邻苯二甲酸二丁酯对KM小鼠神经行为学的影响及芒果苷的拮抗作用
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摘要
探究邻苯二甲酸二丁酯(DBP)对小鼠神经行为学影响的剂量-反应关系,以及芒果苷(MAG)的拮抗作用。36只性成熟雄性KM小鼠随机分为4组:(1)生理盐水组,(2) 5 mg·kg~(-1)DBP组,(3) 25 mg·kg~(-1)DBP组,(4)125 mg·kg~(-1)DBP组,实验周期28d。应用国际通用的高架十字迷宫(EPM)和旷场实验(OFT)检测DBP暴露后KM小鼠的神经行为学变化;通过脑组织病理学切片,检测KM小鼠的靶组织脑海马CA1区病理变化;通过测定活性氧(ROS)、谷胱甘肽(GSH)、丙二醛(MDA)、DNA-蛋白质交联系数(DPC),检测KM小鼠的脑海马组织氧化损伤水平。以MAG作为抗氧化剂,36只KM小鼠随机分为4组:(1)生理盐水组,(2) 50 mg·kg~(-1)MAG组;(3) 125 mg·kg~(-1)DBP组;(4) MAG+DBP组,进行神经行为测试,同时评估各组KM小鼠脑海马组织氧化损伤。与对照组比较,随着DBP暴露剂量的升高,125 mg·kg~(-1)DBP组KM小鼠进入开放臂次数减少,停留时间偏短,运动距离较短,运动轨迹偏离中央区域;脑海马CA1区锥体神经细胞排列紊乱,细胞形态肿胀变形,树突缩短甚至消失;且脑系数下降,ROS、MDA含量及DPC系数逐渐上升,GSH含量逐渐降低,且差异均有统计学意义(P<0.05, P<0.01);加入拮抗剂MAG处理后,与125 mg·kg~(-1)DBP组比较,MAG+DBP组小鼠神经行为学出现一定程度的缓解,脑海马CA1区病理程度减轻,脑系数上升,ROS、MDA含量及DPC系数出现一定程度的下降,GSH含量出现一定程度的上升,且差异均有统计学意义(P<0.05, P<0.01)。DBP所致小鼠的神经行为学变化可能与脑海马组织的氧化损伤有关; MAG可通过降低小鼠脑组织氧化应激水平,对DBP暴露所致的小鼠神经行为学影响起到一定的保护作用。
To explore the dose-dependent effects of dibutyl phthalate(DBP) on neurobehavior of laboratory mice as well as the antagonistic effect of mangiferin(MAG), male Kunming mice were treated with saline(control), 5 mg·kg~(-1) DBP, 25 mg·kg~(-1) DBP, and 125 mg·kg~(-1) DBP lasted for 28 days(n = 9 for each group). The neurobehavioral changes of KM mice after DBP exposure were evaluated by elevated maze plus maze(EPM) and open field test(OFT), and the pathological changes in the hippocampal CA1 region of Kunming mice were examined by sectioning and H&E staining. Reactive oxygen species(ROS), glutathione(GSH), malondialdehyde(MDA), and DNA-protein crosslinking coefficient(DPC) were also measured in brain tissues of Kunming mice. In addition,Kunming mice were also treated with 50 mg·kg~(-1) MAG, 125 mg·kg~(-1) DBP and 50 mg·kg~(-1) MAG+125 mg·kg~(-1) DBP(MAG+DBP) to evaluate the protective effects of MAG. Compared with the control group, the Kunming mice treated with 125 mg·kg~(-1) DBP group showed reduced number of entering the open arm, shorter staying time, decreased movement distance, and deviated movement track from the central region. The pyramidal neurons in the CA1 area of hippocampus were disordered, and the cell shape was swollen and deformed, as well as the dendrites were shortened or even disappeared. In addition, the contents of ROS, MDA and DPC coefficients increased gradually, whereas the GSH content decreased accordingly(P<0.05, P<0.01). After the treatment with antagonist MAG,the neurobehavioral changes, pathological degree of the CA1 area in the hippocampus of 50 mg·kg~(-1) MAG+125 mg·kg~(-1) DBP treated mice were alleviated compared with 125 mg·kg~(-1) DBP group, accompanied by increased brain organ coefficient. The values of ROS, MDA and DPC coefficient decreased, whereas the GSH content increased accordingly(P < 0.05, P < 0.01). The neurobehavioral changes of mice induced by DBP might be related with oxidative damage of hippocampus, whereas MAG may protect Kunming mice from DBP induced adverse neurobehavioral effects by reducing the oxidative stress in brains of mice.
