改变．中国职业医学．2002，29(3)：34-35．
[52] 任春兰，陆荣柱，殷若元．氰戊菊酯对小鼠脑组织脂质过氧化及抗过氧化能力的影响．劳动医学．1995，12(2)：4-6．
[53] Srivastava SP, Das M, Seth PK.Enhancement of lipid peroxidation in rat liver on acute exposure to styrene and acrylamide a consequence of glutathione depletion. Chem Biol Interact. 1983,45(3): 373-380.
[54] Dixit R, Das M, Seth PK, Mukhtar H. Interaction of acrylamide with glutathione in rat erythrocytes. Toxicol Lett. 1984, 23(3): 291-298.
[55] Park J, Kamendulis LM, Friedman MA, Klaunig JE. Acrylamide-induced cellular transformation. Toxicol Sci. 2002,65(2): 177-183.
[56] Turrens J F, et al. Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria. Biochem J. 1980, 191: 421-427.
[57] Shi X L, et al. ESR evidence for the hydroxyl radical formation in aqueous suspension of quartz particles and its possible significance to lipid peroxidation in silicosis. J Toxicol Environ Health. 1988, 25: 237-245.
[58] Kehrer J P, et al. Systematically applied chemicals that damage lung tissue. Toxicology. 1985, 35: 251-293.
[59] Horton A A, et al. Lipid peroxidation and mechanisms of toxicity. Crit Rev Toxicol. 1987, 18: 27-79.
[60] Ruch R J, et al. Inhibition of mouse hepatocyte intercellular communication by paraquat-generated oxygen free radicals. Toxicol Appl Pharmacol. 1988, 94: 427-436.
[61] 李云波，刘世杰．细胞内活性氧系统和化学毒物对其影响的研究概况．卫生毒理学杂志．1990，4(2)：107-112．
[62] Moutaery K, Morais C, Biary N, A1 Deeb S, Tariq M.Effect of acrylamide on neurological recovery following spinal cord injury in rats. Acta Neurochir (Wien). 1999, 141 (9): 989-998.
[63] 贺锡雯，邓海，何凤生，等．丙烯酰胺及其代谢产物神经毒理的研究，卫生毒理学杂志．1992，6(2)：71．
[64] Abou-Donia MB, Ibrahim SM, Corcoran JJ, Lack L, Friedman MA, Lapadula DM. Neurotoxicity of glycidamide, an acrylamide metabolite, following intraperitoneal injections in rats. J Toxicol Environ Health. 1993, 39 (4): 447-464.
[65] Nagano M, Yamamoto H, Haradaet al. Comparative study of modification and degradation of neurofilament proteins in rats subchronically treated with allyl chloride, acrylamide or 2, 5-hexanedione. Environmental Research .1993, 63: 229-240.
[66] Nagano M, Hitoshi T, Futatsuka M et al. Neurotoxicity of allyl chloride in rats: Dose-effect relationship following long-term exposure. Jpn. J. Ind. Health. 1991, 33:73-80.
[67] 郑玉新，梁友信．化学毒物的神经毒性效应及其毒理学评价．卫生毒理学杂志．1995，9(3)：189-192．
[68] 赫秋月，韩漫夫，饶明俐．丙烯酰胺中毒后6J鼠神经组织离子的改变．中国工业医学杂志．2000，13(5)：265-267
[69] Cardoso SM, et al. Biochem Biophys Res Comm. 1998, 246 (3): 703-710.
[70] Miester A, Anderso ME. Glutathion. Annu. Rev. Biochem. 1991, 52:711-722
[71] Smith CV, Jones DP, Guenthner TM, Lash LH, Lauterburg BH. Compartmentation of glutathione: implications for the study of toxicity and disease. Toxicol Appl Pharmacol. 1996, 140 (1): 1-12.
[72] 张铣，刘毓谷．毒理学．北京：北京医科大学中国协和医科大学联合出版社．1997：136-153．
[73] Rowley, et al. FEBS Lett. 1982, 138: 143.
