Nitrofen induces a redox-dependent apoptosis associated with increased p38 activity in P19 teratocarcinoma cells.
Nitrofen induces a redox-dependent apoptosis associated with increased p38 activity in P19 teratocarcinoma cells.
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DOI：
10.1016/j.tiv.2004.04.010
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发表时间：
2005-02
期刊：
影响因子：
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通讯作者：
D. E. Kling;J. Aidlen;J. Fisher;T. Kinane;P. Donahoe;J. Schnitzer
中科院分区：
文献类型：
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作者：
D. E. Kling;J. Aidlen;J. Fisher;T. Kinane;P. Donahoe;J. Schnitzer
硝基芬是一种二苯基醚除草剂，在啮齿动物中产生一系列胎儿异常。为了在细胞水平上表征硝芬介导的出生缺陷的分子机制，我们探讨了硝芬对未分化的P19畸胎癌细胞的影响。硝芬诱导P19细胞的时间依赖性细胞死亡，这与tunel阳性和caspase-3切割的增加有关，表明硝芬诱导P19细胞凋亡。此外，zVAD-fmk抑制了tunel阳性细胞的增加，表明硝芬诱导了caspase依赖性的凋亡。硝芬处理与p38 MAP激酶活性增加相关，尽管使用多种p38抑制剂预处理细胞并不影响硝芬介导的caspase-3切割，这表明caspase-3切割与p38无关。硝基芬诱导活性氧（ROS）呈剂量依赖性增加，同时伴有还原性/氧化性谷胱甘肽比例的降低，表明硝基芬改变了这些细胞的氧化还原状态。此外，用n -乙酰半胱氨酸对细胞进行预处理后，caspase-3切割的减少具有剂量和时间依赖性，这支持了caspase-3切割依赖于细胞氧化还原的观察结果。因此，硝芬诱导P19细胞凋亡，这是细胞氧化还原依赖性的，与p38活性和ROS的增加有关，并可能在硝芬介导的出生缺陷中发挥作用。
Nitrofen is a diphenyl ether herbicide that produces a spectrum of fetal abnormalities in rodents. To characterize the molecular mechanisms of nitrofen-mediated birth defects at the cellular level, we explored its effects on undifferentiated P19 teratocarcinoma cells. Nitrofen induces a time-dependent cell death of P19 cells that is associated with increases in TUNEL-positivity and caspase-3 cleavage suggesting that nitrofen induces P19 cell apoptosis. In addition, the increase in TUNEL-positive cells was inhibited with zVAD-fmk, suggesting that nitrofen induces a caspase-dependent apoptosis. Nitrofen treatment was associated with increased p38 MAP kinase activity, though pretreatment of cells with multiple p38 inhibitors did not affect nitrofen-mediated caspase-3 cleavage, suggesting caspase-3 cleavage is p38-independent. Nitrofen induced a dose-dependent increase in reactive oxygen species (ROS), which was accompanied by a decrease in the ratio of reduced/oxidized glutathione, indicating that nitrofen alters the cellular redox state of these cells. Furthermore, pretreatment of cells with N-acetyl cysteine gave a dose- and time-dependent reduction of caspase-3 cleavage, supporting the observations that caspase-3 cleavage is cell-redox-dependent. Therefore, nitrofen induces P19 cell apoptosis that is cell-redox-dependent and is associated with increases in p38 activity and ROS and may play a role in nitrofen-mediated birth defects.