甲基汞致脑发育损伤及PKC和CaN介导的细胞周期负向调控
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摘要
甲基汞是全球性环境污染物和持续性有机污染物,甲基汞具有很强的神经毒性和蓄积毒性,易于和生物大分子结合,可透过血脑屏障在脑内蓄积,引起以中枢神经系统为主的全身性损害。发育阶段的神经系统和神经细胞对甲基汞尤为敏感。人类孕期暴露于甲基汞可导致胎儿出生后脑发育迟缓、学习记忆能力下降和行为缺陷。
本研究从甲基汞影响细胞周期进程和诱导细胞凋亡方面入手,研究细胞周期调控蛋白、蛋白激酶C(Protein Kinase C,PKC)和钙调神经磷酸酶(Calcineurin,CaN)对细胞增殖分化及细胞周期产生的负向调控,以及在细胞周期调控及细胞凋亡坏死过程中的作用如何影响细胞周期进程。建立甲基汞所致脑发育损伤的实验动物模型,采用冷原子吸收法测定实验动物脑组织汞含量;观察甲基汞对不同发育阶段仔鼠的大脑、海马、小脑的形态学及超微结构改变;流式细胞术检测孕期暴露甲基汞仔鼠大脑、海马和小脑神经元细胞周期改变情况;TUNEL法检测孕期暴露甲基汞仔鼠大脑、海马和小脑细胞凋亡情况;采用Western blot法检测PKCα和CaN蛋白水平的表达;采用RT-PCR检测甲基汞对PKCα和CaN mRNA表达水平的影响;采用分光光度法测定CaN含量及活性。结果表明:孕期暴露甲基汞可引起仔鼠脑内不同脑区(大脑、海马和小脑)甲基汞含量增加,其中海马内总汞含量最高;随着孕期染毒剂量的增加,仔鼠各脑区内的总汞含量增加,仔鼠脑内总汞含量随仔鼠出生时间延长各脑区总汞含量逐渐降低;孕期暴露甲基汞可引起仔鼠大脑、海马和小脑形态学改变并可见超微结构改变和脑神经细胞凋亡;孕期暴露甲基汞可致仔鼠海马和小脑细胞发生G0/G1期和S期细胞阻滞,G2/M期细胞百分数减少;孕期暴露可致仔鼠脑内CaN和PKCα蛋白和mRNA水平降低,随仔鼠出生时间延长CaN和PKCα蛋白和mRNA水平降低,CaN酶活性随剂量增加表达下降,随仔鼠出生时间延长CaN酶活性有下降的趋势。
研究结果提示甲基汞可致脑发育损伤,抑制PKCα和CaN的表达,进而造成细胞周期阻滞,进入G2/M期神经元细胞减少。甲基汞对发育中的脑组织具有损伤作用,PKCα和CaN对发育阶段的脑组织神经元细胞周期具有负向调控作用。
Methylmercury exposure during gestation would induce offspring mouse brain damage. Generally, the MeHg-induced neurotoxicity and brain developmental damge were considered to be correlated with the induced cell apoptosis and influenced cell cycle. It was confirmed that Methylmercury could affect nerve cell proliferation and differentiation, disturb cell cycle regulation, induce cell apoptosis and necrosis, and consequently rendered cerebral dysgenesis and brain damage. This study regarded that methylmercury could affect cell cycle and induce cell apoptosis, and investigated the negative regulation of cell cycle regulating proteins-Protein Kinase C(PKC) and Calcineurin(CaN) on cell proliferation&differentiation and cell cycle as well as their role in affecting cell cycle during the cell cycle regulation and cell apoptosis&necrosis process. And consequently discussed the offspring brain damage mechanism by PKC and CaN in development stage after methylmercury exposure during gestation.
