川楝素对孕鼠的胚胎毒性与子宫局部免疫毒理学研究
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摘要
早期胚胎死亡是生殖生物学领域仍然没有解决的重要问题。据文献介绍，哺乳动物胚胎约有40%～60%不能发育到正常分娩即死亡，其中着床前后发生的早期胚胎死亡约占胚胎死亡的60%。有一定比例的早期胚胎死亡与胚胎染色体畸变、性器官解剖病变及母体内分泌紊乱有关，但是超过40%的早期胚胎死亡原因不明。近年认为不明原因的早期胚胎死亡与母胎界面上的免疫调节紊乱有关。但是对于引起母体免疫调节紊乱的因素是什么，未见有报道。本论文首先对川楝素的胚胎毒性进行了细致研究，进而研究川楝素引起胚胎死亡的免疫毒理学机制，探讨外界化学物质因素对妊娠母体的免疫毒理与其引起早期胚胎死亡的相关性。
1．用50%的乙醇对78%川楝素进行重结晶，得到白色针状结晶。薄层层析结果显示出两个粉红色的斑点，为川楝素的两个同分异构分子。使用高压液相色谱测得的提纯品川楝素含量为99.64%。表明乙醇重结晶方法提纯川楝素粗品效果可靠，切实可行。
2．用寇氏（k?rber）法测定川楝素对昆明小鼠的腹腔注射LD50。用10%丙二醇生理盐水溶液作溶媒溶解含量为99.64%川楝素，测得LD50值95%平均可信限为13.84±1.45 mg/kg，为胚胎毒性实验提供依据。
3．研究川楝素对昆明小鼠的胚胎毒性。取体重18～25g雌鼠，超数排卵后当晚与公鼠交配。获得的孕鼠随机分为6组，分别用于研究孕鼠2-细胞胚、桑葚胚、囊胚3个时期川楝素对胚胎的毒性。每个时期均设对照组，以小鼠腹腔注射半数致死量（LD50）1/30的川楝素剂量对以上3个时期实验组孕鼠染毒2次，对照组孕鼠用等量PBS液注射；研究着床时期胚胎不进行超数排卵，但实验组孕鼠染毒3次，对照组孕鼠用等量PBS液注射。最后计数、观察4个时期孕鼠子宫内的胚胎数量和形态表现。结果：2-细胞胚、桑葚胚、囊胚时期实验组胚胎总数与对照组相比，没有统计学上差异（P > 0.05）； 2-细胞时期实验组正常胚胎、异常胚胎数量与对照组相比，也无统计学上的差异（P > 0.05）；桑葚胚、囊胚时期实验组正常胚胎、异常胚胎数量与对照组相比，具有极显著差异（P < 0.01）。3次染毒对着床后的胚胎毒性最大，子宫内胚胎几乎全部溶解，无法计数。母体组织病理切片观察发现川楝素对主要器官心、肝、肺、肾、子宫仅有轻微损害，提示腹腔注射小剂量川楝素对怀孕小鼠具有特定的胚胎毒性。
4．研究川楝素诱发的小鼠胚胎毒性与子宫局部CD4+、CD8+细胞数量的关系。采用免疫组织化学方法，对桑葚胚、囊胚、着床期子宫局部的CD4+、CD8+细胞进行了检测。结果显示，实验组子宫局部的CD4+、CD8+细胞数在以上三个阶段均明显高于对照
组；对照组子宫局部CD4+数从桑葚胚、囊胚到着床期呈逐步上升趋势，而实验组CD4+数在桑葚胚到囊胚阶段呈陡然上升趋势，在囊胚到着床期阶段又呈陡然下降趋势；对照组子宫局部CD8+数在桑葚胚到囊胚阶段缓慢上升，之后则急剧下降，实验组CD8+数在以上三个阶段则呈缓慢下降趋势。以上结果表明，子宫局部CD4+、CD8+细胞增多与川楝素引起的早期胚胎死亡有关。
5．采用酶联免疫吸附试验，研究川楝素诱发的小鼠胚胎毒性与Th1细胞因子TNF-α和Th2细胞因子IL-10含量的关系。结果显示，在小鼠早期妊娠的以上三个阶段，实验组IL-10含量显著低于对照组，而TNF-α的含量显著高于对照组；三个阶段对照组IL-10、TNF-α的含量均呈缓慢上升趋势，而实验组IL-10、TNF-α的含量上升或下降都呈急剧或陡然的形式。表明川楝素引起的孕鼠子宫局部Th1细胞因子TNF-α增多和Th2细胞因子IL-10减少是川楝素引起的小鼠早期胚胎死亡的免疫毒理学原因。
Early embryo death and miscarriages are unsolved problems in reproductive biology. According to references, 40%～60% embryos in mammal can not carry a pregnancy to term, 60% of which occurred before or after implantation stages. A substantial proportion of early embryo death and miscarriages are caused by chromosomal, anatomical and endocrinological abnormalities, up to 40% of fetal losses remain a consequence of unexplained aetiology. Recently, it is believed that unexplained fetal losses are related with disorder of cytokine net- works in fetomaternal interface. This paper took Toosendanin as a toxic agent, investigating embryotoxicity of Toosendanin on KM mice and immunological toxicological mechanism in uteris, finding out the relationships between embryotoxicity and immunological toxicological mechanism of Toosendanin.
