期刊
ENVIRONMENTAL HEALTH PERSPECTIVES
卷 118, 期 11, 页码 1557-1563出版社
US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE
DOI: 10.1289/ehp.1001928
关键词
CYP2E1; fatty acid beta-oxidation; hepatotoxicity; PPAR alpha; steatosis; trichloroethylene
资金
- Japan Society for the Promotion of Science [B18604020, B21406016]
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 homeo-stasis and anti-inflammation. OBJECTIVE: We examined the role of mouse and human PPAR alpha in TRI-induced hepatic steatosis and toxicity. METHODS: Male wild-type (mPPAR alpha), Ppar alpha-null, and humanized PPAR alpha (hPPAR alpha) 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 Ppar alpha-null and hPPAR alpha mice. No differences were observed in TRI-mediated induction of hepatic PPAR alpha target genes except for a few genes that differed between mPPAR alpha and hPPAR alpha mice. However, TRI significantly increased expression of triglyceride (TG)-synthesizing enzymes, diacylglicerol acyltransferases, and PPAR gamma in Ppar alpha-null and hPPAR alpha mice, which may account for the increased TG in their livers. TRI exposure elevated nuclear factor-kappa B (NF kappa B) p52 mRNA and protein in all mice regardless of PPAR alpha genotype. CONCLUSIONS: NF kappa B-p52 is a candidate molecular marker for inflammation caused by TRI, and PPAR alpha may be involved in TRI-induced hepatosteatosis. However, human PPAR alpha may afford only weak protection against TRI-mediated effects compared with mouse PPAR alpha.
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