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
引文
[1].舒国欣,梁晓天.关于川楝素化学结构的修正[J].化学学报,1980,38(2):196~198
[2].重庆工业试验所.用苦楝皮制除蛔虫药成功[J].药学通报,1955,3(2):96
[3].张茂延,崔之贵,汪怡季,等.川楝素240的毒性及驱蛔作用初步报告[J].中医杂志,1959,(4):42~46
[4].王荫碧,闻永炘. 川楝片驱蛔的临床疗效综合报告[J]. 中医杂志,1959,(4):46~49
[5].顾羽霄.苦楝根(干)皮治疗蛔虫病的初步报告[J]. 中医杂志,1959,(4):50
[6].施玉樑,魏乃森,杨亚琴.一种作用于突触前的神经肌肉接头传递阻断剂——川楝素[J].生理学报,1980,32(3):293~297
[7].李培忠,邹镜,缪武阳.川楝素对肉毒中毒动物的治疗效果[J].中草药,1982,13(6):28~30转32
[8].赵善欢,张兴. 植物性物质川楝素的研究概况[J].华南农业大学学报。1987,8(2):57~67
[9].杨东升,张金桐. 川楝素对家蝇幼虫中肠细胞及淀粉酶活性的影响[J].寄生虫与医学昆虫学报,2002,9(1):39~43
[10].杨东升,张金桐. 川楝素对家蝇生长发育的影响.寄生虫与医学昆虫学报2001,8(4)237~243
[11].河北省人民医院眼科. 用Hela细胞单层培养法筛选抗肿瘤中草药.眼科资料汇编[J].1973,(1):33
[12].吕兰熏. 抗炎中药研究动态[J].陕西中医,1987,(8):367~368转381
[13].张兴. 川楝素对菜青虫生物活性的研究[D],华南农业大学博士论文,1988
[14].钟炽昌,谢晶曦,陈淑凤,等. 川楝素的化学结构[J].1975,33(1):35~47
[15].舒国欣,董瑞物,凌泽红. 川楝素衍生物的制备[J].中草药,1983,14(4):10~12转9
[16].周继铭,顾月翠,冉崇行,等.川楝皮中川楝素动态的研究[J].药学通报,1981,16(6):10~12
[17].钟朝杰,陈云彩,顾月翠. 连续溶剂萃取法从川楝皮水浸液中提取川楝素[J].中草药,1981,12(2):14~17
[18].许隆祺,蒋则孝,余森海,等. 全国人体寄生虫分布调查---人体蠕虫感染的地理分布特点和规律[J],中国寄生虫学与寄生虫病杂志,1995,13(2):99~103
[19].许隆祺,蒋则孝,余森海,等. 全国人体寄生虫分布调查——虫种的人群感染[J]. 中国寄生虫学与寄生虫病杂志,1995,12(1):1~7
[20].沈丽英,于小仙,丁建祖,等. 蛔虫感染对儿童健康发育的影响[J].中国寄生虫病防治杂志,1996,9(2):125~127
[21].刘桂德,姚丹妮,毛本绶. 几种驱虫药在试管内对整体猪蛔虫的麻痹作用[J].生理学
报,1958,22(1):16~21
[22].练梅清,张殿玉,刘芷章.苦楝素驱蛔虫115例之观察报告[J].中华内科杂志,1959,7:241~244
[23].钟广. 复方苦楝皮煎剂治疗胆道蛔虫病86例[J].湖南中医杂志,1997,13(2):43
[24].张秋菊. 生物性神经毒素—A型肉毒杆菌毒素[J].国外医药—合成药、生化药、制剂分册,1994,15(5):282~284
[25].丁风华,李培忠,缪武阳. 甘草酸铵对治疗肉毒中毒药物川楝素的协同作用[J].中草药,1984,15(7):47
[26].熊春生.川楝素与肉毒素在神经肌肉接头相互作用的超微结构观察[J].药学学报,1985,20(7):495~499
[27].曹仁烈,孙在原,王仲德.中药水浸剂在试管内抗皮肤真菌的观察[J].中华皮肤科杂志,1957,4:286~290
[28].高学敏,主编. 中药学[M],人民卫生出版社,2000,867
[29].施玉樑. 刺激频率、温度、钙离子对川楝素阻遏接头传递作用的影响[J].生理学报,1981,(2):141~146.