1.methylmercury exposure during gestation leaded to total mercury content rise in offspring mouse brain
Wistar rat weighing 230±10g were selected and mated by 1:1(female:male). From gestation day 6 (GD6) to gestation day 10 (GD10), the pregant mice were treated with methylmercury via intragastric administration by one of three dosages: 0.75mg/kg, 1.5mg/kg and 3.0mg/kg. Brain tissue of the offspring mice in different developmental stages, namely postnatal day (PND) 1, 7, 14, 21, 30 were collected and determined total mercury content within cerebrum, cerebellum and hippocampus respectively. Study showed that in terms of total mercury concentration, mercury concentrated highestly in hippocampus, secondly in cerebellum and least in cerebrum. From PND14, significant difference started to be observed between exposure groups and control group (P<0.05).
2.total mercury content within different brain regions of offspring mice decreased as postnatal time prolonged
On PND1, PND7, PND14, PND21 and PND30, offspring mice from different pregnant mice were chosen and extracted cerebrum, cerebellum and hippocampus, which were afterwards measured total mercury content by cold vapour atomic absorption spectroscopy. Regarding total mercury concentration, total mercury in each brain region of offspring mice was observed tendency to decrease as postnatal day prolonged. Among them, total mercury concentration on PND30 was significantly different from that on PND1 and PND7 (P<0.05).
3.methylmercury exposure during gestation could induce morphological changes of offpsring mouse cerebrum, cerebellum and hippocampus.
Histopathologic section by HE staining showed that, in control group, nerve cells arranged regularly, lightly stained. Microglia was rarely seen around the neurons; in methylmercury exposure group, nerve cell within cerebrum swelled, disorderly arranged and increased of acidophilia. Microglia increased around the neurons, where neuron nucleus pycnosis, as well as neuron swelling and degeneration could be observed.
Hippocampus in control group presented duckbill shape, with clear and regular cell arrangement, whereas in methylmercury exposure group, neuron cell swelled, disorderly arranged and increased of acidophilia.
Cerebellum in control group showed clear tissue structure and arranged tightly and evenly, whereas in methylmercury exposure group, congestation was observed in cerebellum, cortex and purkinje cell layer arranged loose and disorderly.
4.methylmercury exposure during gestation could induce cell apoptosis of offspring mouse cerebrum, cerebellum and hippocampus.
Cell apoptosis study of cerebrum, cerebellum and hippocampu of offspring mouse by TUNEL found that, as methylmercury exposure dose increased, neurons apoptosis in cerebrum, cerebellum and hippocampus increased. Within hippocampus neurons layer, cell apoptosis was obvious. Similar phenomenon was observed in cerebellum neurons where apoptotic cells increased as methylmercury exposure dose increased. No apoptotic cell was observed in purkinje cell layer whereas cell apoptosis increased in granule cell layer.
5. methylmercury exposure during gestation leaded to microstructure changes of offspring mouse cerebrum, cerebellum and hippocampus
Microstructure observation of offspring mouse cerebrum, cerebellum and hippocampus after methylmercury exposure during gestation by transmission electron microscope found that, in methylmercury exposure group, neuron dark cells in brain cortex presented large nuclei, compact nuclear matrix, obvious nucleole and compact cytoplasm. rough endoplasmic reticulum (RER) and mitochondrion swelling rised, and lysosomes could be found occasionally. Neuro pile was partly vacuolated, with myelinated fiber and medullary sheath separation, as well as axons obturation. Neuron dark cells increased in hippocampus of methylmercury exposure group, and presented irregular shape with small nuclei, compact cytoplasm and dense cytoplasmic matrix. Mitochondrion swelling, ridge fracture and a few lysosomes could be observed. Neuropilus extruded and vacuolizd where myelinbody could be seen. Vessel wall thickened while the surrounding dwelled and cavitated. Purkeinje cells in cerebellum of methylmercury exposure group presented irregular shape, swelling nucleus. Nucleolus enlarged and circular shaped, nuclear matrix condensed, and in the cytoplasm slighted dilated RER was observed. Cytoplasm matrix condensed, around which granulose cells were observed, which were contracted with condensed nuclei and cytoplasm.
