四溴联苯醚对小鼠的神经毒性
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摘要
为探讨持久性有机污染物2,2’,4,4’-四溴联苯醚(BDE-47)对小鼠海马组织的神经毒性,将小鼠每日灌胃25或50 mg·kg-1剂量的BDE-47,6周后检测其记忆能力、海马组织病理学变化、蛋白激酶C(PKC)表达量和半胱氨酸天冬氨酸蛋白酶-3(caspase-3)活性。结果显示,BDE-47损伤了小鼠被动回避实验的记忆保持能力,导致海马安蒙角(CA1)区锥体细胞排列紊乱,神经元胞体体积变小,形态不规则。BDE-47对小鼠海马组织PKCα、β、γ和ζ的表达无影响,但显著上调了PKCδ和PKCλ的表达,促进了caspase-3活性。这些结果提示,BDE-47导致的海马神经毒性可能与PKCδ和PKCλ表达异常及caspase-3活性升高有关。本实验结果为进一步了解BDE-47神经毒作用机制提供了实验依据。
This study was aimed to investigate the neurotoxicity induced by persistent organic pollutant 2,2',4,4'-tetrabromodiphenyl ether( BDE-47) in mice. Mice were received BDE-47( 25 or 50 mg·kg-1) by oral gavage daily for 6 weeks. At the end of treatment,memory function,hippocampal histopathological changes,the expression of protein kinase C( PKC) and cysteinyl aspartate specific proteinase-3( caspase-3) activity in mouse hippocampus was evaluated. The results showed that BDE-47 led to memory retention impairment in the passive avoidance task in mice. Moreover,the pyramidal cells in the hippocampal cornu ammonis 1( CA1) were irregularly arranged and exhibited shrunken and irregular shape in BDE-47-treated mice. There was no significant change in PKCα,β,γ andζ expressions compared with the control. The expression of PKCδ and PKCλ and the activity of caspase-3 was increased in the hippocampus of BDE-47-treated mice. These findings suggested that BDE-47-induced neurotoxicity was associated with the abnormal expression of PKCδ and PKCλ,along with the increased caspase-3 activity. Our results also provide an experimental basis for further understanding the neurotoxicity mechanisms of BDE-47.
This study was aimed to investigate the neurotoxicity induced by persistent organic pollutant 2,2',4,4'-tetrabromodiphenyl ether( BDE-47) in mice. Mice were received BDE-47( 25 or 50 mg·kg-1) by oral gavage daily for 6 weeks. At the end of treatment,memory function,hippocampal histopathological changes,the expression of protein kinase C( PKC) and cysteinyl aspartate specific proteinase-3( caspase-3) activity in mouse hippocampus was evaluated. The results showed that BDE-47 led to memory retention impairment in the passive avoidance task in mice. Moreover,the pyramidal cells in the hippocampal cornu ammonis 1( CA1) were irregularly arranged and exhibited shrunken and irregular shape in BDE-47-treated mice. There was no significant change in PKCα,β,γ andζ expressions compared with the control. The expression of PKCδ and PKCλ and the activity of caspase-3 was increased in the hippocampus of BDE-47-treated mice. These findings suggested that BDE-47-induced neurotoxicity was associated with the abnormal expression of PKCδ and PKCλ,along with the increased caspase-3 activity. Our results also provide an experimental basis for further understanding the neurotoxicity mechanisms of BDE-47.