[30].黄世楷. 川楝素对小白鼠神经肌肉接头的超微结构的影[J]. 生理学报, 1980, 32(4): 385~388
[31].施玉樑,王文萍,颜寿琪.钙离子和神经活动对川楝素引起的小终极电位频率变化的影响[J]. 生理学报, 1982, 34(3): 304~309
[32].叶琴,瞿安连,张春光,川楝素对大鼠肾上腺嗜铬细胞胞内游离钙浓度的影响[J].中国神经科学杂志2001,17(2);105~108
[33].田文皓,王忠兴,魏乃森.川楝素对呼吸中枢的抑制作用[J].生理学报,1980,32(4):338~342
[34].季宇彬.中药有效成分药理与应用[M].黑龙江科学技术出版社,1995
[35].邹镜,贾桂荣,何相义. 川楝素的药代动力学研究[J].中草药,1982,13(8):24~26转42
[36].广西壮族自治区医药研究所. 苦楝素的药理,苦楝素资料汇编,1970,27~36
[37].黄庆彰. 苦楝素药理毒理作用[J].广西卫生,1979,(5):46
[38].贾瑞鹏,周性明,陈甸英. 川楝子油对雄性大鼠的抗生育作用[J].南京铁道医学院学报,1996,15(1):1~3
[39].李培忠,石笑春,徐在海,等. 川楝素的药理毒理学研究[J].中草药1982,13(7):29~32
[40].丁清,主编. 中草药不良反应及防治[M].中国中医药出版社,1992
[41].沈亚琴,张明发,朱白平. 苦楝皮的镇痛抗炎和抗血栓形成作用[J].1998,7(10):30~31
[42]. 张兴,赵善欢. 楝科植物对几种害虫的拒食和忌避作用[J].华南农学院学报,1983,4
(3):1~7
[43].李云寿,邹华英,胡萃,等. 川楝素对斜纹夜蛾幼虫取食行为的影响[J].华东昆虫学报,1999,8(2):4~5
[44].赵善欢,曹毅,彭中健,等. 应用天然植物产品川楝素防治菜青虫试验[J].植物保护学报,1985,12(2):125~131
[45].赵善欢,张兴. 植物质杀虫剂对水稻三化螟的拒食及内吸毒力试验[J].中国农业科学,1982,(2):55~62
[46].吴树忠. 川楝子治疗淋证36例临床疗效观察[J].中国中医急症,1994.(2):67~70
[47].王云玲,耿荣良,丁建新. 川楝素静脉注射剂的研究[J].中草药,1982,13(1):13~20
[48].李发美,主编. 医药高效液相色谱技术[M].第一版.人民卫生出版社,1999
[49].史志诚,主编. 动物毒物学[M]. 中国农业出版社,2001,889~893
[50].江泉观,主编. 基础毒理学[M] 化学工业出版社, 1991,389~390
[51].张兴,王兴林,冯俊涛,等. 植物性杀虫剂川楝素的开发研究[J]. 西北农业大学学报,1993,21(4):1~5
[52].沈国光,卓晓亮,施玉樑.川楝素在大鼠大脑皮层匀浆中的结合点位[J].生理学报,1994,46(6):546~552
[53].上海第一医学院卫生统计学教研组. 医学统计方法[M].第一版.上海科学技术出版社,1979,32~33,110~112
[54].朱蓓蕾,编著. 动物毒物学[M].第一版.上海科学技术出版社,1989
[55].俞慧珠,叶百宽. 小白鼠胚胎发生[M].科学出版社,1985,17~26
[56].王建辰,章孝荣. 动物生殖调控[M].安徽科学技术出版社,1998
[57].甘肃农业大学,主编. 兽医产科学[M].第二版,农业出版社,1994,172~177
[58].李权武,王建华,李明晖. 动物繁殖毒理学[M].陕西科学技术出版社,1999,39~41
[59].李亚军,吉永华. 汞与砷毒理机制的新探索[J].上海中医药杂志,1999,(3):40~42
[60].刘佳,吴克枫,俞红. 三氧化二砷对小鼠免疫功能的影响[J].中国药理学与毒理学杂志,1997,11(2):140
[61].朱寿彭. 放射毒理学[M].第二版.原子能出版社.1992,10~14
[62].朱寿彭.浓缩铀的放射毒理学研究[J].工业卫生与职业病,1987,13(6):371
[63].朱寿彭,赖冠华,王六一. 浓缩铀诱发免疫细胞的放射免疫毒理效应[J].中华劳动卫生职业病杂志,1994,12(4):202~204
[64].寇庆瑞,唐会清,袁淑梅.工频高压电场对小鼠免疫功能的影响[J]. 中国药理学与毒理学杂志,1997,11(2):140
[65].陈成章. 我国免疫毒理学的研究进展[J].卫生毒理学杂志,2000,14 (2):68~71
[66].冯丰,朱兰. 人群免疫毒理学近况[J].国外医学免疫学分册,1999,22(2)61~64
[67].雷志明,薛彬,宁殿峰. 吗啡对小鼠免疫功能的影响[J].中国药理学与毒理学杂志,
1997,11(2):140
[68].王艳华,杨贵贞. 地塞米松诱导大鼠免疫细胞凋亡机制初探[J].中国免疫学杂志,1996,12(4):222~224
[69].高向东,吴梧桐. 当归及其成分阿魏酸对小鼠免疫功能的影响[J].中国生化药物杂志,1994 ,15 (2) :107~110
[70].朱瑞良. 中草药与动物免疫[J].中国兽医杂志,1994 ,28(3) :51~54
[71].骆和生,罗鼎辉. 免疫中药学-中药免疫药理与临床[M].北京医科大学、中国协和医科大学联合出版社,1999
[72].李卓娅,冯新为,Gemsa D. 秋水仙碱对LPS诱导的巨噬细胞TNF-α基因表达的抑制作用[J].中国免疫学杂志,1996,12(1):14~17
[73].崔树玉,薛原,杨建莉. 板蓝根研究进展[J].中草药,2001 ,32 (7) :670~671
[74].葛明珠,赵亚莉,任少林. 南沙参多糖对小鼠免疫器官辐射损伤的保护[J].中草药,1996 ,27 (11) :673~675
[75 ].梁国庆,杨则然,李继承. 含丹参、当归和川芎嗪腹膜透析液对小鼠腹腔巨噬细胞功能的影响[J].杭州医学高等专科学校学报,2001 ,22 (3) :129~131
[76 ].汤新慧. 灵芝水煎剂对小鼠免疫功能的影响[J].中医研究,2000 ,13 (6) :8~10
[77] 贾泰元. 党参对鼠J774巨噬细胞吞噬活性的增强效应[J].时珍国医国药,2000 ,11 (9) :769~770
[78 ].贾泰元.宁夏枸杞对巨噬细胞免疫活性的增强效应[J].中医研究,1999 ,12 (2) :15~16
[79].胡国俊,白惠卿. 枸杞对T、B细胞增殖和T细胞亚群变化的调节作用[J].中国免疫学杂志,1995 ,11 (3) :163~166
[80].余上才,章育正. 枸杞子和白术免疫调节作用的实验研究[J].上海免疫学杂志,1994 ,14 (1) :12~13
[81].叶丽卡,陈济民. 淫羊藿的药理研究进展[J].中国中药杂志,2001 ,26 (5) :293~295.
