慢性氟中毒对大鼠脑海马钙离子信号通路的影响
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摘要
适量氟是维持机体正常生理活动的基础,但氟是一种蓄积性原生质毒物,机体长期过量摄入氟可引起氟骨症、氟斑牙等骨相器官的损害以及血液、神经系统等非骨相器官的损害。神经组织对氟的敏感性很高,海马作为中枢神经系统中氟中毒的靶部位之一,其神经细胞易受氟的影响而发生可塑性变化。近年来,通过对氟神经毒性作用机制的研究,人们主要提出了G蛋白信号转导理论与氧化应激理论。
目前普遍认为,神经毒物引起的神经系统损伤与G蛋白信号转导通路中Ca2+稳态失调有密切关系。其机制可能与神经细胞内对氧化应激敏感且受钙离子调控的核转录因子(nuclear factor kappa-B, NF-κB)表达等有关。因此,本实验通过复制饮水型慢性氟中毒动物模型,以观察和检测氟中毒引起氟斑牙、血氟水平异常及海马神经细胞形态结构改变为基础,首次在氟的神经毒性研究中将钙离子信号通路与氧化应激理论结合,检测氟中毒对大鼠海马突触体内Ca2+浓度以及钙离子信号通路中CaMKⅡ、c-fos、NF-κB、Bcl-2及Bax蛋白表达的影响。
研究方法：152只初断乳雄性SD大鼠随机分为四组,即对照组(饮用自来水,水氟含量低于0.5mg/L),低氟组、中氟组、高氟组(饮水含氟化钠分别为15mg/L、30mg/L、60mg/L)。各组以配制的溶液作为饮水唯一来源,自由摄食、饮水,饲养时间为18个月。染氟初期(3月龄)对大鼠进行氟斑牙和血氟检测,染氟中期(9月龄)和染氟结束(18月龄)分两批断头处死大鼠,HE染色检测海马CA3区病理学改变,荧光指示剂Fura-2/AM检测慢性氟中毒大鼠海马突触体内Ca2+浓度的变化,免疫组化法检测海马CA3区CaMKⅡα、c-fos、NF-κBρ65、Bcl-2及Bax蛋白表达的改变。
1、过量氟摄入会导致大鼠氟斑牙发生,随染氟浓度升高,大鼠氟斑牙症状加剧,切齿明显变形、缺损并出现白垩状横纹；各染氟组血氟浓度与对照组相比显著或极显著升高(P<0.05或P<0.01)。表明动物氟中毒模型复制成功。
2、HE染色结果显示,慢性氟中毒可损伤大鼠神经细胞形态结构。与对照组相比,染氟组大鼠海马神经细胞分布稀疏,细胞轮廓消失,并出现空泡。且这种变化随染氟时间和染氟浓度的递增而更为显著。
3、突触体Ca2+浓度检测结果显示,随大鼠月龄增长,对照组突触体Ca2+浓度有升高的趋势,而染氟处理加剧了Ca2+的超载。染氟中期：与对照组相比,中氟组、高氟组突触体Ca2+浓度显著或极显著升高(P<0.05或P<0.01)；染氟结束：与对照组相比,中氟组、高氟组突触体Ca2+浓度极显著升高(P<0.01)。
4、IHC结果显示,随大鼠月龄增长,对照组及各染氟组CaMKⅡα、c-fos、NF-κBρ65蛋白表达均有不同水平的上升,且染氟时间和染氟剂量的递增使这种变化更为显著。染氟中期：与对照组相比,中氟组、高氟组CaMKⅡα表达显著升高(P<0.05),c-fos表达显著或极显著升高(P<0.05或P<0.01),NF-κBρ65表达虽无显著性差异,但随染氟剂量升高其表达有上升的趋势；染氟结束：与对照组相比,中氟组、高氟组CaMKⅡαc-fos表达极显著升高(P<0.01),中氟组NF-κBρ65表达显著升高(P<0.05)。
5、IHC结果显示,随大鼠月龄增长,对照组及各染氟组Bcl-2和Bax蛋白表达水平均有不同水平的下降,且染氟时间和染氟剂量的递增使这种变化更为显著。染氟中期：与对照组相比,中氟组、高氟组Bcl-2表达显著或极显著下降(P<0.05或P<0.01),Bax表达极显著下降(P<0.01)；染氟结束：与对照组相比,中氟组、高氟组Bcl-2表达显著或极显著下降(P<0.05或P<0.01),低氟组、中氟组、高氟组Bax表达显著或极显著下降(P<0.05,P<0.01,P<0.01)。同时,染氟中期：Bax与Bcl-2比值(Bax/Bcl-2)随染氟时间和染氟浓度的递增有升高的趋势；染氟结束：与对照组相比,中氟组、高氟组Bax/Bcl-2比值显著上升(P<0.05),提示神经细胞处于凋亡状态。
综合上述,慢性氟暴露对中枢神经系统有毒性作用。氟可导致海马神经细胞形态结构发生改变,引起海马突触体Ca2+超载,继而导致钙离子信号通路中CaMKⅡα、c-fos、NF-κBρ65、Bcl-2及Bax的蛋白表达异常,最终诱导神经细胞趋于凋亡。衰老过程中,神经细胞的退行性改变也可导致大鼠神经细胞凋亡,而染氟处理加剧了这种变化。本研究进一步阐明了氟神经毒性对钙离子信号通路影响的分子机理,为深入探讨慢性氟中毒对中枢神经系统毒性作用的分子生物学机制提供了一定的理论基础。此外,NF-κB的表达与染氟时间、浓度有敏感的量效关系,可能是氟神经毒性相关靶分子,这为开展氟神经毒性的生物标志物研究提供一定的理论依据。
