大田软海绵酸类毒素的毒理学研究进展
|
摘要
腹泻性贝类中毒是一类因食用特定毒素污染的海产品而引起的食源性疾病,大田软海绵酸(Okadaic Acid,OA)及其衍生物鳍藻毒素(Dinophysistoxins,DTXs)是腹泻性贝毒(Diarrhetic shellfish poisons,DSP)中分布最广、危害最大的一类组分。研究发现,OA及DTXs能通过抑制蛋白质磷酸化过程而产生诸如腹泻、恶心和呕吐等症状,此外,该类毒素同时具有多种慢性毒性作用,本文在OA类毒素在致毒机制、体内实验、细胞毒性、遗传毒性、神经毒性、免疫毒性等方面进行了综述,总结了此类毒素的研究现状和进展,为该类毒素的进一步毒理学研究提供了依据。
Okadaic acid(OA) and its derivatives(dinophysistoxins, DTXs) are common and widely distributed marine biological toxins. Related studies have proved their acute toxicity(diarrhea, vomiting, etc.) and chronic toxic effects. This paper summarizes recent progress of the OA toxins in the area of toxication mechanism, in vivo assay, cytotoxicity, genotoxicity, neurotoxicity and immunological toxicity, and provides a reference for further toxicology research of the toxins.
Okadaic acid(OA) and its derivatives(dinophysistoxins, DTXs) are common and widely distributed marine biological toxins. Related studies have proved their acute toxicity(diarrhea, vomiting, etc.) and chronic toxic effects. This paper summarizes recent progress of the OA toxins in the area of toxication mechanism, in vivo assay, cytotoxicity, genotoxicity, neurotoxicity and immunological toxicity, and provides a reference for further toxicology research of the toxins.
引文
[1]柳俊秀,何培民.赤潮藻毒素种类与化学结构研究进展[J].中国医药生物技术, 2009, 4(2):144-147.
[2] ALEXANDER J, BENFORD D, COCKBURN A, et al. Marine biotoxins in shellfish-pectenotoxin group[J]. EFSA Journal, 2009,1109(7):1-47.
[3]江涛,江天久.贝类体内麻痹性贝类毒素的提取方法研究[J].分析化学, 2008, 36(11):1 460-1 464.
[4] SUZUKI T, QUILLIAM A M. LC-MS/MS analysis of diarrhetic shellfish poisoning(DSP)toxins, okadaic acid and dinophysistoxin analogues, and other lipophilic toxins[J]. Anaytical Sciences, 2011, 27(6):571-584.
[5] BLANCO J, ARVALO F, CORREA J, et al. Effect of the industrial steaming on the toxicity, estimated by LC-MS/MS, of mussels exposed for a long time to diarrhetic shellfish poisoning(DSP)toxins[J]. Food Chemistry, 2015, 177(103):240-247.
[6] LI Aifeng, MA Jinggang, Cao Jijuan, et al. Toxins in mussels(Mytilus galloprovincialis)associated with diarrhetic shellfish poisoning episodes in China[J]. Toxicon, 2012, 60(3):420-425.
[7] LI Aifeng, Yu Rencheng, Li Jun, et al. Protein phosphatase inhibition assay for detection of diarrhetic shellfish poison in oyster[J]. Chinese Journal of Analytical Chenistry, 2006, 34(3):283-287.
[8] MUNDAY R, REEVE J. Risk assessment of shellfish toxins[J]. Toxins, 2013, 5(11):2 019-2 037.
[9]郭萌萌,吴海燕,李兆新,等.基于聚硫堇/亚甲基蓝和纳米金放大的免疫传感器检测贝类毒素大田软海绵酸[J].分析测试学报, 2014, 33(2):161-166.
[10] BIALOJAN C, TAKAI A. Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases. Specificity and kinetics[J]. The Biochemical Journal, 1988, 256(1):283-290.
[11] REX M. Is protein phosphatase inhibition responsible for the toxic effects of okadaic acid in animals[J]. Toxins, 2013, 5(2):267-285.
[12] ZHANG Z, SIMPKINS J W. An okadaic acid-induced model of tauopathy and cognitive deficiency[J]. Brain Research, 2010,1359(3):233-246.
[13] BALLATORE C, BRUNDEN K R, HURYN D M, et al. Microtubule stabilizing agents as potential treatment for Alzheimer’s disease and related neurodegenerative tauopathies[J]. Medical Chemistry, 2012, 55(21):8 979-8 996.