[82].王筠默. 人参药理研究的进展[J]. 人参研究,2001 ,13(3) :2~10
[83].王金宝,孙月平,张乐萃,等. 中药对免疫抑制鸡某些细胞免疫指标影响的研究[J].中兽医医药杂志, 1999 ,(3) :9~11
[84].符华林. 中药调节动物免疫作用的研究进展[J].兽药与饲料添加剂,2002 ,7 (4) :30~34
[85].董发明,韦旭斌. 中药苍芪散提高鸡新城疫疫苗免疫功能的研究[J].中兽医学杂志,1996 , (1) :4~6
[86].范勇毅,崔光辉,管远志. 雷公藤单体T4体外给药对IL-2R表达的影响[J].中国免疫学杂志,1996,12(3):171~173
[87].范勇毅,崔光辉,张蒲,雷公藤单体T4体外给药对细胞免疫功能的影响、对IL-2产生水平的抑制作用[J].中国实验临床免疫学杂志,1990,(2):6
[88].赵勇,崔正言,张玲,等. 淫羊藿甙协同诱生IL-2,3,6作用[J].中国免疫学杂志,
1996,12(1):43~45
[89].安云庆,解培英,李玉兰,等. 中药本草九代对小鼠血清生物学活性及T、B细胞增殖、分化的影响[J].中国免疫血杂志,1998,14(5):360~362
[90].胡国俊,白惠卿,杜守英,等. 枸杞对IL-2产生和IL-2受体(α、β)表达的调节[J].中国免疫学杂志,1995,11(4):253~256
[91].刘良,李晓娟,王培训,等. 青藤碱对人体外固血单个核细胞IL-1β和IL-8细胞因子基因表达的影响[J].中国免疫学杂志,2002,18(4):241~244
[92].付秀花,王恬,顾宏伟. 中草药的免疫增强作用[J].畜牧与兽医,2002 ,34,(8) :40~43
[93].王文俊,吴咸中,姚智. 大黄素、丹参素对免疫细胞分泌炎性细胞因子的调节[J].中国免疫学杂志,1995,11(6):370~372
[94].肖崇厚,孙奕,骆永珍,等. 川产淫羊藿对羟基脲阳虚小鼠IL-2活性的影响[J].中国免疫学杂志,1995,11(6):373~378
[95].温斌,吕昌龙,曹雅明,等.灰树花提取成分对小鼠免疫功能影响的实验研究[J],中国免疫学杂志,2002,18(8):550~552
[96].万克青,杨旭,郑宣鹤.香菇多糖注射液对慢性活动型肝炎外固血T淋巴细胞亚群和IL-2R表达作用的研究[J].中国免疫学杂志,1995,11(5):298~299
[97].杨奇,王建华. 胚胎毒性研究进展[J].动物医学进展,2001,22(2):29~31
[98].薛彬. 我国免疫毒理学现况及展望[J].卫生毒理学杂志,2000,14(1)8~9
[99].郝利平,主编. 食品添加剂[M].中国农业大学出版社,2002
[100].钟晗. 合成色素危害健康,环球时报,2002,3,11
[101].汪猷,主编. 天花粉蛋白[M].第二版,科学出版社,2001
[102].罗丽兰. 生殖免疫学[M].湖北科学技术出版社,第一版,1998
[103].谭宗建,李尚为,曹泽毅. 早期妊娠的免疫耐受机制[J].生殖与避孕,2002,22(4):236~242
[104].黄荷凤, 何赛男. 子宫前列腺素研究进展[J].国外医学(妇产科分册), 1995, 22(5): 265~269
[105].靳亚平,王爱华,王建辰. 妊娠的细胞免疫调节[J].动物医学进展,2000,21(4):90~95
[106].王建辰,章孝荣,主编. 动物生殖调控[M].安徽科学技术出版社,1998
[107].李引乾,王建华,靳亚平,等. 硒中毒对家兔繁殖机能的影响[J].西北农业大学学报(自然科学版),2001,29(5):30~32
[108].钟秀会. Th1细胞因子反应与奶牛早期胚胎丢失的相关性研究[D].中国农业大学博士学位论文,1999
[109].曹咏清,陈幼珍. 人重组γ干扰素(hrIFN-γ)对人胎盘滋养层HCG分泌和蜕膜蛋白合成的影响[J].生殖与避孕,1996,16(6):413~417
[110].殷国荣,主编. 医学寄生虫学[M].科学出版社,2004,190~191
[111].李引乾. 硒对山羊妊娠调节的细胞与分子免疫学机制[D].西北农林科技大学博士学位论文,2001
[112].钟秀会,周占祥,孙秉贵,等. 黄芩白术对LPS诱导流产小鼠的保胎作用及子宫内TNF-α含量的影响[J].畜牧兽医学报,2000,31(5):430~435
[113].王建华,张树方,主编. 动物中毒病及毒理学[M]第二版,台湾中草药杂志社出版,2002.154~155
[114].龚非力,主编. 医学免疫学[M].人民卫生出版社,2001
[115].魏海明,刘杰,田志刚. 检测Th1/Th2亚群的临床意义[J].中华医学检验杂志,1998
[116].Xu LQ, Suzuki Noriji, Jiang ZX, et al. Pilot study on contamination of soil with ascarid egg and other parasites in rural areas of three southern provinces in china[J]. Chinese Journal of Parasitology & Parasitic Diseases,1997,15(4):246~250
[117].Wang ZF, Shi YL. Modulation of inward rectifier potassium channel by toosendanin, a presynaptic blocker[J].Neuroscience Research,2001,40(3):211~215
[118].Cui ZJ, He XH. The pre-synaptic blocker toosendanin does not inhibit secretion in exocrine cells[J]. World J Gastroenterol , 2002,8(5):918~922
[119].Chen WY,Yin PB,YeWL,et al.Toosendanin-induced change of dopamine level detected by microdialysis in vivo at rat striatum[J].Chinese Science Bulletin, 1999, 44(12): 1106~1110
[120].Shi YL,Chen WY.Effect of Toosendanin on acetylcholine level of rat brain, a microdialysis study [J].Brain Research,1999,850(1-2):173~178
[121].Wang ZF, Shi YL.Toosendanin-induced inhibition of small-conductance calcium- activated potassium channels in CA1 pyramidal neurons of rat hippocampus[J]. Neuroscience Letters,2001,303(1):13~16