To explore the dose-dependent effects of dibutyl phthalate(DBP) on neurobehavior of laboratory mice as well as the antagonistic effect of mangiferin(MAG), male Kunming mice were treated with saline(control), 5 mg·kg~(-1) DBP, 25 mg·kg~(-1) DBP, and 125 mg·kg~(-1) DBP lasted for 28 days(n = 9 for each group). The neurobehavioral changes of KM mice after DBP exposure were evaluated by elevated maze plus maze(EPM) and open field test(OFT), and the pathological changes in the hippocampal CA1 region of Kunming mice were examined by sectioning and H&E staining. Reactive oxygen species(ROS), glutathione(GSH), malondialdehyde(MDA), and DNA-protein crosslinking coefficient(DPC) were also measured in brain tissues of Kunming mice. In addition,Kunming mice were also treated with 50 mg·kg~(-1) MAG, 125 mg·kg~(-1) DBP and 50 mg·kg~(-1) MAG+125 mg·kg~(-1) DBP(MAG+DBP) to evaluate the protective effects of MAG. Compared with the control group, the Kunming mice treated with 125 mg·kg~(-1) DBP group showed reduced number of entering the open arm, shorter staying time, decreased movement distance, and deviated movement track from the central region. The pyramidal neurons in the CA1 area of hippocampus were disordered, and the cell shape was swollen and deformed, as well as the dendrites were shortened or even disappeared. In addition, the contents of ROS, MDA and DPC coefficients increased gradually, whereas the GSH content decreased accordingly(P<0.05, P<0.01). After the treatment with antagonist MAG,the neurobehavioral changes, pathological degree of the CA1 area in the hippocampus of 50 mg·kg~(-1) MAG+125 mg·kg~(-1) DBP treated mice were alleviated compared with 125 mg·kg~(-1) DBP group, accompanied by increased brain organ coefficient. The values of ROS, MDA and DPC coefficient decreased, whereas the GSH content increased accordingly(P < 0.05, P < 0.01). The neurobehavioral changes of mice induced by DBP might be related with oxidative damage of hippocampus, whereas MAG may protect Kunming mice from DBP induced adverse neurobehavioral effects by reducing the oxidative stress in brains of mice.
引文
[1] Smith K. Mental health:A world of depression[J]. Nature, 2014, 515(7526):180-181
[2]陈建新.慢性应激和氟西汀处理后对大鼠海马及前额叶星形胶质细胞谷氨酸转运体GLT-1表达的影响[D].武汉:武汉大学, 2015:1-7Chen J X. Effects of chronic unpredictable stress and fluoxetine on GLT-1 of astrocyte in rat hippocampus and prefrontal cortex[D]. Wuhan:Wuhan University, 2015:1-7(in Chinese)
[3] Mojtabai R, Olfson M, Han B. Nationaltrends in the prevalence and treatment of depression in adolescents and young adults[J]. Pediatrics, 2016, 138(6):e20161878
[4] Shiue I. Urinary heavy metals, phthalates and polyaromatic hydrocarbons independent of health events are associated with adult depression:USA NHANES, 2011-2012[J].Environmental Science&Pollution Research, 2015, 22(21):17095-17103
[5] Lee K S, Lim Y H, Kim K N, et al. Urinary phthalate metabolites concentrations and symptoms of depression in an elderly population[J]. Science of the Total Environment, 2018, 625:1191-1197
[6] Li X J, Jiang L, Chen L, et al. Neurotoxicity of dibutyl phthalate in brain development following perinatal exposure:A study in rats[J]. Environmental Toxicology&Pharmacology, 2013, 36(2):392-402
[7] Wojtowicz A K, Szychowski K A, Wnuk A, et al. Dibutyl phthalate(DBP)-induced apoptosis and neurotoxicity are mediated via the aryl hydrocarbon receptor(AhR)but not by estrogen receptor alpha(ERα), estrogen receptor beta(ERβ), or peroxisome proliferator-activated receptor gamma(PPARγ)in mouse cortical neurons[J]. Neurotoxicity Research, 2017, 31(1):77-89
[8] Engel S M, Amir M, Canfield R L, et al. Prenatalphthalate exposure is associated with childhood behavior and executive functioning[J]. Environmental Health Perspectives,2010, 118(4):565-571
[9] Xu X, Yang Y, Wang R, et al. Perinatal exposure to di-(2-ethylhexyl)phthalate affects anxiety-and depression-like behaviors in mice[J]. Chemosphere, 2015, 124(1):22