引文
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[12] Busquets-Garcia A, Gomis-González M, SalgadoMendialdúa V,et al. Hippocampal protein kinase C signaling mediates the short-term memory impairment induced by delta9-tetrahydrocannabinol[J]. Neuropsychopharmacology,2018,43(5):1021-1031
[13] Freeley M,Kelleher D,Long A. Regulation of protein kinase C function by phosphorylation on conserved and non-conserved sites[J]. Cellular Signalling,2011,23(5):753-762
[14] Kodavanti P R S,Ward T R,Ludewig G,et al. Polybrominated diphenyl ether(PBDE)effects in rat neuronal cultures:14C-PBDE accumulation, biological effects,and structure-activity relationship[J]. Toxicological Sciences,2005,88(1):181-192
[15] Colgan L A,Hu M,Misler J A,et al. PKCαintegrates spatiotemporally distinct Ca2+and autocrine BDNF signaling to facilitate synaptic plasticity[J]. Nature Neuroscience,2018,21(8):1027-1037
[16] Harada K,Maekawa T,Shama K M A,et al. Translocation and down-regulation of protein kinase C-α，-β，and-γisoforms during ischemia-reperfusion in rat brain[J].Journal of Neurochemistry,1999,72(6):2556-2564
[17] Sharma S. The neuroinflammatory role of Fyn-PKC-δsignaling pathway in the mouse kainate model of epileptogenesis[J]. The FASEB Journal,2017,31(1_supplement):lb188
[18] Wu D,Lu J,Zheng Y,et al. Small interfering RNAmediated knockdown of protein kinase C zeta attenuates domoic acid-induced cognitive deficits in mice[J].Toxicological Sciences,2012,128(1):209-222
[19] Ren S Q,Yan J Z,Zhang X Y,et al. PKCλis critical in AMPA receptor phosphorylation and synaptic incorporation during LTP[J]. The EMBO Journal,2013,32(10):1365-1380
[20] Zhuang J,Wen X,Zhang Y,et al. TDP-43 upregulation mediated by the NLRP3 inflammasome induces cognitive impairment in 2,2',4,4'-tetrabromodiphenyl ether(BDE-47)-treated mice[J]. Brain,Behavior,and Immunity,2017,65:99-110
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[23] Zhang H,Li X,Nie J S,et al. Lactation exposure to BDE-153 damages learning and memory,disrupts spontaneous behavior and induces hippocampus neuron death in adult rats[J]. Brain Research,2013,1517:44-56
[24] Roze E,Meijer L,Bakker A,et al. Prenatal exposure to organohalogens,including brominated flame retardants,influences motor,cognitive,and behavioral performance at school age[J]. Environmental Health Perspectives,2009,117(12):1953-1958
[25] Zhang H,Yolton K,Webster G M,et al. Prenatal PBDE and PCB exposures and reading,cognition,and externalizing behavior in children[J]. Environmental Health Perspectives,2017,125(4):746-752
[26] Staskal D F,Diliberto J J,De Vito M J,et al. Toxicokinetics of BDE 47 in female mice:Effect of dose,route of exposure, and time[J]. Toxicological Sciences,2005,83(2):215-223
[27] Fitzgerald E F,Shrestha S,Gomez M I,et al. Polybrominated diphenyl ethers(PBDEs),polychlorinated biphenyls(PCBs)and neuropsychological status among older adults in New York[J]. Neurotoxicology,2012,33(1):8-15
[28] Abeliovich A,Paylor R,Chen C,et al. PKCγmutant mice exhibit mild deficits in spatial and contextual learning[J]. Cell,1993,75(7):1263-1271
[29] Weeber E J,Atkins C M,Selcher J C,et al. A role for theβisoform of protein kinase C in fear conditioning[J]. Journal of Neuroscience,2000,20(16):5906-5914
[30] Sacktor T C,Osten P,Valsamis H,et al. Persistent activation of the zeta isoform of protein kinase C in the maintenance of long-term potentiation[J]. Proceedings of the National Academy of Sciences,1993,90(18):8342-8346
[31] Basu A,Pal D. Two faces of protein kinase Cδ:The contrasting roles of PKCδin cell survival and cell death[J]. The Scientific World Journal,2010,10:2272-2284
[32] Shin E J,Nam Y,Tu T H T,et al. Protein kinase Cδmediates trimethyltin-induced neurotoxicity in mice in vivo via inhibition of glutathione defense mechanism[J]. Archives of Toxicology,2016,90(4):937-953
[33] Shin E J,Duong C X,Nguyen X K T,et al. Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase Cδ[J]. Behavioural Brain Research,2012,232(1):98-113
[34] Gordon R,Singh N,Lawana V,et al. Protein kinase Cδupregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease[J]. Neurobiology of Disease,2016,93:96-114
[35] Lin M,Chandramani-Shivalingappa P,Jin H,et al.Methamphetamine-induced neurotoxicity linked to ubiquitin-proteasome system dysfunction and autophagy-related changes that can be modulated by protein kinase C delta in dopaminergic neuronal cells[J]. Neuroscience,2012,210:308-332
