Fang Xuemei, Feng Yixing, Shi Zhimin, Dai Jiayin
Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Toxicol Sci. 2009 Apr;108(2):367-76. doi: 10.1093/toxsci/kfp019. Epub 2009 Feb 5.
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 NH(2)-terminal kinase (JNK), nuclear factor-kappa B, p65 subunit, and inhibitory protein IkappaBalpha 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-IkappaBalpha 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.
全氟壬酸（PFNA）是一种含有九条碳链的全氟烷基酸，已在全球范围内的非生物和生物基质中被检测到。尽管有一些研究报道了PFNA的毒性作用，但关于其作用机制的信息却很少。在本研究中，我们调查了PFNA暴露对胸腺的影响及其相关机制。雄性大鼠每天经口给予0、1、3或5mg PFNA/kg，持续14天。在接受3或5mg PFNA/kg/天的大鼠中，观察到体重和胸腺重量显著下降。组织病理学检查显示胸腺细胞凋亡呈剂量依赖性增加。接受3或5mg PFNA/kg/天的大鼠血清中白细胞介素（IL）-1浓度升高，IL-2浓度降低，而IL-4和皮质醇水平升高仅出现在最高剂量组。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-α）的表达均增加，两个最高剂量组的PPAR-γ也出现类似趋势。c-Jun NH(2)-末端激酶（JNK）、核因子-κB p65亚基和抑制蛋白IκBα的mRNA水平未发生变化；然而，在暴露于3或5mg 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5mg PFNA/kg/天的大鼠中观察到Bcl-2 mRNA水平下降。在所有PFNA处理的大鼠中，磷酸化JNK的蛋白水平显著增加。在1和3mg 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IκBα保持一致。总之，这些数据表明，除了激活PPARs外，PFNA暴露还导致大鼠血清细胞因子的改变，随后激活丝裂原活化蛋白激酶信号通路，并可能调节免疫系统。此外，血清皮质醇增加和胸腺中Bcl-2表达降低可能导致PFNA诱导的胸腺细胞凋亡。
