卡培他滨对非靶标生物斑马鱼胚胎的发育毒性研究
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摘要
为评价抗肿瘤药物卡培他滨(CAP)对非靶标生物的毒性,以斑马鱼胚胎为受试生物,研究了CAP对斑马鱼胚胎的发育毒性及对其抗氧化酶系的影响。结果表明,直接暴露于卡培他滨中,造成斑马鱼胚胎死亡率和畸形率增加,且其机能有所下降。当暴露浓度高于20μg·L~(-1)时,处理后的斑马鱼胚胎死亡率和畸形率显著升高,与对照组相比有极显著差异。CAP浓度为0.2μg·L~(-1)时,超氧化物歧化酶(SOD)活性和过氧化氢酶(CAT)活性均显著升高,表明机体遭受一定程度的氧化损伤;当浓度高于20μg·L~(-1)时, SOD和CAT活性显著降低,表明斑马鱼仔鱼所受氧化损伤超出其自我修复能力,引发致死性伤害。本文从发育毒性及氧化应激着手,探究了CAP对非靶标生物的潜在危害,为其生态效应提供一定的科学依据。
To investigate the deleterious effects of Capecitabine(CAP) on non-target aquatic organisms, the developmental toxicity of CAP to zebrafish embryos and its effects on the antioxidant enzymes of zebrafish fry were studied. The exposure experiment showed that CAP could cause death and deformity of zebrafish embryos. When the CAP exposure concentration was higher than 20 μg·L~(-1), the mortality rate and malformation rate of the treated embryos were significantly higher than those of the control. In antioxidant enzyme activities assays, results revealed that when exposure to 0.2 μg·L~(-1) CAP, the superoxide dismutase(SOD) and catalase(CAT) activities in zebrafish fry increased significantly(p < 0.05), implying that low concentration of CAP could trigger the oxidative stress response of zebrafish. When the CAP concentration was higher than 20 μg·L~(-1), the SOD and CAT activities greatly decreased, indicating that the oxidative damage caused by CAP exceeded the restoration capability of zebrafish larvae and caused fatal injuries. In this paper, the developmental toxicity and oxidative stress were used to explore the potential hazards of CAP on the non-target organisms, and to provide a scientific basis for its ecological effects.
To investigate the deleterious effects of Capecitabine(CAP) on non-target aquatic organisms, the developmental toxicity of CAP to zebrafish embryos and its effects on the antioxidant enzymes of zebrafish fry were studied. The exposure experiment showed that CAP could cause death and deformity of zebrafish embryos. When the CAP exposure concentration was higher than 20 μg·L~(-1), the mortality rate and malformation rate of the treated embryos were significantly higher than those of the control. In antioxidant enzyme activities assays, results revealed that when exposure to 0.2 μg·L~(-1) CAP, the superoxide dismutase(SOD) and catalase(CAT) activities in zebrafish fry increased significantly(p < 0.05), implying that low concentration of CAP could trigger the oxidative stress response of zebrafish. When the CAP concentration was higher than 20 μg·L~(-1), the SOD and CAT activities greatly decreased, indicating that the oxidative damage caused by CAP exceeded the restoration capability of zebrafish larvae and caused fatal injuries. In this paper, the developmental toxicity and oxidative stress were used to explore the potential hazards of CAP on the non-target organisms, and to provide a scientific basis for its ecological effects.
引文
[1] PETRELLI F, DI C S, LONATI V, et al. Vinorelbine with capecitabine, an evergreen doublet for advanced breast cancer:a systematic literature review and pooled-analysis of phase II-III studies[J]. Clinical Breast Cancer, 2016,16(5):327–334.
[2] BAZARBASHI S, OMAR A, ALJUBRAN A, et al.Pre-operative chemoradiotherapy using capecitabine and cetuximab followed by definitive surgery in patients with operable rectal cancer[J]. Hematology/oncology&Stem Cell Therapy, 2016, 9(4):147–153
[3] LAM S W, GUCHELAAR H J, BOVEN E. The role of pharmacogenetics in capecitabine efficacy and toxicity[J].Cancer Treatment Reviews, 2016, 50:9–22.