[122].Hare WR, Schutzman H, Lee BR, etal. Chinaberry poisoning in two dogs[J].J Amvet Med Ass,1997,210:1638~1640
[123].Mendez MDC, Elias F, Aragao m, et.al, Intoxication of cattle by the fruits of melia azedarch[J].Veterinary and human toxicology 2002,44(3):145~148
[124].Descotes J.Importance of immunotoxicity in safety assessment: a medical toxicologist's perspective[J].Toxicol Lett, 2004,149(1-3): 103~108
[125].Mutti A, Buzio C, Perazzoli F, et al.Lymphocyte subpopulations in workers exposed occupationally to styrene[J].[Article in Italian] Med Lav,1992,83(2):167~77
[126].Moszczynski P, Slowinski S, Bem S, et al.Parameters of immunity acute phase reaction in men in relation to exposure duration to mercury vapours[J].Hyg Epidemiol Microbiol Immunol,1991,35(4):351~60
[127].Tryphonas H. Immunotoxicity of polychlorinated biphenyls: present status and future considerations[J].Exp Clin Immunogenet,1994;11(2-3):149~62
[128].Knutsen AP, Roodman ST, Evans RG, et al. Immune studies in dioxin-exposed Missouri residents[J].Quail Run.Bull Environ Contam Toxicol,1987;39(3):481~489
[129].Singh A, Failla ML, Deuster PA. Exercise-induced changes in immune function:effects of zinc supplementation[J].Journal of Applied Physiology,1994,76( 6)2298~2303
[130].Zedeck MS.Polycyclic aromatic hydrocarbons: a review[J].Environ.Pathol.Toxicol, 1980,3:537~541
[131].Conney AH. Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons. G. H. A. Clowes Memorial Lecture[J]. Cancer Res, 1982, 42: 4875~4891
[132].White Jr, Holsapple MP. Direct suppression of in vitro antibody production by mouse spleen cells by the carcinogen benzo(a)pyrene but not by the noncarcinogenic congener benzo(e)pyrene[J].Cancer Res,1984,44:3388~3398
[133].Wojdani A, Alfred LJ.Alterations in cell-mediated immune functions induced in mouse splenic lymphocytes by polycyclic aromatic hydrocarbons[J]. Cancer Res,1984, 44:942~946
[134].Davila DR, Romero DL, Burchiel SW. Human T cells are highly sensitive to suppression of mitogenesis by polycyclic aromatic hydrocarbons and this effect is differentially reversed by -naphthoflavone[J].Toxicol. Appl. Pharmacol, 1996, 139:333~339.
[135].Kawabata TT, White KL. Suppression of the vitro humoral immune response of mouse splenocytes by benzo(a)pyrene metabolites and inhibition of benzo(a)pyrene-induced immunosuppression by -naphthoflavone[J]. Cancer Res, 1987,47:2317~2325
[136].Yamaguchi K, Matulka RA, Shneider AM, et al. Induction of Pre B-cell apoptosis by 7,12-dimethylbenz[a]anthracene in long-term primary murine bone marrow cultures[J]. Toxicol. Appl. Pharmacol, 1997, 147: 190~199
[137].Yamaguchi K, Near RI, Matulka RA, et al. Activation of the aryl hydrocarbon receptor/transcription factor and bone marrow stromal cell-dependent preB cell apoptosis [J]. J. Immunol, 1997, 158: 2165~2170
[138].Mann KK, Doerre S, Schlezinger JJ, et al. The role of NF-B as a survival factor in environmental chemical-induced pre-B cell apoptosis[J]. Mol. Pharmacol, 2001, 59:302~308
[139].Mann KK, Matulka RA, Hahn ME, et al. The role of polycyclic aromatic hydrocarbon metabolism in dimethylbenz[a]anthracene-induced pre-B lymphocyte apoptosis[J].
