Alterations of Cytokines and MAPK Signaling Pathways are Related to the Immunotoxic Effect of Perfluorononanoic Acid
Alterations of Cytokines and MAPK Signaling Pathways are Related to the Immunotoxic Effect of Perfluorononanoic Acid
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细胞因子和 MAPK 信号通路的改变与全氟壬酸的免疫毒性作用有关
DOI：
10.1093/toxsci/kfp019
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发表时间：
2009-04-01
影响因子：
3.8
通讯作者：
Dai, Jiayin
中科院分区：
文献类型：
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作者：
Fang, Xuemei;Feng, Yixing;Dai, Jiayin
全氟壬酸（PFNA）是一种含有9个碳链的全氟烷基酸，已在世界范围内的非生物和生物基质中检测到。虽然一些研究报告了PFNA的毒性作用，但提供的机制信息很少。本研究探讨了PFNA对胸腺的影响及其机制。雄性大鼠经口给予0、1、3或5 mg PFNA/kg/天，持续14天。在接受3或5 mg PFNA/kg/天的大鼠中观察到体重和胸腺重量显著降低。组织学检查显示胸腺细胞凋亡呈剂量依赖性增加。接受3或5 mg PFNA/kg/天的大鼠血清中白细胞介素（IL）-1升高，IL-2浓度降低，而IL-4和皮质醇水平升高仅发生在最高剂量组。定量实时PCR表明，所有给药大鼠胸腺中过氧化物酶体增殖物激活受体α（PPAR-alpha）的表达均增加，两个最高剂量组中PPAR-gamma的表达趋势相似。c-Jun氨基末端激酶（JNK）、核因子-κ B、p65亚基和抑制蛋白I κ B α的mRNA水平无变化;然而，在暴露于3或5 mg PFNA/kg/天的大鼠中，分别发现p38激酶的mRNA水平升高和降低。在接受5 mg PFNA/kg/天的大鼠中观察到Bcl-2 mRNA水平降低。在所有PFNA处理的大鼠中发现磷酸化JNK蛋白水平显著增加。在1和3 mg PFNA/kg/天组中，磷酸化p38显著增强，而在所有研究的大鼠中，磷酸化I κ B α保持一致。总之，这些数据表明，除了激活PPARs外，大鼠中的PFNA暴露导致血清细胞因子的改变，其随后激活丝裂原活化蛋白激酶信号通路并潜在地调节免疫系统。另外，血清皮质醇水平升高和胸腺Bcl-2表达降低可能是PFNA诱导胸腺细胞凋亡的重要原因。
Perfluorononanoate (PFNA), a perfluorinated alkyl acid containing nine carbon chains, has been detected in abiotic and biotic matrices worldwide. Although a few studies have reported toxic effects of PFNA, little information of the mechanism has been offered. In this study, the effects of PFNA exposure on thymus and the related mechanisms were investigated. Male rats were orally dosed with 0, 1, 3, or 5 mg PFNA/kg/day for 14 days. A significant decrease of body weight and thymus weight were observed in the rats receiving 3 or 5 mg PFNA/kg/day. Histopathological examination revealed dose-dependent increases in thymocyte apoptosis. Rats receiving 3 or 5 mg PFNA/kg/day exhibited increased interleukin (IL)-1 and decreased IL-2 concentrations in sera, whereas elevated IL-4 and cortisol levels only occurred in the highest dose group. Quantitative real-time PCR indicated that expression of peroxisome proliferator-activated receptor alpha (PPAR-alpha) was increased in the thymi of all dosed rats, and a similar trend occurred for PPAR-gamma in the two highest dose groups. The mRNA levels of c-Jun NH2-terminal kinase (JNK), nuclear factor-kappa B, p65 subunit, and inhibitory protein I kappa B alpha were unchanged; however, increased and decreased mRNA levels of p38 kinase were found in rats exposed to 3 or 5 mg PFNA/kg/day, respectively. Decreased Bcl-2 mRNA levels were observed in rats receiving 5 mg PFNA/kg/day. A significant increase in protein levels of phospho-JNK was found in all PFNA-treated rats. Phospho-p38 was significantly enhanced in 1 and 3 mg PFNA/kg/day groups, whereas phospho-I kappa B alpha remained consistent in all rats studied. Together, these data suggested that apart from the activation of PPARs, PFNA exposure in rats lead to the alteration of serum cytokines, which subsequently activated mitogen-activated protein kinase signaling pathways and potentially modulated the immune system. Additionally, increased serum cortisol and decreased expression of Bcl-2 in thymus likely contributed to the PFNA-induced thymocyte apoptosis.