[4] SANTOS M S F, FRANQUET-GRIELL H, LACORTE S,et al. Anticancer drugs in Portuguese surface watersEstimation of concentrations and identification of potentially priority drugs[J]. Chemosphere, 2017, 184:1250–1260.
[5] ANDREU V, GIMENOGARC A E, PASCUAL J A, et al.Presence of pharmaceuticals and heavy metals in the waters of a Mediterranean coastal wetland:Potential interactions and the influence of the environment[J]. Science of the Total Environment, 2016, 540(Pt 1):278–286.
[6] OLALLA A, NEGREIRA N, LOPEZ DE ALDA M, et al. A case study to identify priority cytostatic contaminants in hospital effluents[J]. Chemosphere, 2018, 190:417–430.
[7] NEGREIRA N, DE ALDA M L, BARCEL D. Cytostatic drugs and metabolites in municipal and hospital wastewaters in Spain:Filtration, occurrence, and environmental risk[J]. Science of The Total Environment, 2014,497-498:68–77.
[8] PARRELLA A, LAVORGNA M, CRISCUOLO E, et al.Acute and chronic toxicity of six anticancer drugs on rotifers and crustaceans[J]. Chemosphere, 2014, 115:59–66.
[9] PARRELLA A, LAVORGNA M, CRISCUOLO E, et al.Eco-genotoxicity of six anticancer drugs using comet assay in daphnids[J]. J Hazard Mater, 2015, 286:573–580.
[10] MIMEAULT M, BATRA S K. Emergence of zebrafish models in oncology for validating novel anticancer drug targets and nanomaterials[J]. Drug Discovery Today, 2013,18(3-4):128–140.
[11] LIU Chenwei, XIONG Feng, JIA Huizhen, et al.Graphene-based anticancer nanosystem and its biosafety evaluation using a zebrafish model[J]. Biomacromolecules,2013, 14(2):358–366.
[12] TON C, LIN Yingxin, WILLETT C. Zebrafish as a model for developmental neurotoxicity testing[J]. Birth Defects Research Part A Clinical&Molecular Teratology, 2010,76(7):553–567.
[13] PARK C B, JANG J, KIM S, et al. Single-and mixture toxicity of three organic UV-filters, ethylhexyl methoxycinnamate, octocrylene, and avobenzone on Daphnia magna[J]. Ecotoxicology&Environmental Safety,2017, 137:57–63.
[14] ZHANG Chaojie, WILLETT C, FREMGEN T. Zebrafish:an animal model for toxicological studies[J]. Current Protocols in Toxicology, 2003, Chapter 1(Chapter 1):Unit1.7.
[15] TSANG M, TSANG M. Zebrafish:A tool for chemical screens[J]. Birth Defects Research(Part C):Embryo Today:Reviews, 2010, 90(3):185–192.
[16] YAN Zhengyu, YANG Qiulian, JIANG Weili, et al.Integrated toxic evaluation of sulfamethazine on zebrafish:Including two lifespan stages(embryo-larval and adult)and three exposure periods(exposure, post-exposure and re-exposure)[J]. Chemosphere, 2018, 195:784–792.
[17] LIN Tao, CHEN Yanqiu, CHEN Wei. Impact of toxicological properties of sulfonamides on the growth of zebrafish embryos in the water[J]. Environmental Toxicology&Pharmacology, 2013, 36(3):1068–1076.
[18] QUINTANEIRO C, PATR CIO D, NOVAIS S C, et al.Endocrine and physiological effects of linuron and S-metolachlor in zebrafish developing embryos[J]. Science of the Total Environment, 2017, 586:390–400.
[19] KOV CS R, CSENKI Z, BAKOS K, et al. Assessment of toxicity and genotoxicity of low doses of 5-fluorouracil in zebrafish(Danio rerio)two-generation study[J]. Water Research, 2015, 77:201–212.
