Journal
ARCHIVES OF TOXICOLOGY
Volume 90, Issue 6, Pages 1383-1397Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-015-1559-9
Keywords
Perfluorododecanoic acid (PFDoA); Peroxisome proliferator-activated receptor alpha (PPAR alpha); Reactive oxygen species (ROS); Lentivirus; RNAi
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Funding
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB14040202]
- National Natural Science Foundation of China [31320103915, 21277143, 21377128]
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Perfluorododecanoic acid (PFDoA) is a ubiquitous environmental pollutant known to cause hepatocellular hypertrophy; however, the mechanisms of hepatotoxicity remain poorly understood. In this study, male rats were exposed to 0, 0.05, 0.2 and 0.5 mg/kg/day of PFDoA for 110 days. After two-dimensional differential gel electrophoresis and MALDI-TOF/TOF analysis, 73 differentially expressed proteins involved in lipid metabolism, inflammation, stress response and other functions were successfully identified. Among them, six significantly changed proteins (CTE1, MTE1, HADHA, ECH1, ALDH2 and CPS1) were found to be regulated by peroxisome proliferator-activated receptor alpha (PPAR alpha). The anti-oxidant enzyme activity assays of superoxide dismutase and glutathione peroxidase and the content of thiobarbituric acid-reactive substances in the liver implied that PFDoA caused oxidative stress. The mRNA levels of PPAR alpha in rat primary hepatocytes were knocked down by lentivirus-mediated RNAi. Furthermore, targeted protein levels of CTE1 and MTE1 were down-regulated, while those of HADHA, ALDH2 and CPS1 were up-regulated. After PFDoA exposure, however, the targeted protein levels of CTE1 and ALDH2 increased compared with those of the knockdown untreated group. The reactive oxygen species (ROS) content in rat hepatocytes assayed by flow cytometry significantly increased in the PPAR alpha knockdown groups, consistent with the PPAR alpha antagonist GW6471- and agonist WY14643-treated groups. These results strongly suggested that PPAR alpha played an important role in suppressing ROS content in hepatocytes following PFDoA exposure.
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