Moderate fluoride is the foundation of normal physiological activities. But the fluoride is a long-term accumulated poison, and excess intake of fluorine can cause skeletal fluorosis, dental fluorosis so far as to blood and nervous system damage. Nerve tissues are sensitive to fluorine particularly. Hippocampus as a target site of fluorosis in central nervous systems, which synaptic plasticity of nerve cells is vulnerable by affecting fluorine. In recent years, through the study on neurotoxic mechanism of fluorine, people put forward two theories that the theory of G protein signal transduction and the theory of oxidative stress.
Generally thought, there is a close relation between the nervous system damage caused by nerve poison and Ca2+ steady-state disorder in G protein signal transduction pathways. The mechanism may relate to Nuclear factor-κB (NF-κB) which is sensitive in oxidative stress and regulated by Ca2+. Thus, we chose rat model of chronic fluorosis to explore the effects of different doses of fluoride on dental fluorosis, blood F and nerve cell structure firstly. Then combining calcium signaling pathways theory with oxidative stress theory for the first time, we detected calcium ion concentration ([Ca2+]) and the expression level of CaMKⅡ, c-fos, NF-κB, Bcl-2 and Bax.
152, just weaning male Sprague-Dawley rats were randomly divided into four groups and given 15,30,60 mg/L NaF solution and distilled water respectively for 9 and 18 months. Rats were fed standard diet throughout the experiment and water was given ad libitum. The degree of dental fluorosis and blood F were tested when three months; animals were killed by cervical when exposure was stopped, then evaluated pathological change in hippocampus with HE staining, [Ca2+] in synaptosomes was measured by double wavelength fluorescence spectrophotometer, and expression level of CaMKⅡα、c-fos、NF-κBρ65、Bcl-2、Bax in hippocampus CA3 region with immunohistochemistry (IHC) method.
1. As the concentration of fluoride increased, blood F increased in experimental groups and had differences or significant differences (P<0.05, P<0.01) compared with the control group, and the level and symptom of dental fluorosis in rats had increased. The teeth of high fluoride group rats became deformed and defected to some degree. Both indices also show that the fluorosis model worked in the research.
2. Chronic fluorosis can impair rat's brain nervous cells. HE staining showed that, the distribution of rat's hippocampus pyramidal cells were sparse, cell contour disappeared and vacuole in cells.