Toxicol. Appl. Pharmacol, 1999,161:10~15
[140].Jong WH, Kroese ED, Vos JG. Detection of immunotoxicity of benzo[a]pyrene in a subacute toxicity study after oral exposure in rats, Toxicological Sciences, 1999, 50:214~220
[141].Yang HM,Butterworth L, Munson AE,et al. Respiratory Exposure to Diesel Exhaust Particles Decreases the Spleen IgM Response to a T Cell-Dependent Antigen in Female B6C3F1 Mice[J].Toxicological Sciences,2003,71:207~216
[142].Andrew A. Rooney, Raymond A. Matulka,and Robert W. Luebke Developmental Atrazine Exposure Suppresses Immune Function in Male, but not Female Sprague-Dawley Rats[J].Toxicological Sciences,2003,76:366~375
[143].Hryphonas H, Arnold DL, Bryce F,et al. Effects of toxaphene on the immune system of cynomolgus (Macaca fascicularis) monkeys. Food and chemical [J]. Toxicology, 2001, 39:947~958
[144].McConnachie PR, Zahalsky AC. Immune alterations in humans exposed to the termiticide technical chlordane[J].Arch Environ Health, 1992,47(4): 295~301
[145].Hastings KL. Implications of the new FDA/CDER immunotoxicology guidance for drugs[J].Int Immunopharmacol,2002,2(11):1613~1618
[146].Pelaney B,phillipsk,Bnswell D,et,al.Immunotoxicity of a standardized citrus polymetho -xylated flavone extract [J]. food and chemical Toxicology, 2001, 39:1087~1094
[147].Abuharfeil N, Sarsour E, Hassuneh M. The effect of sodium nitrite on some parameters of the immune system[J].Food and chemical Toxicology,2001,39:119~124
[148].Grassman KA, Fox GA, Scanlon PF.Organocholrine- associated immunosuppression in prefledgling Caspiantems and herring gulls from the Great Lakes: An ecoepidemiological study [J]. Eviron Health Perspect,1996,104: 829~836
[149].Tomer RS, Kerkvliet.Reduced T-helper cell function in mice exposed to 2, 3, 7, 8- tet- rachlorodibenzo-p-dioxin(TCDD) [J].Toxicol Lett 1991, 57: 55~61
[150].Zelikoff JT, Metal pollution-induced immunomodulation in fish[J]. Annu Rev Fish Dsease,1993, 2:305~312
[151].Faisal M, Weeks BA, Vogelbein WK. Aberration in natural cytotoxic activity of anterior kidney leukocytes in Fundulus heteroclitus exposed to toxic chemicals[J].Vet Immunol Immunopathol. 1991, 29: 339~344
[152].Faisal M, Marzouk SM, Smith CL, et al. Proliferative response of spot leukocytes to mitogens from a polycyclic aromatic hydrocarbon contaminated environment[J]. Immunopharmacol Immunotoxicol. 1991, 13: 311~319
[153].Theumer MG, Lopez AG, Masih DT,et al. Immunobiological effects of AFB1 and
AFB1-FB1 mixture in experimental subchronic mycotoxicoses in rats[J]. Toxicology, 2003, 186(1-2):159~70
[154].Roby KF, Laham N, Kroning H, et al. Expressin and localization of messenger RNA for tumor necrosis factor receptor in pregnant mouse uteris and placenta [J]. Endocrine, 1995, 3:557~561
[155].Watanabe M, Iwatani Y, Kaneda T, et al.Changes in T,B,and NK lymphocyte subsets during and after normal pregnancy[J].Am.J.Reprod.Immunol.,1997,37:368~377
[156].Mincheva-Nilsson L, Hammarstr?m S, Hammarstr?m ML.Human decidual leukocytes from early pregnancy contain high numbers of γδ+ cells and show selective down-regulation of alloreactivity [J]. J. Immunol., 1992, 149:2203~2211
[157].McMaster MT, Newton RC, Dey SK, et al. Activation and distribution of inflammatory cells in the mouse uterus during the periimplantation period [J]. J. Immunol, 1992, 148: 1699~1705.
[158].Brierley J,Clark DA.characterization of hormone-dependent suppressor cells in the uterus of pregnant and pseudopregnant mice[J]. J. Reprod. Immunol., 1987, 10:201~211
[159].Bischof RJ, Lee R, lee CS, et al. Dynamic changes in the lymphocyte subpopulation of pig uterine lymph nodes[J].Vet Immunopathol,1996,51:315~324
[160].Bischof RJ, Brandon MR, lee CS. Cellular immune responses in the pig uterus during pregnancy[J]. J.Reprod.Immunol,1995,29:161~178
[161].Choudhury SR, Knapp LA. Human reproductive failureⅠ:Immunological factors[J]. Human Reproduction Update, 2001,7(2):113~134
[162].King A, Hiby SE, Garder L, et al. Recognition of trophoblast HLA classⅠmolecules by decidual NK cell receptors—a review[J]. Placenta, 2000, 21:581~583
[163].Loke YW, Hiby S, King A. Human leukocyte antigen-G and reproduction[J]. J.Reprod.Immunol,1999, 43:235~242
[164].Bulmer JN, Morrison L, Longfellow M, et al. Granulated lymphocytes in human endometrium: histochemical and immnohistochemical studies [J]. Human reproduction, 1991, 6: 791~798
[165].King A,Burrows T, Verma S, et al. human uterine lymphocytes. Human Reproduction Update,1998,4: 480~485
[166].King A.Uterine leukocytes and decidualization[J]. Human Reproduction Update, 2000, 6: 28~36
[167].Vassiliadou N, Bulmer JN. Immnohistochemical evidence for increased numbers of ‘classic’ CD57+ natural killer cells in the endometrium of women suffering spontaneous early pregnancy loss[J]. Human Reproduction,1996,11:1569~1574
[168]. King A, Balendran N, Wooding P, et al. CD3-leukocytes present in the human uterus during early placentation: phenotypic and morphologic characterization of the CD56+ population [J]. Dev. Immunol., 1991, 1:169~190
[169].Loke YW, King A. Human Implantation: Cell Biology and Immunology[M].Cambridge University Press,1995
[170].Healy DL, Hodgen GD. The endocrinology of human endometrium[J].Obstet Gynecol Surv, 1983; 38: 509~530
[171].Jacobs AL, Carson DD. Uterine epithelial cell secretion of Interleukin-1 alpha induces prostaglandin E2 and PGF2α secretion by uterine stromal cells in vitro[J]. Endocrinology, 1993, 132: 300~308
