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Modulation of ammonium perfluorooctanoate-induced hepatic damage by genetically different PPARα in mice

  • Toxicogenomics
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Abstract

Perfluorooctanoic acid is a ligand for peroxisome proliferator-activated receptor (PPARα). Ammonium perfluorooctanoate (APFO) at 0.1 and 0.3 mg/kg doses activated mouse PPARα, but not human PPARα. This study aimed to clarify whether milligram-order APFO can activate human PPARα, and the receptor is involved in APFO-induced chronic hepatic damage. Male Sv/129 wild-type (mPPARα), Pparα-null, and humanized PPARα (hPPARα) mice (8 weeks old) were divided into three groups. The first was treated with water and the other two with 1.0 and 5.0 mg/kg APFO for 6 weeks, orally, respectively. Both doses activated mouse and human PPARα to a similar or lower degree in the latter. APFO dose dependently increased hepatic triglyceride levels in Pparα-null and hPPARα mice, but conversely decreased those in mPPARα ones. APFO-induced hepatic damage differed markedly among the three genotyped groups: single-cell necrosis was observed in all genotyped mice; inflammatory cells and macrovesicular steatosis only in Pparα-null mice; and microvesicular steatosis and hydropic degenerations in hPPARα and Pparα-null mice. The molecular mechanism underlying these differences may be attributable to those of gene expressions involved in lipid homeostasis (PPARα, β- and ω-oxidation enzymes, and diacylglycerol acyltransferases) and uncoupling protein 2. Thus, milligram-order APFO activated both mouse and human PPARα in a different manner, which may reflect histopathologically different types of hepatic damage.

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Abbreviations

ALT:

Alanine aminotransferase

APFO:

Ammonium perfluorooctanoate

CV:

Central vein

CYP4A10:

Cytochrome P450 4A10

DGAT1:

Diacylglycerol acyltransferase 1

DGAT2:

Diacylglycerol acyltransferase 2

H & E:

Hematoxylin and eosin

hPPARα mice:

Humanized PPARα mice

MCAD:

Medium chain acyl-CoA dehydrogenase

NFκB:

Nuclear factor kappa B

PCNA:

Proliferation cell nuclear antigen

PH:

Peroxisomal bifunctional protein

PPARα:

Peroxisome proliferator-activated receptor α

PPARγ:

Peroxisome proliferator-activated receptor γ

PT:

Peroxisomal thiolase

TC:

Total cholesterol

TG:

Triglycerides

TNFα:

Tumor necrosis factor α

UCP2:

Uncoupling protein 2

VLCAD:

Very long chain acyl-CoA dehydrogenase

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Acknowledgments

We wish to thank to Mr. Toshiki Nakamura for his kind assistance with the animal experiments. This study was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (B. 14370121, 17390169).

Conflict of interest

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan

    Tomohiko Nakagawa, Doni Hikmat Ramdhan, Hisao Naito, Hazuki Tamada, Yuki Ito, Yufei Li, Yumi Hayashi, Nozomi Yamagishi, Yukie Yanagiba & Tamie Nakajima

  2. Department of Occupational Health and Safety, Faculty of Public Health, University of Indonesia, Depok, 16424, Jawa Barat, Indonesia

    Doni Hikmat Ramdhan

  3. Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, 390-8621, Japan

    Naoki Tanaka & Toshifumi Aoyama

  4. Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan

    Yuki Ito

  5. National Institute of Occupational Safety and Health, Kawasaki, 214-8585, Japan

    Yukie Yanagiba

  6. Laboratory of Metabolism, National Cancer Institute, NIH, Bethesda, MD, 20892, USA

    Frank J. Gonzalez

Authors
  1. Tomohiko Nakagawa
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  2. Doni Hikmat Ramdhan
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  3. Naoki Tanaka
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  4. Hisao Naito
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  5. Hazuki Tamada
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  6. Yuki Ito
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  7. Yufei Li
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  8. Yumi Hayashi
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  9. Nozomi Yamagishi
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  11. Toshifumi Aoyama
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  12. Frank J. Gonzalez
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  13. Tamie Nakajima
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Corresponding author

Correspondence to Tamie Nakajima.

Additional information

T. Nakagawa and D. H. Ramdhan authors contributed equally to the study.

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Nakagawa, T., Ramdhan, D.H., Tanaka, N. et al. Modulation of ammonium perfluorooctanoate-induced hepatic damage by genetically different PPARα in mice. Arch Toxicol 86, 63–74 (2012). https://doi.org/10.1007/s00204-011-0704-3

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  • DOI: https://doi.org/10.1007/s00204-011-0704-3

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