[14] HONKANAN R E, CODISPOTI B A, TSE K, et al. Characterization of natural toxins with inhibitory activity against serine/threonine protein phosphatases[J]. Toxicon, 1994, 32(3):339-350.
[15] TAKAI A, MURATA M, TORIGOE K, et al. Inhibitory effect of okadaic acid derivatives on protein phosphatases. A study on structure-affinity relationship[J]. Biochemical Journal, 1992, 284(Pt 2)(2):539-544.
[16] MICHAEL J T, GREGORY J D, PANG Y, et al. Structure-Activity Relationship Studies Using Natural and Synthetic Okadaic Acid/Dinophysistoxin Toxins[J]. Marine Drugs, 2016, 14(11):207-218.
[17] HUHN J, JEFFREY P D, LARSEN K, et al. A structural basis for the reduced toxicity of dinophysistoxin-2[J]. Chemical Research in Toxicology, 2009, 22(11):1 782-1 786.
[18] Wang Juan, Wang Yuyu, Gao Yue, et al. Quantitative proteomic analysis of okadaic acid treated mouse small intestines reveals differentially expressed proteins involved in diarrhetic shellfish poisoning[J]. Journal of Proteomics, 2012, 75(7):2 038-2 052.
[19] ANDRES C V, JUAN A R, AMPARO A, et al. Oral toxicity of okadaic acid in Mice:study of lethality, organ damage, distribution and effects on detoxifying gene expression[J]. Toxins, 2013, 5(11):2 093-2 108.
[20] HODAKA S. Influence of body weight of mice on the susceptibility to okadaic acid, a diarrhetic shellfish poisoning toxin[J].Food Additives&Contaminants Part A Chemistry Analysis Control Exposure&Risk Assessment, 2014, 31(4):719-722.
[21] LANGE S, ANDERSSON G L, JENNISHE E, et al. Okadaic acid produces drastic histopathologic changes of the rat intestinal mucosa and with concomitant hypersecretion[C]//Toxic Marine Phytoplankton. Amsterdam:Elsevier, 1990:356-361.
[22] TUBARO A, SOSA S, BORNANCIN A, et al. Pharmacology and toxicology of diarrheic shellfish toxin s[C]//In Seafood and Freshwater Toxins. Boca Raton:CRC Press, 2008:229-253.
[23] BERVEN G, SEATRE F, HALVORSON K, et al. Effect of diarrhetic shellfish toxin, okadaic acid, on cytoskeletal element,viability and functionality of rat liver and intestinal cells[J]. Toxicon, 2001, 39(2-3):349-362.
[24] AUNE T, LARSEN S, SATAKE M, et al. Relative toxicity of dinophysistoxin-2(DTX-2)compared with okadaic acid, based on acute intraperitoneal toxicity in mice[J]. Toxicon, 2007, 49(1):1-7.
[25] YASUMOTO T, MURATA M. Polyeter toxin involved in seafood poisonin g[C]//American Chemical Society. Washington DC:ACS Symposium Series, 1990:120-132.
[26] TUBARO A, SOSA S, CARBONATTO M, et al. Oral and intraperitoneal acute toxicity studies of yessotoxin and homoyessotoxins in mice[J]. Toxicon, 2007, 41(7):783-792.
[27] ITO E, YASUMOTO T, TAKAI A, et al. Investigation of the distribution and excretion of okadaic acid in mice using immunostaining method[J]. Toxicon, 2002, 40(2):159-165.
[28] LAGO J, SANTACLARA F, VIEITES J M, et al. Collapse of mitochondrial membrane potential and caspases activation are early events in okadaic acid-treated Caco-2 cells[J]. Toxicon, 2005, 46(6):579-586.
[29] LEIRA F, ALVAREZ C, VIEITES J M, et al. Study of cytoskeletal changes induced by okadaic acid in BE(2)-M17 cells by means of a quantitative fluorimetric microplate assay[J]. Toxicol, 2001, 15(4-5):277-282.
[30] CABADO A G M, LEIRA F, VIEYTES M R, et al. Cytoskeletal disruption is the key factor that triggers apoptosis in okadaic acid-treated neuroblastoma cells[J]. Archives of Toxicology, 2004, 78(2):74-85.