[74] Friedman, M, Cavins, JF and Wall, JS. Relative nucleophilic reactivities of amino groups and mercaptide ions in addition reactions with alpha, beta-unsaturated compounds. J. Am. Chem. Soc. 1965,87: 3672-3682.
[75] Tong GC, Cornwell WK, Means GE.Reactions of acrylamide with glutathione and serum albumin. Toxicol Lett. 2004, 147(2):127-31.
[76] Kemplay S, Cavanagh JB.Effects of acrylamide and some other sulfhydryl reagents on spontaneous and pathologically induced terminal sprouting from motor end-plates. Muscle Nerve. 1984, 7(2): 101-109.
[77] Selective modulation of glutathione in mouse brain regions and its effect on acrylamide-induced neurotoxicity. Shivakumar BR, Ravindranath V. Biochem Pharmacol. 1992, 43(2):263-269.
[78] Stunner SC, Williams CC, Snyder RW, Krol WL, Asgharian B, Fennell TR. Acrylamide: a comparison of metabolism and hemoglobin adducts in rodents following dermal, intraperitoneal, oral, or inhalation exposure. Toxicol Sci. 2003, 75 (2): 260-70.
[79] Sumner SC, Selvaraj L, Nauhaus SK, Fennell TR.Urinary metabolites from F344 rats and B6C3F1 mice coadministered acrylamide and acrylonitrile for 1 or 5 days. Chem Res Toxicol. 1997,10 (10): 1152-1160.
[80] Rachel Perdn-Nadif, Guyauburtin, Msrtine busch, et al. Blood Antioxdant Enzymes as Markers of Exposure or Effect in Coal Miners. Occup.and Euciron. Med. 1996, 53: 41-134.
[81] 王镜岩，朱圣庚，朱长法．生物化学．北京：高等教育出版社．2002，103
[82] Callahan B.G. Can hormesis be a default for dose-response? Hum Exp Toxicol. 2005, 24 (5): 271-273.
[83] Lopachin RM Jr, Lehning EJ Acrylamide-induced distal axon degeneration: a proposed mechanism of action. Neurotoxicology. 1994, 15 (2): 247-259.
[84] 赫秋月，韩漫夫，饶明俐．丙烯酰胺中毒后小鼠周围神经逆行性坏死的实验病理研究．中华劳动卫生职业病杂志．2001，19(6)：436-438．
[85] Schulze GE, Boysen BG. A neurotoxicity screening battery for use in safety evaluation: effects of acrylamide and 3', 3'-iminodipropionitrile. Fundam Appl Toxicol. 1991, 16 (3): 602-615.
[86] Tanii H, Hashimoto K. Neurotoxicity of acrylamide and related compounds in rats. Effects on rotarod performance, morphology of nerves and neurotubulin. Arch Toxicol. 1983, 54 (3): 203-213.
[87] Howland RD, Vyas IL, Lowndes HE. The etiology of acrylamide neuropathy: possible involvement of neuron specific enolase. Brain Res. 1980, 190 (2): 529-535.
[88] Schaumburg HH, Wisniewski HM, Spencer PS. Ultrastructural studies of the dying-back process. I. Peripheral nerve terminal and axon degeneration in systemic acrylamide intoxication. J Neuropathol Exp Neurol. 1974, 33 (2): 260-284.
[89] 蔡文琴，李海标等．发育神经生物学．科学出版社．2001，76-82．
[90] Alberts, Bruce; Bray, Dennis; Lewis, Julian; Raff, Martin; Roberts, Keith; Watson, James D. Molecular Biology of the Cell. 3rd ed. New York and London: Garland Publishing; 1994
[91] Lodish, Harvey; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Damell, James E. Molecular Cell Biology. 4th ed New York: W H Freeman &Co; 2000.