[10] Ma P, Liu X, Wu J, et al. Cognitive deficits and anxiety induced by diisononyl phthalate in mice and the neuroprotective effects of melatonin[J]. Scientific Report, 2015,5:14676
[11]黄潇,彭志刚.芒果苷药理作用研究概况[J].中国药师,2007, 10(1):73-74Huang X, Peng Z G. Studies on the pharmacological effects of mangiferin[J]. China Pharmacist, 2007, 10(1):73-74(in Chinese)
[12] Márquez L, Garcíabueno B, Madrigal J L, et al. Mangiferin decreases inflammation and oxidative damage in rat brain after stress[J]. European Journal of Nutrition,2012, 51(6):729-739
[13] Dimitrov M, Nikolova I, Benbasat N, et al. Acute toxicity,antidepressive and MAO inhibitory activity of mangiferin isolated from Hypericum aucheri[J]. Biotechnology&Biotechnological Equipment, 2011, 25(4):2668-2671
[14] Garc D, Escalante M, Delgado R, et al. Anthelminthic and antiallergic activities of Mangifera indica L. stem bark components Vimang and mangiferin[J]. Phytotherapy Research, 2003, 17(10):1203-1208
[15] Li Y F, Zhuang M Z, Li T, et al. Neurobehavioral toxicity study of dibutyl phthalate on rats following in utero and lactational exposure[J]. Journal of Applied Toxicology,2010, 29(7):603-611
[16] Zhou D, Wang H, Zhang J. Di-n-butyl phthalate(DBP)exposure induces oxidative stress in epididymis of adult rats[J]. Toxicology&Industrial Health, 2011, 27(1):413-419
[17] Aly H A, Hassan M H, Elbeshbishy H A, et al. Dibutyl phthalate induces oxidative stress and impairs spermatogenesis in adult rat[J]. Toxicology&Industrial Health,2015, 32(8):1467-1477
[18] Sahin E, Gümü爧lüS. Alterations in brain antioxidant status, protein oxidation and lipid peroxidation in response to different stress models[J]. Behavioural Brain Research,2004, 155(2):241-248
[19] Bilici M, Efe H, K9rogˇlu M A, et al. Antioxidative enzyme activities and lipid peroxidation in major depression:Alterations by antidepressant treatments[J]. Journal of Affective Disorders, 2001, 64(1):43-51
[20] Ng F, Berk M, Dean O, et al. Oxidative stress in psychiatric disorders:Evidence base and therapeutic implications[J]. International Journal of Neuropsychopharmacology,2008, 11(6):851-876
[21] Wang W Y, Pan L, Su S C, et al. Interaction of FUS and HDAC1 regulates DNA damage response and repair in neurons[J]. Nature Neuroscience, 2013, 16(10):1383-1391
[22] Ye X, Ji Z, Wei C, et al. Inhaled formaldehyde induces DNA-protein crosslinks and oxidative stress in bone marrow and other distant organs of exposed mice[J]. Environmental&Molecular Mutagenesis, 2013, 54(9):705-718
[23] Márquez L, García-Bueno B, Madrigal J L M, et al. Mangiferin decreases inflammation and oxidative damage in rat brain after stress[J]. European Journal of Nutrition,2012, 51(6):729-739
[24]王小伟,晏慧超,洪俊.芒果苷对神经病理性大鼠坐骨神经的保护作用[J].中国中西医结合外科杂志, 2018,24(1):69-73Wang X W, Yan H C, Hong J. Protective effects of mangiferin on partial sciatic nerve of neuropathic rats[J]. Chinese Journal of Surgery of Integrated Traditional and Western Medicine, 2018, 24(1):69-73(in Chinese)
[2]陈建新.慢性应激和氟西汀处理后对大鼠海马及前额叶星形胶质细胞谷氨酸转运体GLT-1表达的影响[D].武汉:武汉大学, 2015:1-7Chen J X. Effects of chronic unpredictable stress and fluoxetine on GLT-1 of astrocyte in rat hippocampus and prefrontal cortex[D]. Wuhan:Wuhan University, 2015:1-7(in Chinese)
[3] Mojtabai R, Olfson M, Han B. Nationaltrends in the prevalence and treatment of depression in adolescents and young adults[J]. Pediatrics, 2016, 138(6):e20161878
[4] Shiue I. Urinary heavy metals, phthalates and polyaromatic hydrocarbons independent of health events are associated with adult depression:USA NHANES, 2011-2012[J].Environmental Science&Pollution Research, 2015, 22(21):17095-17103
[5] Lee K S, Lim Y H, Kim K N, et al. Urinary phthalate metabolites concentrations and symptoms of depression in an elderly population[J]. Science of the Total Environment, 2018, 625:1191-1197
