Retinoic acid-mediated differentiation protects against nitrofen-induced apoptosis.

Retinoic acid-mediated differentiation protects against nitrofen-induced apoptosis.
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DOI：
10.1002/bdrb.20131
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发表时间：
2007-10
期刊：
Birth defects research. Part B, Developmental and reproductive toxicology
影响因子：
--
通讯作者：
J. Aidlen;P. Nazarey;T. Kinane;P. Donahoe;J. Schnitzer;D. E. Kling
J. Aidlen;P. Nazarey;T. Kinane;P. Donahoe;J. Schnitzer;D. E. Kling
中科院分区：
其他
文献类型：
--
作者：
J. Aidlen;P. Nazarey;T. Kinane;P. Donahoe;J. Schnitzer;D. E. Kling

文献摘要

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背景硝苯草醚是一种二苯醚，其在施用给怀孕啮齿动物后诱导一系列出生缺陷，其中这些缺陷的分子病因学特征很差。由于以前的报告表明，除草醚诱导未分化的P19畸胎瘤细胞的凋亡，我们假设，未分化的胎儿细胞有更大的敏感性除草醚诱导的凋亡比其分化的衍生物。方法为了验证这一假设，用维甲酸将P19和F9细胞系分别分化为神经元和内胚衍生物。凋亡的特点是caspase-3切割和末端转移酶dUTP缺口末端标记（TUNEL）测定。结果两种分化的细胞类型与未处理的对照组相比，减少了除草醚诱导的caspase-3切割和DNA片段化，强烈表明这些细胞的分化保护免受除草醚诱导的凋亡。此外，对凋亡诱导的抗性与分化标志物p27（kip 1）的表达水平成正比，而抗凋亡蛋白Bcl-2未观察到直接的比例关系。结论除草醚可能通过诱导未分化胎儿细胞凋亡而导致出生缺陷。
BACKGROUND Nitrofen is a diphenyl ether that induces a spectrum of birth defects subsequent to administration to pregnant rodents, in which the molecular etiology of these defects are poorly characterized. Because previous reports showed that nitrofen induced apoptosis in undifferentiated P19 teratocarcinoma cells, we hypothesized that undifferentiated fetal cells have greater susceptibility to nitrofen-induced apoptosis than their differentiated derivatives. METHODS To investigate this hypothesis, cell lines including P19 and F9 were differentiated with retinoic acid into neuronal and endodermal derivatives respectively. Apoptosis was characterized by caspase-3 cleavage and Terminal transferase dUTP nick end labeling (TUNEL) assays. RESULTS Both differentiated cell-types had reduced nitrofen-induced caspase-3 cleavage and DNA fragmentation compared with the naive controls, strongly suggesting that differentiation of these cells protects against nitrofen-induced apoptosis. In addition, resistance to apoptotic induction was proportional to the expression levels of the differentiation marker, p27 (kip1) while direct proportionality was not observed for the antiapoptotic protein Bcl-2. CONCLUSIONS These studies show that nitrofen may induce its associated birth defects via a mechanism involving apoptosis of undifferentiated fetal cells.