Journal Article

Alterations of Cytokines and MAPK Signaling Pathways are Related to the Immunotoxic Effect of Perfluorononanoic Acid

Xuemei Fang, Yixing Feng, Zhimin Shi and Jiayin Dai

in Toxicological Sciences

Volume 108, issue 2, pages 367-376
Published in print April 2009 | ISSN: 1096-6080
Published online February 2009 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfp019
Alterations of Cytokines and MAPK Signaling Pathways are Related to the Immunotoxic Effect of Perfluorononanoic Acid

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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, 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-α) was increased in the thymi of all dosed rats, and a similar trend occurred for PPAR-γ 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 IκBα 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-IκBα 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.

Keywords: PFNA; immunotoxicity; PPAR; MAPK; NF-κB

Journal Article.  5285 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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