Ochratoxin A induces oxidative DNA damage and G1 phase arrest in human peripheral blood mononuclear cells in vitro
Ochratoxin A induces oxidative DNA damage and G1 phase arrest in human peripheral blood mononuclear cells in vitro
复制标题
赭曲霉毒素 A 体外诱导人外周血单核细胞氧化 DNA 损伤和 G1 期阻滞
DOI：
10.1016/j.toxlet.2012.03.800
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发表时间：
2012-06-01
影响因子：
3.5
通讯作者：
Zhang, Xianghong
中科院分区：
文献类型：
--
作者：
Liu, Jing;Wang, Yuan;Zhang, Xianghong
赭曲霉毒素A是世界范围内数量最多的食品污染真菌毒素之一，其对人体的免疫抑制作用越来越受到生物医学领域的关注。本研究通过分析OTA对人外周血单个核细胞（hPBMC）氧化途径的参与，探讨OTA对hPBMC的毒性作用。结果发现，OTA处理导致活性氧（ROS）的释放和增加的8-羟基脱氧鸟苷（8-OHdG），氧化DNA应激的重要生物标志物。此外，我们发现OTA处理诱导hPBMC中的DNA链断裂，如DNA彗星尾形成和γ-H2 AX表达增加所证明的。OTA可通过下调CDK 4和cyclinD 1蛋白的表达，诱导hPBMC细胞周期阻滞于G1期，并诱导hPBMC细胞凋亡。用抗氧化剂N-乙酰-L-半胱氨酸（NAC）预处理hPBMC可减少OTA诱导的ROS释放和DNA损伤，从而证实了DNA氧化损伤参与了OTA在hPBMC中的遗传毒性。NAC预处理可显著抑制OTA诱导的hPBMC中CDK 4和cyclinD 1表达下调。以上结果表明OTA介导的细胞毒作用与氧化途径有关，包括ROS积累-DNA氧化损伤-G1期阻滞和细胞凋亡。我们的研究结果提供了新的见解OTA可能促进免疫毒性的分子机制。(C)2012爱思唯尔爱尔兰有限公司保留所有权利。
Ochratoxin A is one of the most abundant food-contaminating mycotoxins worldwide, and its immunosuppressive effects in human caused more and more concern in biomedical field. In the present study, the toxicity of OTA on human peripheral blood mononuclear cells (hPBMC) was explored by analyzing the involvement of oxidative pathway. It was found that OTA treatment led to the release of reactive oxygen species (ROS) and the increase of 8-hydroxydeoxyguanosine (8-OHdG), an important biomarker of oxidative DNA stress. Moreover, we found that OTA treatment induced DNA strand breaks in hPBMC as evidenced by DNA comet tails formation and increased gamma-H2AX expression. In addition, OTA could induce cell cycle arrest at G1 phase by down-regulating the expression of CDK4 and cyclinD1 protein, as well as apoptosis in hPBMC in vitro. Pre-treatment of hPBMC with antioxidant, N-acetyl-L-cysteine (NAC), could reduce OTA-induced ROS release and DNA damage, thus confirming the involvement of oxidative DNA damage in the OTA genotoxicity in hPBMC. NAC pre-treatment could also significantly prevent OTA-induced down-regulation of CDK4 and cyclinD1 expression in hPBMC. All the results demonstrated the involvement of oxidative pathway in OTA mediated cytotoxicity in human immune cells, which including the ROS accumulation-oxidative DNA damage-G1 arrest and apoptosis. Our results provide new insights into the molecular mechanisms by which OTA might promote immunotoxicity. (C) 2012 Elsevier Ireland Ltd. All rights reserved.