3. The test of [Ca2+] in synaptosomes showed that, synaptosomes [Ca2+] increased in the experimental groups with the fluoride concentration increased. Compared with the control group, moderate group had significant difference (P<0.01) and high-fluoride group had difference (P<0.05) in middle-term; moderate group and high-fluoride group had significant difference (P<0.01) in the end of experiment.
4. IHC staning showed that, the expression level of protein CaMKⅡα、c-fos and NF-κBρ65 increased with the growth of fluoride concentration. Compared with control group, CaMKⅡαmoderate group and high-fluoride group had difference (P<0.05), c-fos moderate group and high-fluoride group had difference or statistical difference (P<0.05 or P<0.01), NF-κBρ65 had no significant difference in middle-term; CaMKⅡαand c-fos moderate group and high-fluoride group had statistical difference (P<0.01), NF-κBρ65 moderate group had difference (P<0.05) in the end of experiment.
5. IHC staning also showed that, the expression level of protein Bcl-2 and Bax decreased with the growth of fluoride concentration. Compared with control group, Bcl-2 moderate group and high-fluoride group had difference or significant difference (P<0.05 or P<0.01), Bax moderate group and high-fluoride group had significant difference (P<0.01) in middle-term; Bcl-2 moderate group had difference (P<0.05), high-fluoride group had significant difference (P<0.01), Bax low-fluoride group had difference (P<0.05), moderate group and high-fluoride group had significant difference (P<0.01) in the end of experiment. And Bax/Bcl-2 moderate group and high-fluoride group had increased (P<0.05) in the end of experiment, compared with control group.
Above all, chronic fluoride exposure had toxic effect on the central nervous system. Chronic fluorosis could injure the nerve cells in the hippocampus CA3 region to some degree. Our results show that the hippocampus synaptosomes [Ca+] were overloaded and the expression level of CaMKⅡα、c-fos、NF-κBρ65、Bcl-2 and Bax were abnormally in experimental groups. So chronic fluorosis could induction nerve cells tend to apoptosis eventually. Degenerative change also can cause nerve cell apoptosis, and fluorine aggravated this change. The study on Ca2+ channel signal may be the molecular basis of central nervous system damage by fluorosis. And NF-κB may be one of the related molecular target factors in central nervous system damage by fluorosis. So we can make some deeper research in early-animal-development and it can offer us a theoretical basis in research of NF-κB as an environmental neurotoxic substance biomarker.