[20] HRUBIK J, GLISIC B, SAMARDZIJA D, et al. Effect of PMA-induced protein kinase C activation on development and apoptosis in early zebrafish embryos[J]. Comparative Biochemistry&Physiology Part C Toxicology&Pharmacology, 2016, 190:24–31.
[21] YAN Lu, GONG Chenxue, ZHANG Xiaofeng, et al.Perturbation of metabonome of embryo/larvae zebrafish after exposure to fipronil[J]. Environmental Toxicology&Pharmacology, 2016, 48:39–45.
[22] WIEGAND C, PFLUGMACHER S, GIESE M, et al.Uptake, toxicity, and effects on detoxication enzymes of atrazine and trifluoroacetate in embryos of zebrafish[J].Ecotoxicology and environmental safety, 2000, 45(2):122–131.
[23] LIU Yanhua, GUO Ruixin, TANG Shengkai, et al. Single and mixture toxicities of BDE-47, 6-OH-BDE-47 and6-MeO-BDE-47 on the feeding activity of Daphnia magna:From behavior assessment to neurotoxicity[J].Chemosphere, 2018, 195:542–550.
[24] WAN Jinjin, GUO Peiyong, PENG Xiaofang, et al. Effect of erythromycin exposure on the growth, antioxidant system and photosynthesis of Microcystis flos-aquae[J].Journal of Hazardous Materials, 2015, 283:778–786.
[25] CUI Feng, CHAI Tingting, QIAN Le, et al. Effects of three diamides(chlorantraniliprole, cyantraniliprole and flubendiamide)on life history, embryonic development and oxidative stress biomarkers of Daphnia magna[J].Chemosphere, 2016, 169:107–116.
[26] PARLAK V. Evaluation of apoptosis, oxidative stress responses, AChE activity and body malformations in zebrafish(Danio rerio)embryos exposed to deltamethrin[J].Chemosphere, 2018, 207:397–403.
[2] BAZARBASHI S, OMAR A, ALJUBRAN A, et al.Pre-operative chemoradiotherapy using capecitabine and cetuximab followed by definitive surgery in patients with operable rectal cancer[J]. Hematology/oncology&Stem Cell Therapy, 2016, 9(4):147–153
[3] LAM S W, GUCHELAAR H J, BOVEN E. The role of pharmacogenetics in capecitabine efficacy and toxicity[J].Cancer Treatment Reviews, 2016, 50:9–22.
[4] SANTOS M S F, FRANQUET-GRIELL H, LACORTE S,et al. Anticancer drugs in Portuguese surface watersEstimation of concentrations and identification of potentially priority drugs[J]. Chemosphere, 2017, 184:1250–1260.
[5] ANDREU V, GIMENOGARC A E, PASCUAL J A, et al.Presence of pharmaceuticals and heavy metals in the waters of a Mediterranean coastal wetland:Potential interactions and the influence of the environment[J]. Science of the Total Environment, 2016, 540(Pt 1):278–286.
[6] OLALLA A, NEGREIRA N, LOPEZ DE ALDA M, et al. A case study to identify priority cytostatic contaminants in hospital effluents[J]. Chemosphere, 2018, 190:417–430.
[7] NEGREIRA N, DE ALDA M L, BARCEL D. Cytostatic drugs and metabolites in municipal and hospital wastewaters in Spain:Filtration, occurrence, and environmental risk[J]. Science of The Total Environment, 2014,497-498:68–77.
[8] PARRELLA A, LAVORGNA M, CRISCUOLO E, et al.Acute and chronic toxicity of six anticancer drugs on rotifers and crustaceans[J]. Chemosphere, 2014, 115:59–66.
[9] PARRELLA A, LAVORGNA M, CRISCUOLO E, et al.Eco-genotoxicity of six anticancer drugs using comet assay in daphnids[J]. J Hazard Mater, 2015, 286:573–580.
[10] MIMEAULT M, BATRA S K. Emergence of zebrafish models in oncology for validating novel anticancer drug targets and nanomaterials[J]. Drug Discovery Today, 2013,18(3-4):128–140.