[172]. Scodras JM , Parhar RS, Kennedy TG et al.Prostaglandin-mediated inactivation of natural killer cells in the murine decidua[J]. Cell Immunol, 1990, 127(2) : 352~367
[173].Maka FD, Fouche MB, Geny B, et al. Prostaglandin F2 alpha stimulates inositol phosphate production in human pregnant myometrium[J]. Prostaglandins, 1993,45(3): 269~283
[174].Baines MG, Gendron RL. Natural and experimental animal models of reproductive failure. In Chaouat, G.(ed.), Immunology of Pregnancy. CRC Press, Boca Raton, 1993, 173~203
[175].Alberman, E. The epidemiology of repeated abortion. In Beard, R.W. and Sharp, F. (eds), Early Pregnancy Loss: Mechanisms and Treatment. Springer-Verlag, New York, 1988, pp. 9~17
[176].Haimovici F, Hill JA, Anderson DJ. The effects of soluble products of activated lymphocytes and macrophages on blastocyst implantation events in vitro[J]. Biol. Reprod., 1991, 44, 69~76
[177].Suffys P, Beyaert R, Van Roy F, et al. TNF in combination with interferon-gamma is cytotoxic to normal, untransformed mouse and rat embryo fibroblast-like cells[J].Anticancer Res, 1989,9(1):167~171
[178].Chaouat G, Menu E, Clark DA, et al. Control of fetal survival in CBA x DBA/2 mice by lymphokine therapy[J]. Journal of Reproduction and Fertility 1990, 89: 447~458
[179].Lin H, Mosmann TR, Guilbert L, et al.Synthesis of T helper 2-type cytokines at the maternal-fetal interface[J]. The Journal of Immunology, 1993,151(9): 4562~4573
[180].Paulesu L, Romagnoli R, Fortino V, et al. Distribution of type-I interferon-receptors in human first trimester and term placental tissues and on isolated trophoblast cells[J].Am J Reprod Immunol, 1997, 37(6): 443~448
[181].Wegmann TG., Lin H, Guilbert L, et al. Bidirectional cytokine interactions in the
maternal-fetal relationship: is successful pregnancy a Th2 phenomenon? [J]. Immunol. Today, 1993, 14, 353~356
[182].Chaouat, G, Meliani, A.A., Martal, J. et al. IL-10 prevents naturally occurring fetal loss in the CBA×DBA/2 mating combination, and local defect in IL-10 production in this abortion-prone combination is corrected by in vivo injection of IFN- tau [J]. J. Immunol., 1995, 154: 4261~4268
[183]. McCracken SA, Gallery E, Morris JM. Pregnancy-Specific Down-Regulation of NF-κB Expression in T Cells in Humans Is Essential for the Maintenance of the Cytokine Profile Required for Pregnancy Success[J].The Journal of Immunology, 2004, 172: 4583~4591
[184].Kanda N, Tamaki K. Estrogen enhances immunoglobulin prodution by human PBMCs[J ] . J Allergy Clin Immunol,1999,103:282~288
[185].Piccinni MP, Giudizi MG, Biagiotti R, et al. Progesterone favors the development of human T helper cells producing Th2 type cytokines and and promotes both IL-4 production and membrance CD30 expression in established Th1 cell clones[J].J Immunol,1995,155:128~133
[186].Hill JA. Implications of cytokines in male and female sterility. In Chaouat, G. and Mowbray, J.F. (eds), Cellular and Molecular Biology of the Maternal-fetal Relationship. INSERM/John Libbey Eurotext, Paris, 1991, pp. 269~275
[187].Yui J, Garcia-Lloret M., Wegmann TG, et al. Cytotoxicity of tumor necrosis factor- (TNF-) and gamma-interferon (IFN-) against primary human placental trophoblasts. Placenta, 1994,15, 819~828
[188].Makhseed, M., Raghupathy, R., Azizieh, F. et al. Mitogen-induced cytokine responses of maternal lymphocytes suggest a differential Th-type bias in normal pregnancy and pregnancy failure. Am. J. Reprod. Immunol., 1999, 42, 273~281
[189].Chaouat, G., Menu, E., de Smedt, D. et al. The emerging role of IL-10 in pregnancy[J]. Am. J. Reprod. Immunol. 1996, 35, 325~328
[190].Raghupathy, R. Th1-type immunity is incompatible with successful pregnancy[J]. Immunol. Today, 1997, 18, 478~482
[191].Lin D, Smith MA, Elter J. Porphyromonas gingivalis infection in pregnant mice is associated with placental dissemination, an increase in the placental Th1/Th2 cytokine ratio, and fetal growth restriction[J]. Infect Immun 2003,71(9):5163~5168
[192]. Fried M, Muga RO, Misore AO. Malaria Elicits Type 1 Cytokines in the Human Placenta: IFN-γand TNF-αAssociated with Pregnancy Outcomes[J]. The Journal of Immunology, 1998, 160: 2523~2530
[193].Krishnan L, Guilbert LJ, Wegmann TG. T helper 1 response against Leishmania major in pregnant C57BL/6 mice increases implantation failure and fetal resorptions. Correlation with increased IFN-gamma and TNF and reduced IL-10 production by placental cells[J]. The Journal of Immunology, 1996,156( 2): 653~662
[194].Krishnan L, Guilbert LJ, Russell AS, et al.Pregnancy impairs resistance of C57BL/6 mice to Leishmania major infection and causes decreased antigen-specific IFN-gamma response and increased production of T helper 2 cytokines[J]. The Journal of Immunology, 1996, 156(2): 644~652
[195].Talwar GP, Shah S, Mukherjee S, et al.Induced termination of pregnancy by purified extracts of Azadirachta Indica (Neem): mechanisms involved[J]. Am J Reprod Immunol, 1997,37(6): 485~491
[196].Arck PC, Rose M, Hertwig K, et al. Stress and immune mediators in miscarriage [J]. Human Reproduction, 2001, 16(7): 1505~1511
[197]. Meky FA, Hardie LJ, Evans SW, et al.Deoxynivalenol-induced immunomodulation of human lymphocyte proliferation and cytokine production[J].Food Chem Toxicol, 2001, 39(8): 827~836
[198].Sugita-Konishi Y, Pestka JJ.Differential upregulation of TNF-alpha, IL-6, and IL-8 production by deoxynivalenol (vomitoxin) and other 8-ketotrichothecenes in a human macrophage model [J]. J Toxicol Environ Health A, 2001,64(8): 619~636