目前普遍认为,神经毒物引起的神经系统损伤与G蛋白信号转导通路中Ca2+稳态失调有密切关系。其机制可能与神经细胞内对氧化应激敏感且受钙离子调控的核转录因子(nuclear factor kappa-B, NF-κB)表达等有关。因此,本实验通过复制饮水型慢性氟中毒动物模型,以观察和检测氟中毒引起氟斑牙、血氟水平异常及海马神经细胞形态结构改变为基础,首次在氟的神经毒性研究中将钙离子信号通路与氧化应激理论结合,检测氟中毒对大鼠海马突触体内Ca2+浓度以及钙离子信号通路中CaMKⅡ、c-fos、NF-κB、Bcl-2及Bax蛋白表达的影响。
研究方法：152只初断乳雄性SD大鼠随机分为四组,即对照组(饮用自来水,水氟含量低于0.5mg/L),低氟组、中氟组、高氟组(饮水含氟化钠分别为15mg/L、30mg/L、60mg/L)。各组以配制的溶液作为饮水唯一来源,自由摄食、饮水,饲养时间为18个月。染氟初期(3月龄)对大鼠进行氟斑牙和血氟检测,染氟中期(9月龄)和染氟结束(18月龄)分两批断头处死大鼠,HE染色检测海马CA3区病理学改变,荧光指示剂Fura-2/AM检测慢性氟中毒大鼠海马突触体内Ca2+浓度的变化,免疫组化法检测海马CA3区CaMKⅡα、c-fos、NF-κBρ65、Bcl-2及Bax蛋白表达的改变。
1、过量氟摄入会导致大鼠氟斑牙发生,随染氟浓度升高,大鼠氟斑牙症状加剧,切齿明显变形、缺损并出现白垩状横纹；各染氟组血氟浓度与对照组相比显著或极显著升高(P<0.05或P<0.01)。表明动物氟中毒模型复制成功。
2、HE染色结果显示,慢性氟中毒可损伤大鼠神经细胞形态结构。与对照组相比,染氟组大鼠海马神经细胞分布稀疏,细胞轮廓消失,并出现空泡。且这种变化随染氟时间和染氟浓度的递增而更为显著。
3、突触体Ca2+浓度检测结果显示,随大鼠月龄增长,对照组突触体Ca2+浓度有升高的趋势,而染氟处理加剧了Ca2+的超载。染氟中期：与对照组相比,中氟组、高氟组突触体Ca2+浓度显著或极显著升高(P<0.05或P<0.01)；染氟结束：与对照组相比,中氟组、高氟组突触体Ca2+浓度极显著升高(P<0.01)。
4、IHC结果显示,随大鼠月龄增长,对照组及各染氟组CaMKⅡα、c-fos、NF-κBρ65蛋白表达均有不同水平的上升,且染氟时间和染氟剂量的递增使这种变化更为显著。染氟中期：与对照组相比,中氟组、高氟组CaMKⅡα表达显著升高(P<0.05),c-fos表达显著或极显著升高(P<0.05或P<0.01),NF-κBρ65表达虽无显著性差异,但随染氟剂量升高其表达有上升的趋势；染氟结束：与对照组相比,中氟组、高氟组CaMKⅡαc-fos表达极显著升高(P<0.01),中氟组NF-κBρ65表达显著升高(P<0.05)。
5、IHC结果显示,随大鼠月龄增长,对照组及各染氟组Bcl-2和Bax蛋白表达水平均有不同水平的下降,且染氟时间和染氟剂量的递增使这种变化更为显著。染氟中期：与对照组相比,中氟组、高氟组Bcl-2表达显著或极显著下降(P<0.05或P<0.01),Bax表达极显著下降(P<0.01)；染氟结束：与对照组相比,中氟组、高氟组Bcl-2表达显著或极显著下降(P<0.05或P<0.01),低氟组、中氟组、高氟组Bax表达显著或极显著下降(P<0.05,P<0.01,P<0.01)。同时,染氟中期：Bax与Bcl-2比值(Bax/Bcl-2)随染氟时间和染氟浓度的递增有升高的趋势；染氟结束：与对照组相比,中氟组、高氟组Bax/Bcl-2比值显著上升(P<0.05),提示神经细胞处于凋亡状态。
综合上述,慢性氟暴露对中枢神经系统有毒性作用。氟可导致海马神经细胞形态结构发生改变,引起海马突触体Ca2+超载,继而导致钙离子信号通路中CaMKⅡα、c-fos、NF-κBρ65、Bcl-2及Bax的蛋白表达异常,最终诱导神经细胞趋于凋亡。衰老过程中,神经细胞的退行性改变也可导致大鼠神经细胞凋亡,而染氟处理加剧了这种变化。本研究进一步阐明了氟神经毒性对钙离子信号通路影响的分子机理,为深入探讨慢性氟中毒对中枢神经系统毒性作用的分子生物学机制提供了一定的理论基础。此外,NF-κB的表达与染氟时间、浓度有敏感的量效关系,可能是氟神经毒性相关靶分子,这为开展氟神经毒性的生物标志物研究提供一定的理论依据。
Moderate fluoride is the foundation of normal physiological activities. But the fluoride is a long-term accumulated poison, and excess intake of fluorine can cause skeletal fluorosis, dental fluorosis so far as to blood and nervous system damage. Nerve tissues are sensitive to fluorine particularly. Hippocampus as a target site of fluorosis in central nervous systems, which synaptic plasticity of nerve cells is vulnerable by affecting fluorine. In recent years, through the study on neurotoxic mechanism of fluorine, people put forward two theories that the theory of G protein signal transduction and the theory of oxidative stress.