1. Purification of Toosendanin was performed by re-crystallizing technique with ethanol.Using thin-layer chromatology and high performance liquid chromatography（HPLC）to determine the content of Toosendanin and the results is 99.64%. It indicated that re-crystallizing technique is reliable and feasible in determining the content of Toosendanin.
2. Taking 10% Propylene Glycol physiological saline as dissolvent for Toosendanin.20 of 90 mice which half is male and another half is female was used to measure 100% lethal dose first, the rest was divided into 7 groups randomly. The ratio of high dose group and low dose group is set up as 1.2. The LD50 values in this experiment is 13.84 mg/kg, with the 95% confidence limit of 13.84±1.45 mg/kg.
3. Virgin female mice weighing 18～25g were superovulated, and then mated with male mice. The acquired pregnant mice were divided into 6 groups for embryotoxicity research of toosendanin on fetuses of mice in 2-Cell, Morula, Blastocysts Stages. Control group was set up in each of these three stages. Every pregnant mouse of treated and control groups in the three stages was given the dose of 1/30 LD50 toosendanin and same amount of PBS 2 times by ip injection respectively. Superovulation need not be carried out for embryotoxicity study
of toosendanin in Implantation Stage, but each pregnant mice in treated and control group was given the dose of 1/30 LD50 toosendanin and PBS 3 times by ip injection respectively. Finally, the number and configuration of embryo in uteri of all groups were counted and examined. Results: Total embryo of treated group In 2-Cell, Morula and Blastocysts Stages had no significance difference comparing with corresponding control group(P > 0.05); Number of normal and abnormal embryo of treated group in 2-Cell Stages had no significance difference comparing with control group either(P > 0.05); Number of normal and abnormal embryo of treated group In Morula and Blastocysts Stages had great significance difference comparing with corresponding control group(P < 0.01). Due to injection to the treated group 3 times in Implantation Stage, almost all the fetuses in uteri had been melting, and counting of them could not be performed while healthy fetuses could be seen and counted clearly in control group. There are only mild histological changes in maternal heart, liver, lung, kidney and uteri in the all treated groups. All above means that injecting ip a small amount of toosendanin to pregnant KM mice may has special embryotoxicity.
4. Investigating the relationship between early embryo death inducing by Toosendanin and the numbers of CD4+、CD8+ T lymphocytes in maternal uteris.Using Immunhisto- chemistry technique to determine the CD4+、CD8+ cells, and results show that the numbers of CD4+、CD8+ cells in treated groups are all higher than in controlled groups in above three stages; The numbers of CD4+ lymphocytes in controlled groups ascend gradually, and in treated groups rise sharply first, then descend steeply; The numbers of CD8+ lymphocytes in controlled groups ascend gradually first, then descend steeply, and in treated groups descend gradually.These results indicated that enhancement in CD4+、CD8+ T lymphocytes in the uteris is
1．用50%的乙醇对78%川楝素进行重结晶，得到白色针状结晶。薄层层析结果显示出两个粉红色的斑点，为川楝素的两个同分异构分子。使用高压液相色谱测得的提纯品川楝素含量为99.64%。表明乙醇重结晶方法提纯川楝素粗品效果可靠，切实可行。
2．用寇氏（k?rber）法测定川楝素对昆明小鼠的腹腔注射LD50。用10%丙二醇生理盐水溶液作溶媒溶解含量为99.64%川楝素，测得LD50值95%平均可信限为13.84±1.45 mg/kg，为胚胎毒性实验提供依据。
3．研究川楝素对昆明小鼠的胚胎毒性。取体重18～25g雌鼠，超数排卵后当晚与公鼠交配。获得的孕鼠随机分为6组，分别用于研究孕鼠2-细胞胚、桑葚胚、囊胚3个时期川楝素对胚胎的毒性。每个时期均设对照组，以小鼠腹腔注射半数致死量（LD50）1/30的川楝素剂量对以上3个时期实验组孕鼠染毒2次，对照组孕鼠用等量PBS液注射；研究着床时期胚胎不进行超数排卵，但实验组孕鼠染毒3次，对照组孕鼠用等量PBS液注射。最后计数、观察4个时期孕鼠子宫内的胚胎数量和形态表现。结果：2-细胞胚、桑葚胚、囊胚时期实验组胚胎总数与对照组相比，没有统计学上差异（P > 0.05）； 2-细胞时期实验组正常胚胎、异常胚胎数量与对照组相比，也无统计学上的差异（P > 0.05）；桑葚胚、囊胚时期实验组正常胚胎、异常胚胎数量与对照组相比，具有极显著差异（P < 0.01）。3次染毒对着床后的胚胎毒性最大，子宫内胚胎几乎全部溶解，无法计数。母体组织病理切片观察发现川楝素对主要器官心、肝、肺、肾、子宫仅有轻微损害，提示腹腔注射小剂量川楝素对怀孕小鼠具有特定的胚胎毒性。
4．研究川楝素诱发的小鼠胚胎毒性与子宫局部CD4+、CD8+细胞数量的关系。采用免疫组织化学方法，对桑葚胚、囊胚、着床期子宫局部的CD4+、CD8+细胞进行了检测。结果显示，实验组子宫局部的CD4+、CD8+细胞数在以上三个阶段均明显高于对照
组；对照组子宫局部CD4+数从桑葚胚、囊胚到着床期呈逐步上升趋势，而实验组CD4+数在桑葚胚到囊胚阶段呈陡然上升趋势，在囊胚到着床期阶段又呈陡然下降趋势；对照组子宫局部CD8+数在桑葚胚到囊胚阶段缓慢上升，之后则急剧下降，实验组CD8+数在以上三个阶段则呈缓慢下降趋势。以上结果表明，子宫局部CD4+、CD8+细胞增多与川楝素引起的早期胚胎死亡有关。