[31] LEIRA F, LOUZAO M C, VIEITES J M, et al. Fluorescent microplate cell assay to measure uptake and metabolism of glucose in normal human lung fibroblasts[J]. Toxicology in Vitro, 2002, 16(3):267-273.
[32] RIORDAN F A, FORONI L, HOFFBRAND A V, et al. Okadaic acid-induced apoptosis of HL60 leukemia cells is preceded by destabilization of bcl-2 mRNA and downregulation of bcl-2 protein[J]. FEBS Letters, 1998, 435(2/3):195-198.
[33] ROSSINI G P, SGARBI N, MALAGUTI C. The toxic responses induced by okadaic acid involve processing of multiple caspase isoforms[J]. Toxicon, 2001, 39(6):763-770.
[34] VALDIGLESIAS V, PASARO E, MENDEZ J, et al. Okadaic Acid:More than a Diarrheic Toxin[J]. Marine Drugs, 2013, 11(11):4 328-4 349.
[35] OKADA T,NARAI A,MATSUNAGA S, et al. Assessment of the marine toxins by monitoring the integrity of human intestinal Caco-2 cell monolayers[J]. Toxicology in Vitro, 2000, 14(3):219-226.
[36] ROMASHKO A A, YOUNG M R. Protein phosphatase-2A maintains focal adhesion complexes in keratinocytes and the loss of this regulation in squamous cell carcinomas[J]. Clinical and Experimental Metastasis, 2004, 21(4):371-379.
[37] AO Lin, LIU Jinyi, GAO Lihong, et al. Differential expression of genes associated with cell proliferation and apoptosis induced by okadaic acid during the transformation process of BALB/c 3T3 cells[J]. Toxicology in vitro, 2008, 22(1):116-127.
[38] FIEBER L A, GREER J B, GUO F, et al. Gene expression profiling of human liver carcinoma(HEPG2)cells exposed to the marine toxin okadaic acid[J]. Toxicological&Environmental Chemistry Reviews, 2012, 94(9):1 805-1 821.
[39]陈洋,颜天,于仁成,等. OA对人肝细胞HL-7702和肝癌细胞Bel-7402增殖的影响和对细胞凋亡的诱导作用研究[J].中山大学学报(自然科学版), 2008, 47(5):86-92.
[40] SOLINO L, SUREDA F X, DIOGENE J. Evaluation of okadaic acid, dinophysistoxin-1 and dinophysistoxin-2 toxicity on Neuro-2a, NG108-15 and MCF-7 cell lines[J]. Toxicology in Vitro An International Journal Published in Association with Bibra, 2015, 29(1):59-62.
[41] HEGARAT L, PUECH V, FESSARD J M, et al. Aneugenic potential of okadaic acid revealed by the micronucleus assay combined with the FISH technique in CHO-K1 cells[J]. Mutagenesis, 2003, 18(3):293-298.
[42] FESSARD V, GROSSE A Y, PFOHL-LESZKOWICZ S, et al. Okadaic acid treatment induces DNA adduct formation in BHK21 C13 fibroblasts and HESV keratinocytes[J]. Mutation Research, 1996, 361(2/3):133-141.
[43] NAKAGAMA H, KANEKO S, SHIMA H, et al. Induction of Minisatellite Mutation in NIH 3T3 Cells by Treatment with the Tumor Promoter Okadaic Acid[J]. Proceedings of the National Academy of Sciences of the United States of America, 1997, 94(20):10 813-10 816.
[44] PINTO S C, CATIA R, SERGE M, et al. Comparative study of domoic acid and okadaic acid induced-chromosomal abnormalities in the CACO-2 cell line[J]. International Journal of Environmental Research&Public Health, 2006, 3(1):4-10.
[45] HEGARAT L, FESSARD V, DRAGACCI S, et al. Marine toxin okadaic acid induces aneuploidy in CHO-K1 cells in presence of rat liver postmitochondrial fraction, revealed by cytokinesis-block micronucleus assay coupled to FIS H[J]. Environmental toxicology, 2010, 19(2):123-128.
[46] VALDIGLESIAS V, PASARO E, MENDEZ L B, et al. Assays to determine the DNA repair ability[J]. Journal of toxicology and environmetal health, 2011, 74(15/16):1 094-1 109.
[47] VALDIGLESIAS V, MENDEZ J, PASARO E, et al. Assessment of okadaic acid effects on cytotoxicity, DNA damage and DNA repair in human cells[J]. Mutation Research, 2010, 689(1/2):74-79.