6.MeHg exposure during gestation rendered hippocampus and cerebellum cell S phase arrest
At each time point, cells of offspring cerebrum in G2/M phase decreased as exposure dose increased. At each dose group, cells of offspring cerebrum increased in G0/G1 phase while decreased in G2/M phase as postnatal days prolonged; at each time point, as exposure dose increased, cells of offspring hippocampus increased in S phase while decreased in G2/M phase. But at each dose group, cells of offspring hippocampus increased in G2/M phase as postnatal days prolonged; at each time point, cells of offspring cerebellum decreased in G2/M on PND1. No time dependence was observed at any exposure dose group within the cerebellum.
7.cell cycle regulatory protein expression level by Western-blot
By Western-blot, PKCαand CaN in offspring cerebrum at high exposure dose group were observed to be decreased as postnatal days prolonged. PKCαin offspring hippocampus increased on postnatal day 7, and decreased gradually afterward. At each exposure dose group, PKCαand CaN in offspring hippocampus decreased as postnatal days prolonged. PKCαand CaN in offspring cerebellum increased as postnatal days prolonged and reached highest on postnatal day 14, afterward decreased gradually. Comparisons between the three brain regions on postnatal day 14 were conducted, analysis showed that PKCαand CaN levels in cerebrum had no significant difference among every dose group and NC group, while in hippocampus and cerebellum, PKCαand CaN levels were significantly lower in dose group than in NC group. Hippocampus had the highest expression levels, followed by cerebellum and cerebrum had the least.
8.PKCα, CaN and P21 genes in each brain region in different dose group at different time point by RT-PCR
PKCαmRNA expression in hippocampus was observed, of which every dose group was lower than NC group.
CaNαmRNA expressed in cerebrum, which increased as exposure dose increased. CaNαmRNA expression in hippocampus was lower in every dose group than in NC group. CaNαmRNA expression in cerebellum was higher in each dose group than in NC group.
CaNβmRNA expressed in all the three regions and decreased as exposure dose increased. CaNβmRNA expressed lower in the three regions than in NC group.
CaNαmRNA expression in cerebrum was decreased as postnatal days prolonged. CaNαmRNA expressed in hippocampus and cerebellum, and decreased as postnatal days prolonged.
CaNβmRNA expression in cerebrum showed no significant difference at each time point after birth. CaNβmRNA expression in hippocampus and cerebellum decreased as postnatal days prolonged.
In high exposure dose group, PKCαmRNA expression lowered as postnatal days prolonged; PKCαmRNA expression in hippocampus increased as postnatal days prolonged. No significant difference was observed in cerebellum upon PKCαmRNA. 9.CaN enzyme activity by spectrophotometry
Generally, CaN enzyme activity decreased in each brain region as postnatal days prolonged. CaN enzyme activity was lowest in cerebrum while relatively higher in hippocampus and cerebellum.
Overall, total mercury content in each brain region of neonatal rat increased after intrauterine methylmercury exposure. And as exposure dose increased, total mercury content increased, where hippocampus had the most content, followed by cerebellum, and cerebrum had the least; as postnatal days prolonged, total mercury content decreased. Brain morphologic changes were also observed during developmental stage and presented a dose-effect relationship. Ultrastructure of each brain region altered and brain neurons apoptosis rate increased. Ca2+ concentration increased within hippocampus and cerebellum during developmental stage, while CaN enzyme activity decreased with lower expression than counterpart in control group. CaN could regulate PKC via inhibitory factor, leading consequently to PKCαexpression decline. This was proved by Western-blot and RT-PCR. The synergic negative-regulation action of CaN and PKC rendered cell cycle G0/G1 and S phase arrest. The toxicity of methylmercury prevent cell from stepping into G2/M phase, causing neuron cells proliferation decline followed by cell counts decrease and finally leaded to cell translocation failure, which affected the brain development process and caused brain damage during developmental stage. This combined with the fact that neuron cells cannot be regenerated, made the methylmercury-caused brain damage during developmental stage irreversible.