[36] Li B,Chen R,Chen L,et al. Effects of DDIT4 in methamphetamine-induced autophagy and apoptosis in dopaminergic neurons[J]. Molecular Neurobiology,2017,54(3):1642-1660
[37] Dang D K,Shin E J,Kim D J,et al. PKCδ-dependent p47phox activation mediates methamphetamine-induced dopaminergic neurotoxicity[J]. Free Radical Biology and Medicine,2018,115:318-337
[38] Ren S Q,Yan J Z,Zhang X Y,et al. PKCλis critical in AMPA receptor phosphorylation and synaptic incorporation during LTP[J]. The EMBO Journal,2013,32(10):1365-1380
[39] Jalil S J,Sacktor T C,Shouval H Z. Atypical PKCs in memory maintenance:The roles of feedback and redundancy[J]. Learning&Memory,2015,22(7):344-353
[40] Rossner S,Mehlhorn G,Schliebs R,et al. Increased neuronal and glial expression of protein kinase C isoforms in neocortex of transgenic Tg2576 mice with amyloid pathology[J]. European Journal of Neuroscience,2001,13(2):269-278
[41] Reyland M E. Protein kinase C isoforms:Multi-functional regulators of cell life and death[J]. Frontiers in Bioscience(Landmark Edition),2009,14:2386-2399
[42] Nakanishi Y,Reina-Campos M,Nakanishi N,et al.Control of paneth cell fate,intestinal inflammation,and tumorigenesis by PKCλ/ι[J]. Cell Reports,2016,16(12):3297-3310
[2] Lorber M. Exposure of Americans to polybrominated diphenyl ethers[J]. Journal of Exposure Science and Environmental Epidemiology,2008,18(1):2-19
[3]rn U,Klasson-Wehler E. Metabolism of 2,2’,4,4’-tetrabromodiphenyl ether in rat and mouse[J]. Xenobiotica,1998,28(2):199-211
[4] Staskal D F,Diliberto J J,Birnbaum L S. Impact of repeated exposure on the toxicokinetics of BDE 47 in mice[J]. Toxicological Sciences,2006,89(2):380-385
[5] Mitchell M M,Woods R,Chi L H,et al. Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder[J]. Environmental and Molecular Mutagenesis,2012,53(8):589-598
[6] Tang Y,Li X,Jiang X J,et al. Spatial learning and memory deficit of low level polybrominated diphenyl ethers-47 in male adult rat is modulated by intracellular glutamate receptors[J]. Journal of Toxicological Sciences,2012,37(2):223-233
[7] Dingemans M M L,Ramakers G M J,Gardoni F,et al.Neonatal exposure to brominated flame retardants BDE-47 reduces long-term potentiation and postsynaptic protein levels in mouse hippocampus[J]. Environmental Health Perspectives,2007,115(6):865-870
[8] Herbstman J B,Sjodin A,Kurzon M,et al. Prenatal exposure to PBDEs and neurodevelopment[J]. Environmental Health Perspectives,2010,118(5):712-719
[9] Eskenazi B,Chevrier J,Rauch S A,et al. In utero and childhood polybrominated diphenyl ether(PBDE)exposures and neurodevelopment in the CHAMACOS study[J]. Environmental Health Perspectives,2013,121(2):257-262
[10] Wang J,Gallagher D,De Vito L M,et al. Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation[J]. Cell Stem Cell,2012,11(1):23-35
[11] Sun M K,Alkon D L. The“memory kinases”:Roles of PKC isoforms in signal processing and memory formation[J]. Progress in Molecular Biology and Translational Science,2014,122:31-59
[12] Busquets-Garcia A, Gomis-González M, SalgadoMendialdúa V,et al. Hippocampal protein kinase C signaling mediates the short-term memory impairment induced by delta9-tetrahydrocannabinol[J]. Neuropsychopharmacology,2018,43(5):1021-1031
[13] Freeley M,Kelleher D,Long A. Regulation of protein kinase C function by phosphorylation on conserved and non-conserved sites[J]. Cellular Signalling,2011,23(5):753-762
[14] Kodavanti P R S,Ward T R,Ludewig G,et al. Polybrominated diphenyl ether(PBDE)effects in rat neuronal cultures:14C-PBDE accumulation, biological effects,and structure-activity relationship[J]. Toxicological Sciences,2005,88(1):181-192
[15] Colgan L A,Hu M,Misler J A,et al. PKCαintegrates spatiotemporally distinct Ca2+and autocrine BDNF signaling to facilitate synaptic plasticity[J]. Nature Neuroscience,2018,21(8):1027-1037
[16] Harada K,Maekawa T,Shama K M A,et al. Translocation and down-regulation of protein kinase C-α，-β，and-γisoforms during ischemia-reperfusion in rat brain[J].Journal of Neurochemistry,1999,72(6):2556-2564
[17] Sharma S. The neuroinflammatory role of Fyn-PKC-δsignaling pathway in the mouse kainate model of epileptogenesis[J]. The FASEB Journal,2017,31(1_supplement):lb188
[18] Wu D,Lu J,Zheng Y,et al. Small interfering RNAmediated knockdown of protein kinase C zeta attenuates domoic acid-induced cognitive deficits in mice[J].Toxicological Sciences,2012,128(1):209-222