[92] Dau J, Wenthold RJ. Immuno-cytochemical localization of neuro-filament subunits in the spiral ganglion of normal and neomycin-treated guinea pigs. Hear Res. 1989, 42 (2-3): 253-263.
[93] Halpain S. Actin in a supporting role. Nat Neurosci. 2003, 6 (2): 101-102.
[94] Vandekerckhove J, Weber K. At least six diferent actins are expressed in a higher mammal: an analysis based on the amino acid sequence of the amino-terminal tryptic peptide. J Mol Biol.1978, 126(4): 783-802.
[95] Bassell GJ, Zhang H, Byrd AL, Femino AM, Singer RH, Taneja KL, Lifshitz LM, Herman IM, Kosik KS. Sorting of beta-actin mRNA and protein to neurites and growth cones in culture. The Journal of Neuroscience. 1998, 18(1): 251-265.
[96] Sase I, Miyata H, Ishiwata S, Kinosita K Jr. Axial rotation of sliding actin filaments revealed by single-fluorophore imaging-Proc Natl Acad Sci U S A. 1997,94(11): 5646-5650.
[97] Kuznetsov SA, Langford GM, Weiss DG. Actin-dependent organelle movement in squid axoplasm. Nature. 1992,356(6371): 722-725.
[98] Bearer EL, DeGiorgis JA, Bodner RA, Kao AW, Reese TS. Evidence for myosin motors on organelles in squid axoplasm. Proc Natl Acad Sci U S A. 1993,90(23): 11252-11256.
[99] Evans LL, Bridgman PC. Particles move along actin filament bundles in nerve growth cones. Proc Natl Acad Sci USA. 1995, 92 (24): 10954-10958.
[100] Gozes I, Walker MD, Kaye AM, Littauer UZ. Synthesis of tubulin and actin by neuronal and glial nuclear preparations from devloping rat brain. J Biol Chem. 1977, 252 (5): 1819-1825.
[101] Hou L, Lanni F, Luby-Phelps K. Tracer diffusion in F-actin and Ficoll mixtures. Toward a model for cytoplasm. Biophys J. 1990, 58 (1): 31-43.
[102] Provance DW Jr, McDowall A, Marko M, Luby-Phelps K. Cytoarchitecture of size-excluding compartments in living cells. J Cell Sci. 1993, 106 (2): 565-577.
[103] 李岩，谢克勤，赵丽，张忠彬，段化伟．氯丙烯对原代培养的大鼠大脑神经 细胞G蛋白的影响．卫生毒理学杂志．2003，17：6-9
[104] 陈诗书，汤雪明主编．膜受体介导的信使作用，医学细胞与分子生物学，上海医科大学出版社，1999；333-338．
[105] 于素芳，谢克勤，赵秀兰．丙烯酰胺中毒对大鼠脊髓细胞骨架蛋白表达的影响毒理学杂志，2005，19(3)增刊：L221．
[106] Cooper JA. The role of actin polymerization in cell motility. Annu Rev Physiol 1991, 53:585-605
[107] Ivan V. Maly and Gary G. Borisy. Self-organization of a propulsive actin network as an evolutionary process. Proc. Natl. Acad. Sci. USA. 2001 98 (20): 11324-11329
[108] Dominique Didry, Made-France Carlier, and Dominique Pantaloni. Synergy between actin depolymerizing factor/cofilin and profilin in increasing actin Filament Turnover. J. Biol. Chem., 1998; 273:25602-25611.
[109] Kinosian HJ, Newman J, Lincoln B, Selden LA, Gershman LC, Estes JE.Ca2+ regulation of gelsolin activity: binding and severing of F-actin. Biophys J. 1998, 75 (6): 3101-3109.
[110] Schindelholz B, Reber BF. L-type Ca2+ channels and purinergic P2X2 cation channels participate in calcium-tyrosine kinase-mediated PC 12 growth cone arrest. Eur J Neurosci. 2000, 12 (1): 194-204