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Activation of peroxisome proliferator-activated receptor α ameliorates perfluorododecanoic acid-induced production of reactive oxygen species in rat liver

  • Molecular Toxicology
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Abstract

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 (PPARα). 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 PPARα 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 PPARα knockdown groups, consistent with the PPARα antagonist GW6471- and agonist WY14643-treated groups. These results strongly suggested that PPARα played an important role in suppressing ROS content in hepatocytes following PFDoA exposure.

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Abbreviations

CTE1:

Cytosolic acyl-CoA thioesterase 1, also known as Acot1 (acyl-CoA thioesterase 1)

MTE1:

Mitochondrial acyl-CoA thioesterase 1, also known as Acot2 (acyl-CoA thioesterase 2)

HADHA:

Hydroxyacyl-coenzyme A dehydrogenase/3-ketoacyl-coenzyme A thiolase/enoyl-coenzyme A hydratase (trifunctional protein), alpha subunit

ALDH2:

Aldehyde dehydrogenase 2 family (mitochondrial)

ECH1:

Enoyl CoA hydratase 1, peroxisomal

CPS1:

Carbamoyl-phosphate synthetase 1

SOD:

Superoxide dismutase

GPx:

Glutathione peroxidase

TBARS:

Thiobarbituric acid-reactive substances

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Acknowledgments

This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB14040202) and the National Natural Science Foundation of China (Grants Nos. 31320103915, 21277143 and 21377128).

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    Authors and Affiliations

    1. Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, People’s Republic of China

      Hui Liu, Hongxia Zhang, Ruina Cui & Jiayin Dai

    2. State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 210029, People’s Republic of China

      Xuejiang Guo

    3. State Key Laboratory of Marine Environmental Science/Environmental Science Research Center, Xiamen University, Xiamen, 361005, People’s Republic of China

      Dazhi Wang & Jiayin Dai

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    Correspondence to Jiayin Dai.

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    Hui Liu and Hongxia Zhang have contributed equally to this paper.

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    Liu, H., Zhang, H., Cui, R. et al. Activation of peroxisome proliferator-activated receptor α ameliorates perfluorododecanoic acid-induced production of reactive oxygen species in rat liver. Arch Toxicol 90, 1383–1397 (2016). https://doi.org/10.1007/s00204-015-1559-9

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