[19] Ren S Q,Yan J Z,Zhang X Y,et al. PKCλis critical in AMPA receptor phosphorylation and synaptic incorporation during LTP[J]. The EMBO Journal,2013,32(10):1365-1380
[20] Zhuang J,Wen X,Zhang Y,et al. TDP-43 upregulation mediated by the NLRP3 inflammasome induces cognitive impairment in 2,2',4,4'-tetrabromodiphenyl ether(BDE-47)-treated mice[J]. Brain,Behavior,and Immunity,2017,65:99-110
[21] Wong S T,Athos J,Figueroa X A,et al. Calcium-stimulated adenylyl cyclase activity is critical for hippocampus-dependent long-term memory and late phase LTP[J]. Neuron,1999,23(4):787-798
[22] Izquierdo I,Bevilaqua L R M,Rossato J I,et al. Different molecular cascades in different sites of the brain control memory consolidation[J]. Trends in Neurosciences,2006,29(9):496-505
[23] Zhang H,Li X,Nie J S,et al. Lactation exposure to BDE-153 damages learning and memory,disrupts spontaneous behavior and induces hippocampus neuron death in adult rats[J]. Brain Research,2013,1517:44-56
[24] Roze E,Meijer L,Bakker A,et al. Prenatal exposure to organohalogens,including brominated flame retardants,influences motor,cognitive,and behavioral performance at school age[J]. Environmental Health Perspectives,2009,117(12):1953-1958
[25] Zhang H,Yolton K,Webster G M,et al. Prenatal PBDE and PCB exposures and reading,cognition,and externalizing behavior in children[J]. Environmental Health Perspectives,2017,125(4):746-752
[26] Staskal D F,Diliberto J J,De Vito M J,et al. Toxicokinetics of BDE 47 in female mice:Effect of dose,route of exposure, and time[J]. Toxicological Sciences,2005,83(2):215-223
[27] Fitzgerald E F,Shrestha S,Gomez M I,et al. Polybrominated diphenyl ethers(PBDEs),polychlorinated biphenyls(PCBs)and neuropsychological status among older adults in New York[J]. Neurotoxicology,2012,33(1):8-15
[28] Abeliovich A,Paylor R,Chen C,et al. PKCγmutant mice exhibit mild deficits in spatial and contextual learning[J]. Cell,1993,75(7):1263-1271
[29] Weeber E J,Atkins C M,Selcher J C,et al. A role for theβisoform of protein kinase C in fear conditioning[J]. Journal of Neuroscience,2000,20(16):5906-5914
[30] Sacktor T C,Osten P,Valsamis H,et al. Persistent activation of the zeta isoform of protein kinase C in the maintenance of long-term potentiation[J]. Proceedings of the National Academy of Sciences,1993,90(18):8342-8346
[31] Basu A,Pal D. Two faces of protein kinase Cδ:The contrasting roles of PKCδin cell survival and cell death[J]. The Scientific World Journal,2010,10:2272-2284
[32] Shin E J,Nam Y,Tu T H T,et al. Protein kinase Cδmediates trimethyltin-induced neurotoxicity in mice in vivo via inhibition of glutathione defense mechanism[J]. Archives of Toxicology,2016,90(4):937-953
[33] Shin E J,Duong C X,Nguyen X K T,et al. Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase Cδ[J]. Behavioural Brain Research,2012,232(1):98-113
[34] Gordon R,Singh N,Lawana V,et al. Protein kinase Cδupregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease[J]. Neurobiology of Disease,2016,93:96-114
[35] Lin M,Chandramani-Shivalingappa P,Jin H,et al.Methamphetamine-induced neurotoxicity linked to ubiquitin-proteasome system dysfunction and autophagy-related changes that can be modulated by protein kinase C delta in dopaminergic neuronal cells[J]. Neuroscience,2012,210:308-332
[36] Li B,Chen R,Chen L,et al. Effects of DDIT4 in methamphetamine-induced autophagy and apoptosis in dopaminergic neurons[J]. Molecular Neurobiology,2017,54(3):1642-1660
[37] Dang D K,Shin E J,Kim D J,et al. PKCδ-dependent p47phox activation mediates methamphetamine-induced dopaminergic neurotoxicity[J]. Free Radical Biology and Medicine,2018,115:318-337
[38] Ren S Q,Yan J Z,Zhang X Y,et al. PKCλis critical in AMPA receptor phosphorylation and synaptic incorporation during LTP[J]. The EMBO Journal,2013,32(10):1365-1380
[39] Jalil S J,Sacktor T C,Shouval H Z. Atypical PKCs in memory maintenance:The roles of feedback and redundancy[J]. Learning&Memory,2015,22(7):344-353
[40] Rossner S,Mehlhorn G,Schliebs R,et al. Increased neuronal and glial expression of protein kinase C isoforms in neocortex of transgenic Tg2576 mice with amyloid pathology[J]. European Journal of Neuroscience,2001,13(2):269-278
[41] Reyland M E. Protein kinase C isoforms:Multi-functional regulators of cell life and death[J]. Frontiers in Bioscience(Landmark Edition),2009,14:2386-2399
[42] Nakanishi Y,Reina-Campos M,Nakanishi N,et al.Control of paneth cell fate,intestinal inflammation,and tumorigenesis by PKCλ/ι[J]. Cell Reports,2016,16(12):3297-3310