[6] Li X J, Jiang L, Chen L, et al. Neurotoxicity of dibutyl phthalate in brain development following perinatal exposure:A study in rats[J]. Environmental Toxicology&Pharmacology, 2013, 36(2):392-402
[7] Wojtowicz A K, Szychowski K A, Wnuk A, et al. Dibutyl phthalate(DBP)-induced apoptosis and neurotoxicity are mediated via the aryl hydrocarbon receptor(AhR)but not by estrogen receptor alpha(ERα), estrogen receptor beta(ERβ), or peroxisome proliferator-activated receptor gamma(PPARγ)in mouse cortical neurons[J]. Neurotoxicity Research, 2017, 31(1):77-89
[8] Engel S M, Amir M, Canfield R L, et al. Prenatalphthalate exposure is associated with childhood behavior and executive functioning[J]. Environmental Health Perspectives,2010, 118(4):565-571
[9] Xu X, Yang Y, Wang R, et al. Perinatal exposure to di-(2-ethylhexyl)phthalate affects anxiety-and depression-like behaviors in mice[J]. Chemosphere, 2015, 124(1):22
[10] Ma P, Liu X, Wu J, et al. Cognitive deficits and anxiety induced by diisononyl phthalate in mice and the neuroprotective effects of melatonin[J]. Scientific Report, 2015,5:14676
[11]黄潇,彭志刚.芒果苷药理作用研究概况[J].中国药师,2007, 10(1):73-74Huang X, Peng Z G. Studies on the pharmacological effects of mangiferin[J]. China Pharmacist, 2007, 10(1):73-74(in Chinese)
[12] Márquez L, Garcíabueno B, Madrigal J L, et al. Mangiferin decreases inflammation and oxidative damage in rat brain after stress[J]. European Journal of Nutrition,2012, 51(6):729-739
[13] Dimitrov M, Nikolova I, Benbasat N, et al. Acute toxicity,antidepressive and MAO inhibitory activity of mangiferin isolated from Hypericum aucheri[J]. Biotechnology&Biotechnological Equipment, 2011, 25(4):2668-2671
[14] Garc D, Escalante M, Delgado R, et al. Anthelminthic and antiallergic activities of Mangifera indica L. stem bark components Vimang and mangiferin[J]. Phytotherapy Research, 2003, 17(10):1203-1208
[15] Li Y F, Zhuang M Z, Li T, et al. Neurobehavioral toxicity study of dibutyl phthalate on rats following in utero and lactational exposure[J]. Journal of Applied Toxicology,2010, 29(7):603-611
[16] Zhou D, Wang H, Zhang J. Di-n-butyl phthalate(DBP)exposure induces oxidative stress in epididymis of adult rats[J]. Toxicology&Industrial Health, 2011, 27(1):413-419
[17] Aly H A, Hassan M H, Elbeshbishy H A, et al. Dibutyl phthalate induces oxidative stress and impairs spermatogenesis in adult rat[J]. Toxicology&Industrial Health,2015, 32(8):1467-1477
[18] Sahin E, Gümü爧lüS. Alterations in brain antioxidant status, protein oxidation and lipid peroxidation in response to different stress models[J]. Behavioural Brain Research,2004, 155(2):241-248
[19] Bilici M, Efe H, K9rogˇlu M A, et al. Antioxidative enzyme activities and lipid peroxidation in major depression:Alterations by antidepressant treatments[J]. Journal of Affective Disorders, 2001, 64(1):43-51
[20] Ng F, Berk M, Dean O, et al. Oxidative stress in psychiatric disorders:Evidence base and therapeutic implications[J]. International Journal of Neuropsychopharmacology,2008, 11(6):851-876
[21] Wang W Y, Pan L, Su S C, et al. Interaction of FUS and HDAC1 regulates DNA damage response and repair in neurons[J]. Nature Neuroscience, 2013, 16(10):1383-1391
[22] Ye X, Ji Z, Wei C, et al. Inhaled formaldehyde induces DNA-protein crosslinks and oxidative stress in bone marrow and other distant organs of exposed mice[J]. Environmental&Molecular Mutagenesis, 2013, 54(9):705-718
[23] Márquez L, García-Bueno B, Madrigal J L M, et al. Mangiferin decreases inflammation and oxidative damage in rat brain after stress[J]. European Journal of Nutrition,2012, 51(6):729-739
[24]王小伟,晏慧超,洪俊.芒果苷对神经病理性大鼠坐骨神经的保护作用[J].中国中西医结合外科杂志, 2018,24(1):69-73Wang X W, Yan H C, Hong J. Protective effects of mangiferin on partial sciatic nerve of neuropathic rats[J]. Chinese Journal of Surgery of Integrated Traditional and Western Medicine, 2018, 24(1):69-73(in Chinese)
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