5．采用酶联免疫吸附试验，研究川楝素诱发的小鼠胚胎毒性与Th1细胞因子TNF-α和Th2细胞因子IL-10含量的关系。结果显示，在小鼠早期妊娠的以上三个阶段，实验组IL-10含量显著低于对照组，而TNF-α的含量显著高于对照组；三个阶段对照组IL-10、TNF-α的含量均呈缓慢上升趋势，而实验组IL-10、TNF-α的含量上升或下降都呈急剧或陡然的形式。表明川楝素引起的孕鼠子宫局部Th1细胞因子TNF-α增多和Th2细胞因子IL-10减少是川楝素引起的小鼠早期胚胎死亡的免疫毒理学原因。
Early embryo death and miscarriages are unsolved problems in reproductive biology. According to references, 40%～60% embryos in mammal can not carry a pregnancy to term, 60% of which occurred before or after implantation stages. A substantial proportion of early embryo death and miscarriages are caused by chromosomal, anatomical and endocrinological abnormalities, up to 40% of fetal losses remain a consequence of unexplained aetiology. Recently, it is believed that unexplained fetal losses are related with disorder of cytokine net- works in fetomaternal interface. This paper took Toosendanin as a toxic agent, investigating embryotoxicity of Toosendanin on KM mice and immunological toxicological mechanism in uteris, finding out the relationships between embryotoxicity and immunological toxicological mechanism of Toosendanin.
1. Purification of Toosendanin was performed by re-crystallizing technique with ethanol.Using thin-layer chromatology and high performance liquid chromatography（HPLC）to determine the content of Toosendanin and the results is 99.64%. It indicated that re-crystallizing technique is reliable and feasible in determining the content of Toosendanin.
2. Taking 10% Propylene Glycol physiological saline as dissolvent for Toosendanin.20 of 90 mice which half is male and another half is female was used to measure 100% lethal dose first, the rest was divided into 7 groups randomly. The ratio of high dose group and low dose group is set up as 1.2. The LD50 values in this experiment is 13.84 mg/kg, with the 95% confidence limit of 13.84±1.45 mg/kg.
3. Virgin female mice weighing 18～25g were superovulated, and then mated with male mice. The acquired pregnant mice were divided into 6 groups for embryotoxicity research of toosendanin on fetuses of mice in 2-Cell, Morula, Blastocysts Stages. Control group was set up in each of these three stages. Every pregnant mouse of treated and control groups in the three stages was given the dose of 1/30 LD50 toosendanin and same amount of PBS 2 times by ip injection respectively. Superovulation need not be carried out for embryotoxicity study
of toosendanin in Implantation Stage, but each pregnant mice in treated and control group was given the dose of 1/30 LD50 toosendanin and PBS 3 times by ip injection respectively. Finally, the number and configuration of embryo in uteri of all groups were counted and examined. Results: Total embryo of treated group In 2-Cell, Morula and Blastocysts Stages had no significance difference comparing with corresponding control group(P > 0.05); Number of normal and abnormal embryo of treated group in 2-Cell Stages had no significance difference comparing with control group either(P > 0.05); Number of normal and abnormal embryo of treated group In Morula and Blastocysts Stages had great significance difference comparing with corresponding control group(P < 0.01). Due to injection to the treated group 3 times in Implantation Stage, almost all the fetuses in uteri had been melting, and counting of them could not be performed while healthy fetuses could be seen and counted clearly in control group. There are only mild histological changes in maternal heart, liver, lung, kidney and uteri in the all treated groups. All above means that injecting ip a small amount of toosendanin to pregnant KM mice may has special embryotoxicity.
4. Investigating the relationship between early embryo death inducing by Toosendanin and the numbers of CD4+、CD8+ T lymphocytes in maternal uteris.Using Immunhisto- chemistry technique to determine the CD4+、CD8+ cells, and results show that the numbers of CD4+、CD8+ cells in treated groups are all higher than in controlled groups in above three stages; The numbers of CD4+ lymphocytes in controlled groups ascend gradually, and in treated groups rise sharply first, then descend steeply; The numbers of CD8+ lymphocytes in controlled groups ascend gradually first, then descend steeply, and in treated groups descend gradually.These results indicated that enhancement in CD4+、CD8+ T lymphocytes in the uteris is
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