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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.

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Medical School of Ningbo University, Ningbo, 315211, China.
Ningbo College of Health Sciences, Ningbo, 315100, China.
Shenyang Pharmaceutical University, Shenyang, 110016, China.
Laboratory of Metabolism, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
Medical School of Ningbo University, Ningbo, 315211, China.


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.


Hepatotoxicity; PPARα; Perfluorodecanoic acid

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