Generally thought, there is a close relation between the nervous system damage caused by nerve poison and Ca2+ steady-state disorder in G protein signal transduction pathways. The mechanism may relate to Nuclear factor-κB (NF-κB) which is sensitive in oxidative stress and regulated by Ca2+. Thus, we chose rat model of chronic fluorosis to explore the effects of different doses of fluoride on dental fluorosis, blood F and nerve cell structure firstly. Then combining calcium signaling pathways theory with oxidative stress theory for the first time, we detected calcium ion concentration ([Ca2+]) and the expression level of CaMKⅡ, c-fos, NF-κB, Bcl-2 and Bax.
152, just weaning male Sprague-Dawley rats were randomly divided into four groups and given 15,30,60 mg/L NaF solution and distilled water respectively for 9 and 18 months. Rats were fed standard diet throughout the experiment and water was given ad libitum. The degree of dental fluorosis and blood F were tested when three months; animals were killed by cervical when exposure was stopped, then evaluated pathological change in hippocampus with HE staining, [Ca2+] in synaptosomes was measured by double wavelength fluorescence spectrophotometer, and expression level of CaMKⅡα、c-fos、NF-κBρ65、Bcl-2、Bax in hippocampus CA3 region with immunohistochemistry (IHC) method.
1. As the concentration of fluoride increased, blood F increased in experimental groups and had differences or significant differences (P<0.05, P<0.01) compared with the control group, and the level and symptom of dental fluorosis in rats had increased. The teeth of high fluoride group rats became deformed and defected to some degree. Both indices also show that the fluorosis model worked in the research.
2. Chronic fluorosis can impair rat's brain nervous cells. HE staining showed that, the distribution of rat's hippocampus pyramidal cells were sparse, cell contour disappeared and vacuole in cells.
3. The test of [Ca2+] in synaptosomes showed that, synaptosomes [Ca2+] increased in the experimental groups with the fluoride concentration increased. Compared with the control group, moderate group had significant difference (P<0.01) and high-fluoride group had difference (P<0.05) in middle-term; moderate group and high-fluoride group had significant difference (P<0.01) in the end of experiment.
4. IHC staning showed that, the expression level of protein CaMKⅡα、c-fos and NF-κBρ65 increased with the growth of fluoride concentration. Compared with control group, CaMKⅡαmoderate group and high-fluoride group had difference (P<0.05), c-fos moderate group and high-fluoride group had difference or statistical difference (P<0.05 or P<0.01), NF-κBρ65 had no significant difference in middle-term; CaMKⅡαand c-fos moderate group and high-fluoride group had statistical difference (P<0.01), NF-κBρ65 moderate group had difference (P<0.05) in the end of experiment.
5. IHC staning also showed that, the expression level of protein Bcl-2 and Bax decreased with the growth of fluoride concentration. Compared with control group, Bcl-2 moderate group and high-fluoride group had difference or significant difference (P<0.05 or P<0.01), Bax moderate group and high-fluoride group had significant difference (P<0.01) in middle-term; Bcl-2 moderate group had difference (P<0.05), high-fluoride group had significant difference (P<0.01), Bax low-fluoride group had difference (P<0.05), moderate group and high-fluoride group had significant difference (P<0.01) in the end of experiment. And Bax/Bcl-2 moderate group and high-fluoride group had increased (P<0.05) in the end of experiment, compared with control group.
Above all, chronic fluoride exposure had toxic effect on the central nervous system. Chronic fluorosis could injure the nerve cells in the hippocampus CA3 region to some degree. Our results show that the hippocampus synaptosomes [Ca+] were overloaded and the expression level of CaMKⅡα、c-fos、NF-κBρ65、Bcl-2 and Bax were abnormally in experimental groups. So chronic fluorosis could induction nerve cells tend to apoptosis eventually. Degenerative change also can cause nerve cell apoptosis, and fluorine aggravated this change. The study on Ca2+ channel signal may be the molecular basis of central nervous system damage by fluorosis. And NF-κB may be one of the related molecular target factors in central nervous system damage by fluorosis. So we can make some deeper research in early-animal-development and it can offer us a theoretical basis in research of NF-κB as an environmental neurotoxic substance biomarker.
引文
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