Apoptosis in tissues of the central nervous system of fetuses with neural tube defects: a preliminary study
WANG Caiyun, LIN Shanshan, YI Deqing, WANG Linlin, JIN Lei, REN Aiguo
Department of Biostatistics and Epidemiology, School of Public Health and Institute of Reproductive and Child Health/Ministry of Health Key Laboratory of Reproductive Health,Peking University, Beijing 100191, China
Abstract:Objective To examine the role of apoptosis in the development of human neural tube defects (NTDs). Methods A case-control study was conducted. Cases were fetuses terminated due to prenatal diagnosis of NTDs or stillborn neonates with NTDS, and controls were terminated fetuses without congenital malformations. Fetal spinal cord tissues from 23 NTD cases and 21 controls, and fetal brain tissues from 30 NTD cases and 20 controls were obtained by autopsy. To evaluate apoptosis and apoptotic pathway, the expression levels of caspase 3/ 8/ 9 proteins in fetal spinal cord and brain tissues were determined by Western blot. Results Stripes of caspase and cleaved caspase were observed in fetal spinal cord tissues and fetal brain tissues of both NTD cases and controls, but stripes of cleaved caspase were more obvious in NTD cases. The expression levels of cleaved caspase 3 (17 kD) and cleaved caspase 8 (18 kD) in fetal spinal cord and brain tissues of NTD cases were tended to be higher than those of the controls, and there was no significant difference in the expression of cleaved caspase 9 (37/35 kD) between NTD cases and controls both in fetal spinal cord and brain tissues. However, the expression level of cleaved caspase 3 (17 kD) was significantly higher in fetal spinal cord tissues of anencephalic cases and fetal brain tissues of encephalocele cases than in controls (P<0.05). The expression levels of cleaved caspase 8 (18 kD) in fetal spinal cord tissues of anencephalic cases and cleaved caspase 8 (43/41 kD) in fetal brain tissues of spina bifida cases were also significantly higher than those in controls (P<0.05). Conclusion Excessive apoptosis in fetal central nervous tissues was associated with the development of NTDs. Apoptosis may be activated through extrinsic apoptosis pathway mediated by caspase 8.
王彩云, 林珊珊, 易德青, 王琳琳, 靳蕾, 任爱国. 胎儿中枢神经组织细胞凋亡与神经管缺陷关系的初探[J]. 中国生育健康杂志, 2015, 26(5): 393-396.
WANG Caiyun, LIN Shanshan, YI Deqing, WANG Linlin, JIN Lei, REN Aiguo. Apoptosis in tissues of the central nervous system of fetuses with neural tube defects: a preliminary study. Chinese Journal of Reproductive Health, 2015, 26(5): 393-396.
1 Sadler TW.Embryology of neural tube development.Am J Med Genet C Semin Med Genet,2005,135C:2-8.2 Wallingford JB,Niswander LA,Shaw GM,et al.The continuing challenge of understanding,preventing,and treating neural tube defects.Science,2013,339:1222002. 3 Wang X,Wang J,Guan T,et al.Role of methotrexate exposure in apoptosis and proliferation during early neurulation.J Appl Toxicol,2014,34:862-869. 4 Gao Q,Gao YM.Hyperglycemic condition disturbs the proliferation and cell death of neural progenitors in mouse embryonic spinal cord.Int J Dev Neurosci,2007,25:349-357. 5 马金龙,高英茂,刘凯,等.高温致神经管畸形中细胞增殖和细胞凋亡的定量研究.中国体视学与图像分析,2001,6:65-69. 6 Tung EW,Winn LM.Valproic acid increases formation of reactive oxygen species and induces apoptosis in postimplantation embryos:a role for oxidative stress in valproic acid-induced neural tube defects.Mol Pharmacol,2011,80:979-987. 7 栾世钦,陈乃文,姜恩亭,等.环磷酰胺致神经管畸形与细胞凋亡的关系.卫生毒理学杂志,2000,14:225. 8 Boatright KM,Salvesen GS.Mechanisms of caspase activation.Current Opinion in Cell Biology,2003,15:725-731. 9 Porter AG,Janicke RU.Emerging roles of caspase-3 in apoptosis.Cell Death Differ,1999,6:99-104. 10 Tung EW,Winn LM.Valproic acid-induced DNA damage increases embryonic p27(KIP1) and caspase-3 expression:a mechanism for valproic-acid induced neural tube defects.Reprod Toxicol,2011,32:255-260. 11 Li X,Weng H,Xu C,et al.Oxidative stress-induced JNK1/2 activation triggers proapoptotic signaling and apoptosis that leads to diabetic embryopathy.Diabetes,2012,61:2084-2092. 12 肖荣,赵海峰,李学敏.细胞凋亡在环磷酰胺致大鼠神经管畸形中作用.中国公共卫生,2003,19:824-826. 13 马永臻,武玉玲.Caspase-3、P53在神经上皮及间充质细胞的表达和意义.中国妇幼保健,2013,28:301-304. 14 何乐,杨君杰,彭玉立,等.氯乙烯诱导小鼠胚胎神经管发育畸形的研究.第三军医大学学报,2010,32:159-163. 15 Dong Y,Wang X,Zhang J,et al.Raltitrexed's effect on the development of neural tube defects in mice is associated with DNA damage,apoptosis,and proliferation.Mol Cell Biochem,2015,398:223-231. 16 杨绍杰,孟金萍,屈祎,等.细胞凋亡信号传导通路的研究进展.中国比较医学杂志,2007,20:297-301. 17 Zhao Z,Yang P,Eckert RL,et al.Caspase-8:a key role in the pathogenesis of diabetic embryopathy.Birth Defects Res B Dev Reprod Toxicol,2009,86:72-77. 18 Yang P,Li X,Xu C,et al.Maternal hyperglycemia activates an ASK1-FoxO3a-caspase 8 pathway that leads to embryonic neural tube defects.Sci Signal,2013,6:ra74. 19 Donauer J,Schreck I,Liebel U,et al.Role and interaction of p53,BAX and the stress-activated protein kinases p38 and JNK in benzo(a)pyrene-diolepoxide induced apoptosis in human colon carcinoma cells.Arch Toxicol,2012,86:329-337.