[199].O'Hare T, Creed F. Life events and miscarriage[J]. Br. J. Psychiatry, 1995, 167: 799~805
[200].Wasser, S.K. Stress and reproductive failure: an evolutionary approach with applications to premature labor [J]. Am. J. Obstet. Gynecol., 1999, 180: 272~274
[201].Neugebauer, R., Kline, J., Stein, Z. et al. Association of stressful life events with chromosomally normal spontaneous abortion [J]. Am. J. Epidemiol., 1996, 143: 588~ 596
[202].Stray-Pedersen B., Stray-Pedersen, M. Etiologic factors and subsequent reproductive performance in 195 couples with a prior history of habitual abortion[J]. Am. J. Obstet. Gynecol., 1984, 148: 140~146
[203].Edmonds DK, Lindsay KI, Miller JF. Early embryonic mortality in women [J]. Fertil Steril, 1982, 38:447~453
[204]. Christiansen OB. A fresh look at the causes and treatments of recurrent miscarrige, especially its immunological aspects[J]. Hum. Reprod. Update.1996, 2:271~293
[205].Boue A, Boue J, Gropp A. Cytogenetics of pregnancy wastage.Adv.Hum.Genet., 1985, 14:1~19
[206].Hill JA. Immunologic factors in recurrent spontaneous abortion [M]. In Kurpisz M.and Fernandez N.(eds), Immunology of Human Reproduction, BIOS Scientific, Oxford,
[207].Weetman AP. The immunology of pregnancy[J]. Thyroid, 1999, 9:643–646
[208].Confavreux C, Hutchinson M, Hours MM, et al. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group [J]. N Engl J Med, 1998, 339: 285~291
[209].Nelson JL, Hughes KA, Smith AG, et al.Maternal-fetal disparity in HLA class II alloantigens and the pregnancy-induced amelioration of rheumatoid arthritis[J]. N Engl J Med, 1993, 329:466~471
[210].Viganò P, Somigliana E, Mangioni S,et al. Expression of Interleukin-10 and Its Receptor Is Up-Regulated in Early Pregnant Versus Cycling Human Endometrium[J]. The Journal of Clinical Endocrinology & Metabolism. 2002,87(12): 5730~5736
[211].Chaouat G. Immunoregulatory placental functions in normal and pathological pregnancies[J]. Am J Reprod Immunol Microbiol, May 1, 1988,17(1): 18~21
[212].Noun A, Acker GM, Chaouat G, et al. Cells bearing granulocyte-macrophage and T lymphocyte antigens in the rat uterus before and during ovum implantation [J]. Clin Exp Immunol, 1989, 78(3): 494~498
[213].Clark DA.T cells in pregnancy: illusion and reality [J]. Am J Reprod Immunol, 1999, 41(4): 233~238
[214].Kwak-Kim JYH, Chung-Bang HS, Ng SC. Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF[J]. Human Reproduction, 2003,18(4): 767~773
[215].Lin H, Mosmann TR, Guilbert L, et al. Synthesis of T helper 2-type cytokines at the maternal-fetal interface[J]. J Immunol 1993,151:4562–4573.21:56~59
[216].Wilder RL. Hormones, pregnancy, and autoimmune diseases[J]. Ann. NY Acad. Sci. 1998, 840:45~50
[217].Ostensen M. Sex hormone and pregnancy in rheumatoid arthritis and systemic lupus erythematosus[J]. Ann. NY Acad. Sci. 1999, 876:131~144
[218].Miyaura H, Iwata M. Direct and indirect inhibition of Th1 development by progesterone and glucocorticoids[J]. The Journal of Immunology, 2002, 168: 1087~1094
[219].Beutler B, Cerami A. The biology of cachectin/TNF-α primary mediator of the host response [J]. Annu. Rev. Immunol, 1989, 7:625~655
[220].Robaye BR, Fiers W, Dumont JE, et al. Tumor necrosis factor induces apoptosis (programmed cell death) in normal endothelial cells in vitro[J]. Am. J. Pathol. 1991, 138: 447~453
[221].Terranova PF, Hunter VJ, Roby KF, et al. Tumor necrosis factor- alpha in the female
reproductive tract[J]. Proc. Soc. Exp. Biol. Med. 1995, 209:325~342
[222].Parr EL, Chen HL, Parr MB, et al. Synthesis and granular localization of tumor necrosis factor-alpha in activated NK cells in the pregnant mouse uterus[J].J Reprod Immunol, 1995, 28(1): 31~40
[223].Roby KF, Hunt JS. Mouse endometrial tumor necrosis factor- alpha mRNA and protein localization and regulation by estradiol and progesterone [J]. Endocrinology, 1994, 135: 2780~2783
[224].Gorivodsky M, Zemlyak I, Orenstein H, et al.TNF- alpha Messenger RNA and protein expression in the uteroplacental unit of mice with pregnancy loss [J]. The Journal of Immunology, 1998, 160: 4280~4288
[225]. Romero R, Sirtori M, Oyarzun E, et al. Infection and labor. V. Prevalence, microbiology, and clinical significance of intraamniotic infection in women with preterm labor and intact membranes[J]. Am J Obstet Gynecol, 1989, 161(3): 817~824
[226].Romero R, Manogue KR, Mitchell MD, et al.Infection and labor. IV. Cachectin-tumor necrosis factor in the amniotic fluid of women with intraamniotic infection and preterm labor[J].Am J Obstet Gynecol, Aug 1989; 161(2): 336~341
[227].Gendron RL, Nestel FP, Lapp WS, et al. Lipopolysaccharide-induced fetal resorption in mice is associated with the intrauterine production of tumor necrosis factor-alpha[J]. J. Reprod. Fertil. 1990,90:395~402
[228]. Heyborne KD, Witkin SS, McGregor JA. Tumor necrosis factor- in midtrimester amniotic fluid is associated with impaired intrauterine fetal growth [J]. Am. J. Obstet. Gynecol. 1992, 167:920~925
[229]. Arck PC, Troutt AB, Clark DA. Soluble receptors neutralizing TNF- and IL-1 block stress-triggered murine abortion [J]. Am. J. Reprod. Immunol. 1997,37:262~366
[230].Arck PC, Meroli FS, Manuel J, et al. Stress-triggered abortion: inhibition of protective suppression and promotion of tumor necrosis factor- (TNF-) release as a mechanism triggering resorptions in mice [J]. Am. J. Reprod. Immunol. 1995,33:74~80.
