ToxSci Advance Access published online on February 5, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp019
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Alterations of Cytokines and MAPK Signaling Pathways Are Related to the Immunotoxic Effect of Perfluorononanoic Acid
Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100190, China
Graduate School of the Chinese Academy of Sciences, Beijing 100080, China
* To whom correspondence should be addressed: Dai JY, Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China, Fax: +86-10-64807099, E-mail: daijy{at}ioz.ac.cn
Received November 24, 2008; revision received January 22, 2009; accepted January 23, 2009
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Abstract |
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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, while elevated IL-4 and cortisol levels only occurred in the highest dose group. Quantitative real time-PCR (qRT-PCR) indicated that expression of peroxisome proliferator-activated receptor alpha (PPAR
) was increased in the thymi of all dosed rats, and a similar trend occurred for PPAR
in the two highest dose groups. The mRNA levels of c-Jun NH2-terminal kinase (JNK), nuclear factor 
B (NF-B), p65 subunit, and inhibitory protein IB 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, while phospho-IB 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 MAPK 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.
Key Words: PFNA; immunotoxicity; PPAR; MAPK; NF-B.