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

Tomohiko Nakagawa, Doni Hikmat Ramdhan, Naoki Tanaka, Hisao Naito, Hazuki Tamada, Yuki Ito, Yufei Li, Yumi Hayashi, Nozomi Yamagishi, Yukie Yanagiba, Toshifumi Aoyama, Frank J. Gonzalez, Tamie Nakajima

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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.

Original languageEnglish
Pages (from-to)63-74
Number of pages12
JournalArchives of Toxicology
Volume86
Issue number1
DOIs
Publication statusPublished - 01-01-2012

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perfluorooctanoic acid
Peroxisome Proliferator-Activated Receptors
Modulation
Liver
Diacylglycerol O-Acyltransferase

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Nakagawa, Tomohiko ; Ramdhan, Doni Hikmat ; Tanaka, Naoki ; Naito, Hisao ; Tamada, Hazuki ; Ito, Yuki ; Li, Yufei ; Hayashi, Yumi ; Yamagishi, Nozomi ; Yanagiba, Yukie ; Aoyama, Toshifumi ; Gonzalez, Frank J. ; Nakajima, Tamie. / Modulation of ammonium perfluorooctanoate-induced hepatic damage by genetically different PPARα in mice. In: Archives of Toxicology. 2012 ; Vol. 86, No. 1. pp. 63-74.
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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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Nakagawa, T, Ramdhan, DH, Tanaka, N, Naito, H, Tamada, H, Ito, Y, Li, Y, Hayashi, Y, Yamagishi, N, Yanagiba, Y, Aoyama, T, Gonzalez, FJ & Nakajima, T 2012, 'Modulation of ammonium perfluorooctanoate-induced hepatic damage by genetically different PPARα in mice', Archives of Toxicology, vol. 86, no. 1, pp. 63-74. https://doi.org/10.1007/s00204-011-0704-3

Modulation of ammonium perfluorooctanoate-induced hepatic damage by genetically different PPARα in mice. / Nakagawa, Tomohiko; Ramdhan, Doni Hikmat; Tanaka, Naoki; Naito, Hisao; Tamada, Hazuki; Ito, Yuki; Li, Yufei; Hayashi, Yumi; Yamagishi, Nozomi; Yanagiba, Yukie; Aoyama, Toshifumi; Gonzalez, Frank J.; Nakajima, Tamie.

In: Archives of Toxicology, Vol. 86, No. 1, 01.01.2012, p. 63-74.

Research output: Contribution to journalArticle

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T1 - Modulation of ammonium perfluorooctanoate-induced hepatic damage by genetically different PPARα in mice

AU - Nakagawa, Tomohiko

AU - Ramdhan, Doni Hikmat

AU - Tanaka, Naoki

AU - Naito, Hisao

AU - Tamada, Hazuki

AU - Ito, Yuki

AU - Li, Yufei

AU - Hayashi, Yumi

AU - Yamagishi, Nozomi

AU - Yanagiba, Yukie

AU - Aoyama, Toshifumi

AU - Gonzalez, Frank J.

AU - Nakajima, Tamie

PY - 2012/1/1

Y1 - 2012/1/1

N2 - 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.

AB - 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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