[11] LIU Chenwei, XIONG Feng, JIA Huizhen, et al.Graphene-based anticancer nanosystem and its biosafety evaluation using a zebrafish model[J]. Biomacromolecules,2013, 14(2):358–366.
[12] TON C, LIN Yingxin, WILLETT C. Zebrafish as a model for developmental neurotoxicity testing[J]. Birth Defects Research Part A Clinical&Molecular Teratology, 2010,76(7):553–567.
[13] PARK C B, JANG J, KIM S, et al. Single-and mixture toxicity of three organic UV-filters, ethylhexyl methoxycinnamate, octocrylene, and avobenzone on Daphnia magna[J]. Ecotoxicology&Environmental Safety,2017, 137:57–63.
[14] ZHANG Chaojie, WILLETT C, FREMGEN T. Zebrafish:an animal model for toxicological studies[J]. Current Protocols in Toxicology, 2003, Chapter 1(Chapter 1):Unit1.7.
[15] TSANG M, TSANG M. Zebrafish:A tool for chemical screens[J]. Birth Defects Research(Part C):Embryo Today:Reviews, 2010, 90(3):185–192.
[16] YAN Zhengyu, YANG Qiulian, JIANG Weili, et al.Integrated toxic evaluation of sulfamethazine on zebrafish:Including two lifespan stages(embryo-larval and adult)and three exposure periods(exposure, post-exposure and re-exposure)[J]. Chemosphere, 2018, 195:784–792.
[17] LIN Tao, CHEN Yanqiu, CHEN Wei. Impact of toxicological properties of sulfonamides on the growth of zebrafish embryos in the water[J]. Environmental Toxicology&Pharmacology, 2013, 36(3):1068–1076.
[18] QUINTANEIRO C, PATR CIO D, NOVAIS S C, et al.Endocrine and physiological effects of linuron and S-metolachlor in zebrafish developing embryos[J]. Science of the Total Environment, 2017, 586:390–400.
[19] KOV CS R, CSENKI Z, BAKOS K, et al. Assessment of toxicity and genotoxicity of low doses of 5-fluorouracil in zebrafish(Danio rerio)two-generation study[J]. Water Research, 2015, 77:201–212.
[20] HRUBIK J, GLISIC B, SAMARDZIJA D, et al. Effect of PMA-induced protein kinase C activation on development and apoptosis in early zebrafish embryos[J]. Comparative Biochemistry&Physiology Part C Toxicology&Pharmacology, 2016, 190:24–31.
[21] YAN Lu, GONG Chenxue, ZHANG Xiaofeng, et al.Perturbation of metabonome of embryo/larvae zebrafish after exposure to fipronil[J]. Environmental Toxicology&Pharmacology, 2016, 48:39–45.
[22] WIEGAND C, PFLUGMACHER S, GIESE M, et al.Uptake, toxicity, and effects on detoxication enzymes of atrazine and trifluoroacetate in embryos of zebrafish[J].Ecotoxicology and environmental safety, 2000, 45(2):122–131.
[23] LIU Yanhua, GUO Ruixin, TANG Shengkai, et al. Single and mixture toxicities of BDE-47, 6-OH-BDE-47 and6-MeO-BDE-47 on the feeding activity of Daphnia magna:From behavior assessment to neurotoxicity[J].Chemosphere, 2018, 195:542–550.
[24] WAN Jinjin, GUO Peiyong, PENG Xiaofang, et al. Effect of erythromycin exposure on the growth, antioxidant system and photosynthesis of Microcystis flos-aquae[J].Journal of Hazardous Materials, 2015, 283:778–786.
[25] CUI Feng, CHAI Tingting, QIAN Le, et al. Effects of three diamides(chlorantraniliprole, cyantraniliprole and flubendiamide)on life history, embryonic development and oxidative stress biomarkers of Daphnia magna[J].Chemosphere, 2016, 169:107–116.
[26] PARLAK V. Evaluation of apoptosis, oxidative stress responses, AChE activity and body malformations in zebrafish(Danio rerio)embryos exposed to deltamethrin[J].Chemosphere, 2018, 207:397–403.
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