本研究从甲基汞影响细胞周期进程和诱导细胞凋亡方面入手,研究细胞周期调控蛋白、蛋白激酶C(Protein Kinase C,PKC)和钙调神经磷酸酶(Calcineurin,CaN)对细胞增殖分化及细胞周期产生的负向调控,以及在细胞周期调控及细胞凋亡坏死过程中的作用如何影响细胞周期进程。建立甲基汞所致脑发育损伤的实验动物模型,采用冷原子吸收法测定实验动物脑组织汞含量;观察甲基汞对不同发育阶段仔鼠的大脑、海马、小脑的形态学及超微结构改变;流式细胞术检测孕期暴露甲基汞仔鼠大脑、海马和小脑神经元细胞周期改变情况;TUNEL法检测孕期暴露甲基汞仔鼠大脑、海马和小脑细胞凋亡情况;采用Western blot法检测PKCα和CaN蛋白水平的表达;采用RT-PCR检测甲基汞对PKCα和CaN mRNA表达水平的影响;采用分光光度法测定CaN含量及活性。结果表明:孕期暴露甲基汞可引起仔鼠脑内不同脑区(大脑、海马和小脑)甲基汞含量增加,其中海马内总汞含量最高;随着孕期染毒剂量的增加,仔鼠各脑区内的总汞含量增加,仔鼠脑内总汞含量随仔鼠出生时间延长各脑区总汞含量逐渐降低;孕期暴露甲基汞可引起仔鼠大脑、海马和小脑形态学改变并可见超微结构改变和脑神经细胞凋亡;孕期暴露甲基汞可致仔鼠海马和小脑细胞发生G0/G1期和S期细胞阻滞,G2/M期细胞百分数减少;孕期暴露可致仔鼠脑内CaN和PKCα蛋白和mRNA水平降低,随仔鼠出生时间延长CaN和PKCα蛋白和mRNA水平降低,CaN酶活性随剂量增加表达下降,随仔鼠出生时间延长CaN酶活性有下降的趋势。
研究结果提示甲基汞可致脑发育损伤,抑制PKCα和CaN的表达,进而造成细胞周期阻滞,进入G2/M期神经元细胞减少。甲基汞对发育中的脑组织具有损伤作用,PKCα和CaN对发育阶段的脑组织神经元细胞周期具有负向调控作用。
Methylmercury exposure during gestation would induce offspring mouse brain damage. Generally, the MeHg-induced neurotoxicity and brain developmental damge were considered to be correlated with the induced cell apoptosis and influenced cell cycle. It was confirmed that Methylmercury could affect nerve cell proliferation and differentiation, disturb cell cycle regulation, induce cell apoptosis and necrosis, and consequently rendered cerebral dysgenesis and brain damage. This study regarded that methylmercury could affect cell cycle and induce cell apoptosis, and investigated the negative regulation of cell cycle regulating proteins-Protein Kinase C(PKC) and Calcineurin(CaN) on cell proliferation&differentiation and cell cycle as well as their role in affecting cell cycle during the cell cycle regulation and cell apoptosis&necrosis process. And consequently discussed the offspring brain damage mechanism by PKC and CaN in development stage after methylmercury exposure during gestation.
1.methylmercury exposure during gestation leaded to total mercury content rise in offspring mouse brain
Wistar rat weighing 230±10g were selected and mated by 1:1(female:male). From gestation day 6 (GD6) to gestation day 10 (GD10), the pregant mice were treated with methylmercury via intragastric administration by one of three dosages: 0.75mg/kg, 1.5mg/kg and 3.0mg/kg. Brain tissue of the offspring mice in different developmental stages, namely postnatal day (PND) 1, 7, 14, 21, 30 were collected and determined total mercury content within cerebrum, cerebellum and hippocampus respectively. Study showed that in terms of total mercury concentration, mercury concentrated highestly in hippocampus, secondly in cerebellum and least in cerebrum. From PND14, significant difference started to be observed between exposure groups and control group (P<0.05).
