Microgram-order ammonium perfluorooctanoate may activate mouse peroxisome proliferator-activated receptor α, but not human PPARα

Toshiki Nakamura, Yuki Ito, Yukie Yanagiba, Doni Hikmat Ramdhan, Yasuhide Kono, Hisao Naito, Yumi Hayashi, Yufei Li, Toshifumi Aoyama, Frank J. Gonzalez, Tamie Nakajima

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Perfluorooctanoic acid (PFOA) is a ligand for peroxisome proliferator-activated receptor (PPAR) α, which exhibits marked species differences in expression and function, especially between rodents and humans. We investigated the functional difference in PFOA response between mice and humans, using a humanized PPARα transgenic mouse line. Three genotyped mice, 129/Sv wild-type (mPPARα), Pparα-null mice and humanized PPARα (hPPARα) mice (8-week-old males) were divided into three groups: the first was treated with water daily for 2 weeks by gavage (control group), and the remaining two groups were treated with 0.1 and 0.3 mg/kg ammonium perflurooctanate (APFO), respectively, for 2 weeks by gavage. The APFO dosages used did not influence the plasma triglyceride or total cholesterol levels in any mouse line, but the high dose increased both hepatic lipid levels only in mPPARα mice. APFO increased mRNA and/or protein levels of PPARα target genes cytochrome P450 Cyp4a10, peroxisomal thiolase and bifunctional protein only in the liver of mPPARα mice, but not in Pparα-null or hPPARα mice. This chemical also increased expression of mitochondrial very long chain acyl-CoA dehydrogenase only in the liver of mPPARα mice. Taken together, human PPARα may be less responsive to PFOA than that of mice when a relatively low dose is applied. This information may be very valuable in considering whether PFOA influences the lipid metabolism in humans.

Original languageEnglish
Pages (from-to)27-33
Number of pages7
JournalToxicology
Volume265
Issue number1-2
DOIs
Publication statusPublished - 09-11-2009

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perfluorooctanoic acid
Peroxisome Proliferator-Activated Receptors
Ammonium Compounds
Liver
Long-Chain Acyl-CoA Dehydrogenase
129 Strain Mouse
Cytochrome P-450 Enzyme System
Triglycerides
Proteins
Genes
Cholesterol

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Nakamura, Toshiki ; Ito, Yuki ; Yanagiba, Yukie ; Ramdhan, Doni Hikmat ; Kono, Yasuhide ; Naito, Hisao ; Hayashi, Yumi ; Li, Yufei ; Aoyama, Toshifumi ; Gonzalez, Frank J. ; Nakajima, Tamie. / Microgram-order ammonium perfluorooctanoate may activate mouse peroxisome proliferator-activated receptor α, but not human PPARα. In: Toxicology. 2009 ; Vol. 265, No. 1-2. pp. 27-33.
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abstract = "Perfluorooctanoic acid (PFOA) is a ligand for peroxisome proliferator-activated receptor (PPAR) α, which exhibits marked species differences in expression and function, especially between rodents and humans. We investigated the functional difference in PFOA response between mice and humans, using a humanized PPARα transgenic mouse line. Three genotyped mice, 129/Sv wild-type (mPPARα), Pparα-null mice and humanized PPARα (hPPARα) mice (8-week-old males) were divided into three groups: the first was treated with water daily for 2 weeks by gavage (control group), and the remaining two groups were treated with 0.1 and 0.3 mg/kg ammonium perflurooctanate (APFO), respectively, for 2 weeks by gavage. The APFO dosages used did not influence the plasma triglyceride or total cholesterol levels in any mouse line, but the high dose increased both hepatic lipid levels only in mPPARα mice. APFO increased mRNA and/or protein levels of PPARα target genes cytochrome P450 Cyp4a10, peroxisomal thiolase and bifunctional protein only in the liver of mPPARα mice, but not in Pparα-null or hPPARα mice. This chemical also increased expression of mitochondrial very long chain acyl-CoA dehydrogenase only in the liver of mPPARα mice. Taken together, human PPARα may be less responsive to PFOA than that of mice when a relatively low dose is applied. This information may be very valuable in considering whether PFOA influences the lipid metabolism in humans.",
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Nakamura, T, Ito, Y, Yanagiba, Y, Ramdhan, DH, Kono, Y, Naito, H, Hayashi, Y, Li, Y, Aoyama, T, Gonzalez, FJ & Nakajima, T 2009, 'Microgram-order ammonium perfluorooctanoate may activate mouse peroxisome proliferator-activated receptor α, but not human PPARα', Toxicology, vol. 265, no. 1-2, pp. 27-33. https://doi.org/10.1016/j.tox.2009.09.004

