Microgram-order ammonium perfluorooctanoate may activate mouse peroxisome proliferator-activated receptor alpha, but not human PPARalpha.
Perfluorooctanoic acid (PFOA) is a ligand for peroxisome proliferator-activated receptor (PPAR) alpha, 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 PPARalpha transgenic mouse line. Three genotyped mice, 129/Sv wild-type (mPPARalpha), Pparalpha-null mice and humanized PPARalpha (hPPARalpha) 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 0.3mg/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 mPPARalpha mice. APFO increased mRNA and/or protein levels of PPARalpha target genes cytochrome P450 Cyp4a10, peroxisomal thiolase and bifunctional protein only in the liver of mPPARalpha mice, but not in Pparalpha-null or hPPARalpha mice. This chemical also increased expression of mitochondrial very long chain acyl-CoA dehydrogenase only in the liver of mPPARalpha mice. Taken together, human PPARalpha 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.
Nakamura
Toshiki
T
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
Ito
Yuki
Y
Yanagiba
Yukie
Y
Ramdhan
Doni Hikmat
DH
Kono
Yasuhide
Y
Naito
Hisao
H
Hayashi
Yumi
Y
Li
Yufei
Y
Aoyama
Toshifumi
T
Gonzalez
Frank J
FJ
Nakajima
Tamie
T
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001711:Biotransformation; D015153:Blotting, Western; D001835:Body Weight; D016466:CHO Cells; D002210:Caprylates / Q000493:pharmacokinetics / Q000633:toxicity*; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D005466:Fluorocarbons / Q000493:pharmacokinetics / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D047493:PPAR alpha / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity
D002210:Caprylates; D005466:Fluorocarbons; D008055:Lipids; D047493:PPAR alpha; D012333:RNA, Messenger; C023036:perfluorooctanoic acid; D000410:Alanine Transaminase