2.total mercury content within different brain regions of offspring mice decreased as postnatal time prolonged
On PND1, PND7, PND14, PND21 and PND30, offspring mice from different pregnant mice were chosen and extracted cerebrum, cerebellum and hippocampus, which were afterwards measured total mercury content by cold vapour atomic absorption spectroscopy. Regarding total mercury concentration, total mercury in each brain region of offspring mice was observed tendency to decrease as postnatal day prolonged. Among them, total mercury concentration on PND30 was significantly different from that on PND1 and PND7 (P<0.05).
3.methylmercury exposure during gestation could induce morphological changes of offpsring mouse cerebrum, cerebellum and hippocampus.
Histopathologic section by HE staining showed that, in control group, nerve cells arranged regularly, lightly stained. Microglia was rarely seen around the neurons; in methylmercury exposure group, nerve cell within cerebrum swelled, disorderly arranged and increased of acidophilia. Microglia increased around the neurons, where neuron nucleus pycnosis, as well as neuron swelling and degeneration could be observed.
Hippocampus in control group presented duckbill shape, with clear and regular cell arrangement, whereas in methylmercury exposure group, neuron cell swelled, disorderly arranged and increased of acidophilia.
Cerebellum in control group showed clear tissue structure and arranged tightly and evenly, whereas in methylmercury exposure group, congestation was observed in cerebellum, cortex and purkinje cell layer arranged loose and disorderly.
4.methylmercury exposure during gestation could induce cell apoptosis of offspring mouse cerebrum, cerebellum and hippocampus.
Cell apoptosis study of cerebrum, cerebellum and hippocampu of offspring mouse by TUNEL found that, as methylmercury exposure dose increased, neurons apoptosis in cerebrum, cerebellum and hippocampus increased. Within hippocampus neurons layer, cell apoptosis was obvious. Similar phenomenon was observed in cerebellum neurons where apoptotic cells increased as methylmercury exposure dose increased. No apoptotic cell was observed in purkinje cell layer whereas cell apoptosis increased in granule cell layer.
5. methylmercury exposure during gestation leaded to microstructure changes of offspring mouse cerebrum, cerebellum and hippocampus
Microstructure observation of offspring mouse cerebrum, cerebellum and hippocampus after methylmercury exposure during gestation by transmission electron microscope found that, in methylmercury exposure group, neuron dark cells in brain cortex presented large nuclei, compact nuclear matrix, obvious nucleole and compact cytoplasm. rough endoplasmic reticulum (RER) and mitochondrion swelling rised, and lysosomes could be found occasionally. Neuro pile was partly vacuolated, with myelinated fiber and medullary sheath separation, as well as axons obturation. Neuron dark cells increased in hippocampus of methylmercury exposure group, and presented irregular shape with small nuclei, compact cytoplasm and dense cytoplasmic matrix. Mitochondrion swelling, ridge fracture and a few lysosomes could be observed. Neuropilus extruded and vacuolizd where myelinbody could be seen. Vessel wall thickened while the surrounding dwelled and cavitated. Purkeinje cells in cerebellum of methylmercury exposure group presented irregular shape, swelling nucleus. Nucleolus enlarged and circular shaped, nuclear matrix condensed, and in the cytoplasm slighted dilated RER was observed. Cytoplasm matrix condensed, around which granulose cells were observed, which were contracted with condensed nuclei and cytoplasm.