Microgram-order ammonium perfluorooctanoate may activate mouse peroxisome proliferator-activated receptor α, but not human PPARα. / Nakamura, Toshiki; Ito, Yuki; Yanagiba, Yukie; Ramdhan, Doni Hikmat; Kono, Yasuhide; Naito, Hisao; Hayashi, Yumi; Li, Yufei; Aoyama, Toshifumi; Gonzalez, Frank J.; Nakajima, Tamie.

In: Toxicology, Vol. 265, No. 1-2, 09.11.2009, p. 27-33.

Research output: Contribution to journalArticle

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T1 - Microgram-order ammonium perfluorooctanoate may activate mouse peroxisome proliferator-activated receptor α, but not human PPARα

AU - Nakamura, Toshiki

AU - Ito, Yuki

AU - Yanagiba, Yukie

AU - Ramdhan, Doni Hikmat

AU - Kono, Yasuhide

AU - Naito, Hisao

AU - Hayashi, Yumi

AU - Li, Yufei

AU - Aoyama, Toshifumi

AU - Gonzalez, Frank J.

AU - Nakajima, Tamie

PY - 2009/11/9

Y1 - 2009/11/9

N2 - Perfluorooctanoic acid (PFOA) is a ligand for peroxisome proliferator-activated receptor (PPAR) α, which exhibits marked species differences in expression and function, especially between rodents and humans. We investigated the functional difference in PFOA response between mice and humans, using a humanized PPARα transgenic mouse line. Three genotyped mice, 129/Sv wild-type (mPPARα), Pparα-null mice and humanized PPARα (hPPARα) mice (8-week-old males) were divided into three groups: the first was treated with water daily for 2 weeks by gavage (control group), and the remaining two groups were treated with 0.1 and 0.3 mg/kg ammonium perflurooctanate (APFO), respectively, for 2 weeks by gavage. The APFO dosages used did not influence the plasma triglyceride or total cholesterol levels in any mouse line, but the high dose increased both hepatic lipid levels only in mPPARα mice. APFO increased mRNA and/or protein levels of PPARα target genes cytochrome P450 Cyp4a10, peroxisomal thiolase and bifunctional protein only in the liver of mPPARα mice, but not in Pparα-null or hPPARα mice. This chemical also increased expression of mitochondrial very long chain acyl-CoA dehydrogenase only in the liver of mPPARα mice. Taken together, human PPARα may be less responsive to PFOA than that of mice when a relatively low dose is applied. This information may be very valuable in considering whether PFOA influences the lipid metabolism in humans.

AB - Perfluorooctanoic acid (PFOA) is a ligand for peroxisome proliferator-activated receptor (PPAR) α, which exhibits marked species differences in expression and function, especially between rodents and humans. We investigated the functional difference in PFOA response between mice and humans, using a humanized PPARα transgenic mouse line. Three genotyped mice, 129/Sv wild-type (mPPARα), Pparα-null mice and humanized PPARα (hPPARα) mice (8-week-old males) were divided into three groups: the first was treated with water daily for 2 weeks by gavage (control group), and the remaining two groups were treated with 0.1 and 0.3 mg/kg ammonium perflurooctanate (APFO), respectively, for 2 weeks by gavage. The APFO dosages used did not influence the plasma triglyceride or total cholesterol levels in any mouse line, but the high dose increased both hepatic lipid levels only in mPPARα mice. APFO increased mRNA and/or protein levels of PPARα target genes cytochrome P450 Cyp4a10, peroxisomal thiolase and bifunctional protein only in the liver of mPPARα mice, but not in Pparα-null or hPPARα mice. This chemical also increased expression of mitochondrial very long chain acyl-CoA dehydrogenase only in the liver of mPPARα mice. Taken together, human PPARα may be less responsive to PFOA than that of mice when a relatively low dose is applied. This information may be very valuable in considering whether PFOA influences the lipid metabolism in humans.

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