[48] ARIAS C, SHARMA N, DAVIES P, et al. Okadaic acid induces early changes in microtubule-associated protein 2 and tau phosphorylation prior to neurodegeneration in cultured cortical neurons[J]. Journal of Neurochemistry, 1993, 61(2):673-682.
[49] NUYDENS R, HEERS C, JONG M D, et al. Okadaic acid-induced apoptosis in neuronal cells, evidence for an abortive mitotic attempt[J]. Journal of neurochemistry, 1998, 70(3):1 124-1 133.
[50] FERNANDEZ M T, ZITKO V, GASCON S, NOVELLI A. The marine toxin okadaic acid is a potent neurotoxin for cultured cerebellar neurons[J]. Life Sciences, 1991, 49(19):157-162.
[51] VALDIGLESIAS V, FERNANDEZTAJES J, PASARO E, et al. Identification of differentially expressed genes in SHSY5Y cells exposed to okadaic acid by suppression subtractive hybridization[J]. Bmc Genomics, 2012, 13(1):46.
[52] KAMAT P K, TOTA S, NATH C, et al. A study on neuroinflammatory marker in brain areas of okadaic acid(ICV)induced memory impaired rats[J]. Life Sciences, 2012, 90(19/20):713-720.
[53] ARIAS C, BECERRA-GARCIA F, ARRIETA I, et al. The protein phosphatase inhibitor okadaic acid induces heat shock protein expression and neurodegeneration in rat hippocampus in vivo[J]. Experimental Neurology, 1998, 153(2):242-254.
[54] KAMAT P K, RAI S, SWARNKAR S, et al. Okadaic acid-induced tau phosphorylation in rat brain:role of NMDA receptor[J].Neuroscience, 2013, 238(2):97-113.
[55] COSTA A P, TRAMONTINA A C, BIASIBETTI R, et al. Neuroglial alterations in rats submitted to the okadaic acid-induced model of dementia[J]. Behavioral Brain Research, 2012, 226(2):420-427.
[56] PRADIP K, SHIVIKA R, CHANDISHWAR N. Okadaic acid induced neurotoxicity:An emerging tool to study Alzheimer’s disease pathology[J]. NeuroToxicology, 2013, 37:163-172.
[57] CHI C, GIRI S S, JUN J W, et al. Marine Toxin Okadaic Acid Affects the Immune Function of Bay Scallop(Argopecten irradians)[J]. Molecules, 2016, 21(9):1 108.
[58] MARTN-LPEZ A, GALLARDO-RODRGUEZ J J, SNCHEZ-MIRN A, et al. Cytotoxicity of yessotoxin and okadaic acid in mouse T lymphocyte cell line EL-4[J]. Toxicon, 2012, 60(6):1 049-1 056.
[59] FRANCHINIA A, MARCHESINI E, POLETTI R, et al. Swiss mice CD1 fed on mussels contaminated by okadaic acid and yessotoxins:Effects on thymus and spleen[J]. Eourpean journal of histochemistry, 2005, 49(2):179-188.
[2] ALEXANDER J, BENFORD D, COCKBURN A, et al. Marine biotoxins in shellfish-pectenotoxin group[J]. EFSA Journal, 2009,1109(7):1-47.
[3]江涛,江天久.贝类体内麻痹性贝类毒素的提取方法研究[J].分析化学, 2008, 36(11):1 460-1 464.
[4] SUZUKI T, QUILLIAM A M. LC-MS/MS analysis of diarrhetic shellfish poisoning(DSP)toxins, okadaic acid and dinophysistoxin analogues, and other lipophilic toxins[J]. Anaytical Sciences, 2011, 27(6):571-584.
[5] BLANCO J, ARVALO F, CORREA J, et al. Effect of the industrial steaming on the toxicity, estimated by LC-MS/MS, of mussels exposed for a long time to diarrhetic shellfish poisoning(DSP)toxins[J]. Food Chemistry, 2015, 177(103):240-247.
[6] LI Aifeng, MA Jinggang, Cao Jijuan, et al. Toxins in mussels(Mytilus galloprovincialis)associated with diarrhetic shellfish poisoning episodes in China[J]. Toxicon, 2012, 60(3):420-425.
