title: Differential response to trichloroethylene-induced hepatosteatosis in wild-type and PPARalpha-humanized mice.
abstract: BACKGROUND
  Trichloroacetic acid, an oxidative metabolite of trichloroethylene (TRI), is a ligand of the peroxisome proliferator-activated receptor alpha (PPAR) alpha, which is involved in lipid homeostasis and anti-inflammation.
  
  
  OBJECTIVE
  We examined the role of mouse and human PPARalpha in TRI-induced hepatic steatosis and toxicity.
  
  
  METHODS
  Male wild-type (mPPARalpha), Pparalpha-null, and humanized PPARalpha (hPPARalpha) mice on an Sv/129 background were exposed via inhalation to 0, 1,000, and 2,000 ppm TRI for 8 hr/day for 7 days. We assessed TRI-induced steatosis or hepatic damage through biochemical and histopathological measurements.
  
  
  RESULTS
  Plasma alanine aminotransferase and aspartate aminotransferase activities increased in all mouse lines after exposure to 1,000 and 2,000 ppm TRI. Exposure induced hepatocyte necrosis and inflammatory cells in all mouse lines, but hepatic lipid accumulation was observed only in Pparalpha-null and hPPARalpha mice. No differences were observed in TRI-mediated induction of hepatic PPARalpha target genes except for a few genes that differed between mPPARalpha and hPPARalpha mice. However, TRI significantly increased expression of triglyceride (TG)-synthesizing enzymes, diacyl-glicerol acyltransferases, and PPARgamma in Pparalpha-null and hPPARalpha mice, which may account for the increased TG in their livers. TRI exposure elevated nuclear factor-kappa B (NFkappaB) p52 mRNA and protein in all mice regardless of PPARalpha genotype.
  
  
  CONCLUSIONS
  NFkappaB-p52 is a candidate molecular marker for inflammation caused by TRI, and PPARalpha may be involved in TRI-induced hepatosteatosis. However, human PPARalpha may afford only weak protection against TRI-mediated effects compared with mouse PPARalpha.
authors: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Doni Hikmat
authors: DH
authors: Ramdhan
authors: Michihiro
authors: M
authors: Kamijima
authors: Dong
authors: D
authors: Wang
authors: Yuki
authors: Y
authors: Ito
authors: Hisao
authors: H
authors: Naito
authors: Yukie
authors: Y
authors: Yanagiba
authors: Yumi
authors: Y
authors: Hayashi
authors: Naoki
authors: N
authors: Tanaka
authors: Toshifumi
authors: T
authors: Aoyama
authors: Frank J
authors: FJ
authors: Gonzalez
authors: Tamie
authors: T
authors: Nakajima
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012997:Solvents / Q000633:toxicity*; D014241:Trichloroethylene / Q000633:toxicity*
chemical_list: D015415:Biomarkers; D052002:NF-kappa B p50 Subunit; D047493:PPAR alpha; D012333:RNA, Messenger; D012997:Solvents; D014241:Trichloroethylene