6.MeHg exposure during gestation rendered hippocampus and cerebellum cell S phase arrest
At each time point, cells of offspring cerebrum in G2/M phase decreased as exposure dose increased. At each dose group, cells of offspring cerebrum increased in G0/G1 phase while decreased in G2/M phase as postnatal days prolonged; at each time point, as exposure dose increased, cells of offspring hippocampus increased in S phase while decreased in G2/M phase. But at each dose group, cells of offspring hippocampus increased in G2/M phase as postnatal days prolonged; at each time point, cells of offspring cerebellum decreased in G2/M on PND1. No time dependence was observed at any exposure dose group within the cerebellum.
7.cell cycle regulatory protein expression level by Western-blot
By Western-blot, PKCαand CaN in offspring cerebrum at high exposure dose group were observed to be decreased as postnatal days prolonged. PKCαin offspring hippocampus increased on postnatal day 7, and decreased gradually afterward. At each exposure dose group, PKCαand CaN in offspring hippocampus decreased as postnatal days prolonged. PKCαand CaN in offspring cerebellum increased as postnatal days prolonged and reached highest on postnatal day 14, afterward decreased gradually. Comparisons between the three brain regions on postnatal day 14 were conducted, analysis showed that PKCαand CaN levels in cerebrum had no significant difference among every dose group and NC group, while in hippocampus and cerebellum, PKCαand CaN levels were significantly lower in dose group than in NC group. Hippocampus had the highest expression levels, followed by cerebellum and cerebrum had the least.
8.PKCα, CaN and P21 genes in each brain region in different dose group at different time point by RT-PCR
PKCαmRNA expression in hippocampus was observed, of which every dose group was lower than NC group.
CaNαmRNA expressed in cerebrum, which increased as exposure dose increased. CaNαmRNA expression in hippocampus was lower in every dose group than in NC group. CaNαmRNA expression in cerebellum was higher in each dose group than in NC group.
CaNβmRNA expressed in all the three regions and decreased as exposure dose increased. CaNβmRNA expressed lower in the three regions than in NC group.
CaNαmRNA expression in cerebrum was decreased as postnatal days prolonged. CaNαmRNA expressed in hippocampus and cerebellum, and decreased as postnatal days prolonged.
CaNβmRNA expression in cerebrum showed no significant difference at each time point after birth. CaNβmRNA expression in hippocampus and cerebellum decreased as postnatal days prolonged.
In high exposure dose group, PKCαmRNA expression lowered as postnatal days prolonged; PKCαmRNA expression in hippocampus increased as postnatal days prolonged. No significant difference was observed in cerebellum upon PKCαmRNA. 9.CaN enzyme activity by spectrophotometry
Generally, CaN enzyme activity decreased in each brain region as postnatal days prolonged. CaN enzyme activity was lowest in cerebrum while relatively higher in hippocampus and cerebellum.
Overall, total mercury content in each brain region of neonatal rat increased after intrauterine methylmercury exposure. And as exposure dose increased, total mercury content increased, where hippocampus had the most content, followed by cerebellum, and cerebrum had the least; as postnatal days prolonged, total mercury content decreased. Brain morphologic changes were also observed during developmental stage and presented a dose-effect relationship. Ultrastructure of each brain region altered and brain neurons apoptosis rate increased. Ca2+ concentration increased within hippocampus and cerebellum during developmental stage, while CaN enzyme activity decreased with lower expression than counterpart in control group. CaN could regulate PKC via inhibitory factor, leading consequently to PKCαexpression decline. This was proved by Western-blot and RT-PCR. The synergic negative-regulation action of CaN and PKC rendered cell cycle G0/G1 and S phase arrest. The toxicity of methylmercury prevent cell from stepping into G2/M phase, causing neuron cells proliferation decline followed by cell counts decrease and finally leaded to cell translocation failure, which affected the brain development process and caused brain damage during developmental stage. This combined with the fact that neuron cells cannot be regenerated, made the methylmercury-caused brain damage during developmental stage irreversible.
引文
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