title: Dual action of peroxisome proliferator-activated receptor alpha in perfluorodecanoic acid-induced hepatotoxicity.
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.
authors.affiliation: Medical School of Ningbo University, Ningbo, 315211, China.
authors.forename: Min
authors.initials: M
authors.lastname: Luo
authors.affiliation: Medical School of Ningbo University, Ningbo, 315211, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Medical School of Ningbo University, Ningbo, 315211, China.
authors.forename: Manyun
authors.initials: M
authors.lastname: Dai
authors.affiliation: Medical School of Ningbo University, Ningbo, 315211, China.
authors.forename: Danjun
authors.initials: D
authors.lastname: Song
authors.affiliation: Medical School of Ningbo University, Ningbo, 315211, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Lin
authors.affiliation: Medical School of Ningbo University, Ningbo, 315211, China.
authors.forename: Minzhu
authors.initials: M
authors.lastname: Xie
authors.affiliation: Ningbo College of Health Sciences, Ningbo, 315100, China.
authors.forename: Julin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Shenyang Pharmaceutical University, Shenyang, 110016, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.affiliation: Medical School of Ningbo University, Ningbo, 315211, China.
authors.forename: Dengming
authors.initials: D
authors.lastname: Wei
authors.affiliation: Medical School of Ningbo University, Ningbo, 315211, China.
authors.forename: Jinshun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Medical School of Ningbo University, Ningbo, 315211, China. liuaiming@nbu.edu.cn.
authors.forename: Aiming
authors.initials: A
authors.lastname: Liu
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D003652:Decanoic Acids / Q000633:toxicity*; D005466:Fluorocarbons / Q000633:toxicity*; D006706:Homeostasis / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055442:Metabolome / Q000187:drug effects; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D066007:Toxicokinetics; D014496:Urachal Cyst
chemical_list: D001647:Bile Acids and Salts; D003652:Decanoic Acids; D005466:Fluorocarbons; D047493:PPAR alpha; C036567:perfluorodecanoic acid
keywords: Hepatotoxicity; PPARα; Perfluorodecanoic acid