[7] LI Aifeng, Yu Rencheng, Li Jun, et al. Protein phosphatase inhibition assay for detection of diarrhetic shellfish poison in oyster[J]. Chinese Journal of Analytical Chenistry, 2006, 34(3):283-287.
[8] MUNDAY R, REEVE J. Risk assessment of shellfish toxins[J]. Toxins, 2013, 5(11):2 019-2 037.
[9]郭萌萌,吴海燕,李兆新,等.基于聚硫堇/亚甲基蓝和纳米金放大的免疫传感器检测贝类毒素大田软海绵酸[J].分析测试学报, 2014, 33(2):161-166.
[10] BIALOJAN C, TAKAI A. Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases. Specificity and kinetics[J]. The Biochemical Journal, 1988, 256(1):283-290.
[11] REX M. Is protein phosphatase inhibition responsible for the toxic effects of okadaic acid in animals[J]. Toxins, 2013, 5(2):267-285.
[12] ZHANG Z, SIMPKINS J W. An okadaic acid-induced model of tauopathy and cognitive deficiency[J]. Brain Research, 2010,1359(3):233-246.
[13] BALLATORE C, BRUNDEN K R, HURYN D M, et al. Microtubule stabilizing agents as potential treatment for Alzheimer’s disease and related neurodegenerative tauopathies[J]. Medical Chemistry, 2012, 55(21):8 979-8 996.
[14] HONKANAN R E, CODISPOTI B A, TSE K, et al. Characterization of natural toxins with inhibitory activity against serine/threonine protein phosphatases[J]. Toxicon, 1994, 32(3):339-350.
[15] TAKAI A, MURATA M, TORIGOE K, et al. Inhibitory effect of okadaic acid derivatives on protein phosphatases. A study on structure-affinity relationship[J]. Biochemical Journal, 1992, 284(Pt 2)(2):539-544.
[16] MICHAEL J T, GREGORY J D, PANG Y, et al. Structure-Activity Relationship Studies Using Natural and Synthetic Okadaic Acid/Dinophysistoxin Toxins[J]. Marine Drugs, 2016, 14(11):207-218.
[17] HUHN J, JEFFREY P D, LARSEN K, et al. A structural basis for the reduced toxicity of dinophysistoxin-2[J]. Chemical Research in Toxicology, 2009, 22(11):1 782-1 786.
[18] Wang Juan, Wang Yuyu, Gao Yue, et al. Quantitative proteomic analysis of okadaic acid treated mouse small intestines reveals differentially expressed proteins involved in diarrhetic shellfish poisoning[J]. Journal of Proteomics, 2012, 75(7):2 038-2 052.
[19] ANDRES C V, JUAN A R, AMPARO A, et al. Oral toxicity of okadaic acid in Mice:study of lethality, organ damage, distribution and effects on detoxifying gene expression[J]. Toxins, 2013, 5(11):2 093-2 108.
[20] HODAKA S. Influence of body weight of mice on the susceptibility to okadaic acid, a diarrhetic shellfish poisoning toxin[J].Food Additives&Contaminants Part A Chemistry Analysis Control Exposure&Risk Assessment, 2014, 31(4):719-722.
[21] LANGE S, ANDERSSON G L, JENNISHE E, et al. Okadaic acid produces drastic histopathologic changes of the rat intestinal mucosa and with concomitant hypersecretion[C]//Toxic Marine Phytoplankton. Amsterdam:Elsevier, 1990:356-361.
[22] TUBARO A, SOSA S, BORNANCIN A, et al. Pharmacology and toxicology of diarrheic shellfish toxin s[C]//In Seafood and Freshwater Toxins. Boca Raton:CRC Press, 2008:229-253.
[23] BERVEN G, SEATRE F, HALVORSON K, et al. Effect of diarrhetic shellfish toxin, okadaic acid, on cytoskeletal element,viability and functionality of rat liver and intestinal cells[J]. Toxicon, 2001, 39(2-3):349-362.
[24] AUNE T, LARSEN S, SATAKE M, et al. Relative toxicity of dinophysistoxin-2(DTX-2)compared with okadaic acid, based on acute intraperitoneal toxicity in mice[J]. Toxicon, 2007, 49(1):1-7.
[25] YASUMOTO T, MURATA M. Polyeter toxin involved in seafood poisonin g[C]//American Chemical Society. Washington DC:ACS Symposium Series, 1990:120-132.
