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Arch Toxicol. 2017 Feb;91(2):897-907. doi: 10.1007/s00204-016-1779-7. Epub 2016 Jun 25.

Dual action of peroxisome proliferator-activated receptor alpha in perfluorodecanoic acid-induced hepatotoxicity.

Author information

1
Medical School of Ningbo University, Ningbo, 315211, China.
2
Ningbo College of Health Sciences, Ningbo, 315100, China.
3
Shenyang Pharmaceutical University, Shenyang, 110016, China.
4
Laboratory of Metabolism, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
5
Medical School of Ningbo University, Ningbo, 315211, China. liuaiming@nbu.edu.cn.

Abstract

Perfluorodecanoic acid (PFDA) is widely used in production of many daily necessities based on their surface properties and stability. It was assigned as a Persistent Organic Pollutant in 2009 and became a public concern partly because of its potential for activation of the peroxisome proliferator-activated receptor alpha (PPARα). In this study, wild-type and Ppara-null mice were administered PFDA (80 mg/kg). Blood and liver tissues were collected and subjected to systemic toxicological and mechanistic analysis. UPLC-ESI-QTOFMS-based metabolomics was used to explore the contributing components of the serum metabolome that led to variation between wild-type and Pparα-null mice. Bile acid homeostasis was disrupted, and slight hepatocyte injury in wild-type mice accompanied by adaptive regulation of bile acid synthesis and transport was observed. The serum metabolome in wild-type clustered differently from that in Pparα-null, featured by sharp increases in bile acid components. Differential toxicokinetic tendency was supported by regulation of UDP-glucuronosyltransferases dependent on PPARα, but it did not contribute to the hepatotoxic responses. Increase in Il-10 and activation of the JNK pathway indicated inflammation was induced by disruption of bile acid homeostasis in wild-type mice. Inhibition of p-p65 dependent on PPARα activation by PFDA stopped the inflammatory cascade, as indicated by negative response of Il-6, Tnf-α, and STAT3 signaling. These data suggest disruptive and protective role of PPARα in hepatic responses induced by PFDA.

KEYWORDS:

Hepatotoxicity; PPARα; Perfluorodecanoic acid

PMID:
27344344
PMCID:
PMC6350782
DOI:
10.1007/s00204-016-1779-7
[Indexed for MEDLINE]
Free PMC Article

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