[231].Chaouat G, Menu E, Szeerkeres-Bartho J, et al. Lymphokines, steroids, placental factors and trophoblast intrinsic resistance to immune cell-mediated lysis are involved in pregnancy success or immunologically mediated pregnancy failure. T. G. Wegmann, and T. G. Gill, eds. Molecular Biology of the Feto-Maternal Interface. Oxford University Press, New York. 1989.
[232]. Pampfer S, Wuu YD, Vanderheyden I, et al. Expression oftumor necrosis factor- receptors and selective effect of TNF on the inner cell mass in mouse blastocysts [J]. Endocrinology, 1994, 134:206.~212
[233].Tartakovsky B, Ben-Yair E. Cytokines modulate preimplantation development and pregnancy [J]. Dev. Biol. 1991,146: 345~352
[234].Tangri S, Raghupathy R. Expression of cytokines in placentas of mice undergoing immunologically mediated spontaneous fetal resorptions [J]. Biol. Reprod. 1993, 49: 850~856
[235].Tangri S, Wegmann TG., Lin H. Maternal anti-placental reactivity in natural, immunologically mediated fetal resorptions [J].J.Immunol.1994.152:4903~4911
[236].Warner SJ, Libby P. Human vascular smooth muscle cells: Target for and source of tumor necrosis factor [J]. J. Immunol., Jan 1989, 142: 100~109.
[237]. Silen ML, Firpo A, Morgello S, et al.Interleukin-1 alpha and tumor necrosis factor alpha cause placental injury in the rat Am. J. Pathol., Aug 1989, 135: 239~244.
[238]. Shimomura K, Manda T, Mukumoto S, et al. Recombinant human tumor necrosis factor-alpha: thrombus formation is a cause of anti-tumor activity[J]. Int J Cancer, Feb 1988; 41(2): 243~247.
[239]. Shaarawy M, Nagui AR. Enhanced expression of cytokines may play a fundamental role in the mechanisms of immunologically mediated recurrent spontaneous abortion[J]. Acta Obstet Gynecol Scand, Mar 1997; 76(3): 205~211.
[240].Toder V, Strassburger D, Irlin Y, et al. Nonspecific immunopotentiators and pregnancy loss: complete Freund adjuvant reverses high fetal resorption rate in CBA x DBA/2 mouse combination[J].Am. J. Reprod. Immunol.,1990, 24:63~66
[241].Torchinsky A, Fein A, Carp HJA, et al. MHC-associated immunopotentiation affects the embryo response to teratogens[J].Clin. Exp. Immunol. 1994, 98:513~519
[242].Torchinsky A, Toder V, Savion S, et al. Immunostimulation increases the resistance of mouse embryos to the teratogenic effect of diabetes mellitus [J]. Diabetologia, 1997, 40:635~640
[243].Fasouliotis SJ, Spandorfer SD, Witkin SS. Maternal serum levels of interferon-γ and interleukin- 2 soluble receptor-α predict the outcome of early IVF pregnancies[M]. Human Reproduction, Hum. Reprod. Advance Access published online on April 22, 2004
[244].Toder V, Savion S, Gorivodsky M, et al. Teratogen-induced apoptosis may be affected by immunopotentiation[J]. J. Reprod. Immunol. 1996, 30:173~185
[245]. Wuu YD, Pampfer S, Becquet P, et al. Tumor Necrosis Factor {alpha} Decreases the Viability of Mouse Blastocysts In Vitro and In Vivo[J]. Biol. Reprod.,?1999, 60(2): 479~483
[246].Piccinni MP, Scaletti C, Vultaggio A, et al Defective production of LIF, M-CSF and Th2-type cytokines by T cells at fetomaternal interface is associated with pregnancy
loss[J]. J Reprod Immunol. 2001, 52(1-2):35~43
[247].Mellor AL, Munn DH. Extinguishing maternal immune responses during pregnancy: implications for immunosuppression[J]. Semin Immunol. 2001, 13(4):213~8
[248].Shimada S, Kato EH, Morikawa M, et al. No difference in natural killer or natural killer T-cell population, but aberrant T-helper cell population in the endometrium of women with repeated miscarriage[J]. Human Reproduction, 2004, 19, (4):1018~1024
[249] Ding J, Xu TH, Shi YL. Different effects of toosendanin on perineurially recorded Ca2+ currents in mouse and frog motor nerve?terminals [J]. Neuroscience Research, 2001, 41(3): 243~249
[250] Shi YL, Chen WY. Effect of Toosendanin on acetylcholine level of rat brain, a microdialysis study[J]. Brain Research,1999, 850: 173~178
[251] Tang MZ, Wang ZF and Shi YL .Toosendanin induces outgrowth of neuronal processes and apoptosis in PC12 cells[J]. Neuroscience Research, 2003, 45(2): 225~231
[252] Wang ZF, Shi YL. Toosendanin-induced inhibition of small-conductance calcium- activated potassium channels in CA1 pyramidal neurons of rat hippocampus[J]. Neuroscience letters, 2001, 303(1): 13~16
[253] Shaarawy M, Nagui AR. Enhanced Expression of cytokines may play a fundamental role in the mechanisms of immunologically mediated recurrent spontaneous abortion[J]. Acta Obstet Gynecol Scand, 1997, 76:205~211