[26] TUBARO A, SOSA S, CARBONATTO M, et al. Oral and intraperitoneal acute toxicity studies of yessotoxin and homoyessotoxins in mice[J]. Toxicon, 2007, 41(7):783-792.
[27] ITO E, YASUMOTO T, TAKAI A, et al. Investigation of the distribution and excretion of okadaic acid in mice using immunostaining method[J]. Toxicon, 2002, 40(2):159-165.
[28] LAGO J, SANTACLARA F, VIEITES J M, et al. Collapse of mitochondrial membrane potential and caspases activation are early events in okadaic acid-treated Caco-2 cells[J]. Toxicon, 2005, 46(6):579-586.
[29] LEIRA F, ALVAREZ C, VIEITES J M, et al. Study of cytoskeletal changes induced by okadaic acid in BE(2)-M17 cells by means of a quantitative fluorimetric microplate assay[J]. Toxicol, 2001, 15(4-5):277-282.
[30] CABADO A G M, LEIRA F, VIEYTES M R, et al. Cytoskeletal disruption is the key factor that triggers apoptosis in okadaic acid-treated neuroblastoma cells[J]. Archives of Toxicology, 2004, 78(2):74-85.
[31] LEIRA F, LOUZAO M C, VIEITES J M, et al. Fluorescent microplate cell assay to measure uptake and metabolism of glucose in normal human lung fibroblasts[J]. Toxicology in Vitro, 2002, 16(3):267-273.
[32] RIORDAN F A, FORONI L, HOFFBRAND A V, et al. Okadaic acid-induced apoptosis of HL60 leukemia cells is preceded by destabilization of bcl-2 mRNA and downregulation of bcl-2 protein[J]. FEBS Letters, 1998, 435(2/3):195-198.
[33] ROSSINI G P, SGARBI N, MALAGUTI C. The toxic responses induced by okadaic acid involve processing of multiple caspase isoforms[J]. Toxicon, 2001, 39(6):763-770.
[34] VALDIGLESIAS V, PASARO E, MENDEZ J, et al. Okadaic Acid:More than a Diarrheic Toxin[J]. Marine Drugs, 2013, 11(11):4 328-4 349.
[35] OKADA T,NARAI A,MATSUNAGA S, et al. Assessment of the marine toxins by monitoring the integrity of human intestinal Caco-2 cell monolayers[J]. Toxicology in Vitro, 2000, 14(3):219-226.
[36] ROMASHKO A A, YOUNG M R. Protein phosphatase-2A maintains focal adhesion complexes in keratinocytes and the loss of this regulation in squamous cell carcinomas[J]. Clinical and Experimental Metastasis, 2004, 21(4):371-379.
[37] AO Lin, LIU Jinyi, GAO Lihong, et al. Differential expression of genes associated with cell proliferation and apoptosis induced by okadaic acid during the transformation process of BALB/c 3T3 cells[J]. Toxicology in vitro, 2008, 22(1):116-127.
[38] FIEBER L A, GREER J B, GUO F, et al. Gene expression profiling of human liver carcinoma(HEPG2)cells exposed to the marine toxin okadaic acid[J]. Toxicological&Environmental Chemistry Reviews, 2012, 94(9):1 805-1 821.
[39]陈洋,颜天,于仁成,等. OA对人肝细胞HL-7702和肝癌细胞Bel-7402增殖的影响和对细胞凋亡的诱导作用研究[J].中山大学学报(自然科学版), 2008, 47(5):86-92.
[40] SOLINO L, SUREDA F X, DIOGENE J. Evaluation of okadaic acid, dinophysistoxin-1 and dinophysistoxin-2 toxicity on Neuro-2a, NG108-15 and MCF-7 cell lines[J]. Toxicology in Vitro An International Journal Published in Association with Bibra, 2015, 29(1):59-62.
[41] HEGARAT L, PUECH V, FESSARD J M, et al. Aneugenic potential of okadaic acid revealed by the micronucleus assay combined with the FISH technique in CHO-K1 cells[J]. Mutagenesis, 2003, 18(3):293-298.
[42] FESSARD V, GROSSE A Y, PFOHL-LESZKOWICZ S, et al. Okadaic acid treatment induces DNA adduct formation in BHK21 C13 fibroblasts and HESV keratinocytes[J]. Mutation Research, 1996, 361(2/3):133-141.
