Differential response to trichloroethylene-induced hepatosteatosis in wild-type and PPARalpha-humanized mice.
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.
Ramdhan
Doni Hikmat
DH
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Kamijima
Michihiro
M
Wang
Dong
D
Ito
Yuki
Y
Naito
Hisao
H
Yanagiba
Yukie
Y
Hayashi
Yumi
Y
Tanaka
Naoki
N
Aoyama
Toshifumi
T
Gonzalez
Frank J
FJ
Nakajima
Tamie
T
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*
D015415:Biomarkers; D052002:NF-kappa B p50 Subunit; D047493:PPAR alpha; D012333:RNA, Messenger; D012997:Solvents; D014241:Trichloroethylene