Phosphoproteome analysis reveals an important role for glycogen synthase kinase-3 in perfluorododecanoic acid-induced rat liver toxicity.
Perfluorododecanoic acid (PFDoA) is a member of the perfluoroalkyl acid (PFAA) family and has broad applications and a wide distribution in the environment. Here, we used TiO(2)-based phosphopeptide enrichment coupled with LC-MS/MS analysis to identify phosphopeptides in rat livers that were influenced by PFDoA treatment. We identified a total of 1443 unique phosphopeptides from among 769 phosphoproteins identified in normal and PFDoA-treated rat livers, 849 unique phosphorylation sites were also identified. Of these sites, 143 were considered to be novel phosphorylation sites. Many phosphoproteins were found to be associated with hepatic injuries and diseases, such as hepatotoxicity, regeneration, fatty liver, neoplasms and carcinoma. Furthermore, 25 of the identified phosphoproteins were found to be related to glycogen synthase kinase-3 (GSK3), either directly or indirectly. Western blot and qPCR results suggested that chronic PFDoA exposure inhibited insulin signal pathways and that inhibition of GSK3 might contribute to the observed increases of lipid levels in the liver.
Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Hongxia
H
Zhang
Junjie
J
Hou
Ruina
R
Cui
Xuejiang
X
Guo
Zhimin
Z
Shi
Fuquan
F
Yang
Jiayin
J
Dai
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004785:Environmental Pollutants / Q000633:toxicity*; D005234:Fatty Liver / Q000378:metabolism; D005466:Fluorocarbons; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D007850:Lauric Acids / Q000633:toxicity*; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000737:chemistry / Q000378:metabolism; D008115:Liver Regeneration / Q000502:physiology; D008297:Male; D010748:Phosphopeptides / Q000032:analysis / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry
D004785:Environmental Pollutants; D005466:Fluorocarbons; D007850:Lauric Acids; D010748:Phosphopeptides; D038362:Glycogen Synthase Kinase 3; C522391:perfluorododecanoic acid