[43] NAKAGAMA H, KANEKO S, SHIMA H, et al. Induction of Minisatellite Mutation in NIH 3T3 Cells by Treatment with the Tumor Promoter Okadaic Acid[J]. Proceedings of the National Academy of Sciences of the United States of America, 1997, 94(20):10 813-10 816.
[44] PINTO S C, CATIA R, SERGE M, et al. Comparative study of domoic acid and okadaic acid induced-chromosomal abnormalities in the CACO-2 cell line[J]. International Journal of Environmental Research&Public Health, 2006, 3(1):4-10.
[45] HEGARAT L, FESSARD V, DRAGACCI S, et al. Marine toxin okadaic acid induces aneuploidy in CHO-K1 cells in presence of rat liver postmitochondrial fraction, revealed by cytokinesis-block micronucleus assay coupled to FIS H[J]. Environmental toxicology, 2010, 19(2):123-128.
[46] VALDIGLESIAS V, PASARO E, MENDEZ L B, et al. Assays to determine the DNA repair ability[J]. Journal of toxicology and environmetal health, 2011, 74(15/16):1 094-1 109.
[47] VALDIGLESIAS V, MENDEZ J, PASARO E, et al. Assessment of okadaic acid effects on cytotoxicity, DNA damage and DNA repair in human cells[J]. Mutation Research, 2010, 689(1/2):74-79.
[48] ARIAS C, SHARMA N, DAVIES P, et al. Okadaic acid induces early changes in microtubule-associated protein 2 and tau phosphorylation prior to neurodegeneration in cultured cortical neurons[J]. Journal of Neurochemistry, 1993, 61(2):673-682.
[49] NUYDENS R, HEERS C, JONG M D, et al. Okadaic acid-induced apoptosis in neuronal cells, evidence for an abortive mitotic attempt[J]. Journal of neurochemistry, 1998, 70(3):1 124-1 133.
[50] FERNANDEZ M T, ZITKO V, GASCON S, NOVELLI A. The marine toxin okadaic acid is a potent neurotoxin for cultured cerebellar neurons[J]. Life Sciences, 1991, 49(19):157-162.
[51] VALDIGLESIAS V, FERNANDEZTAJES J, PASARO E, et al. Identification of differentially expressed genes in SHSY5Y cells exposed to okadaic acid by suppression subtractive hybridization[J]. Bmc Genomics, 2012, 13(1):46.
[52] KAMAT P K, TOTA S, NATH C, et al. A study on neuroinflammatory marker in brain areas of okadaic acid(ICV)induced memory impaired rats[J]. Life Sciences, 2012, 90(19/20):713-720.
[53] ARIAS C, BECERRA-GARCIA F, ARRIETA I, et al. The protein phosphatase inhibitor okadaic acid induces heat shock protein expression and neurodegeneration in rat hippocampus in vivo[J]. Experimental Neurology, 1998, 153(2):242-254.
[54] KAMAT P K, RAI S, SWARNKAR S, et al. Okadaic acid-induced tau phosphorylation in rat brain:role of NMDA receptor[J].Neuroscience, 2013, 238(2):97-113.
[55] COSTA A P, TRAMONTINA A C, BIASIBETTI R, et al. Neuroglial alterations in rats submitted to the okadaic acid-induced model of dementia[J]. Behavioral Brain Research, 2012, 226(2):420-427.
[56] PRADIP K, SHIVIKA R, CHANDISHWAR N. Okadaic acid induced neurotoxicity:An emerging tool to study Alzheimer’s disease pathology[J]. NeuroToxicology, 2013, 37:163-172.
[57] CHI C, GIRI S S, JUN J W, et al. Marine Toxin Okadaic Acid Affects the Immune Function of Bay Scallop(Argopecten irradians)[J]. Molecules, 2016, 21(9):1 108.
[58] MARTN-LPEZ A, GALLARDO-RODRGUEZ J J, SNCHEZ-MIRN A, et al. Cytotoxicity of yessotoxin and okadaic acid in mouse T lymphocyte cell line EL-4[J]. Toxicon, 2012, 60(6):1 049-1 056.
[59] FRANCHINIA A, MARCHESINI E, POLETTI R, et al. Swiss mice CD1 fed on mussels contaminated by okadaic acid and yessotoxins:Effects on thymus and spleen[J]. Eourpean journal of histochemistry, 2005, 49(2):179-188.