Differential response to trichloroethylene-induced hepatosteatosis in wild-type and pparα-humanized mice

Doni Hikmat Ramdhan, Michihiro Kamijima, Dong Wang, Yuki Ito, Hisao Naito, Yukie Yanagiba, Yumi Hayashi, Naoki Tanaka, Toshifumi Aoyama, Frank J. Gonzalez, Tamie Nakajima

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Background: Trichloroacetic acid, an oxidative metabolite of trichloroethylene (TRI), is a ligand of the peroxisome proliferator-activated receptor α (PPAR) α, which is involved in lipid homeostasis and anti-inflammation. Objective: We examined the role of mouse and human PPARα in TRI-induced hepatic steatosis and toxicity. Methods: Male wild-type (mPPARα), Pparα-null, and humanized PPARα (hPPARα) 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 Pparα-null and hPPARα mice. No differences were observed in TRI-mediated induction of hepatic PPARα target genes except for a few genes that differed between mPPARα and hPPARα mice. However, TRI significantly increased expression of triglyceride (TG)-synthesizing enzymes, diacylglicerol acyltransferases, and PPARγ in Pparα-null and hPPARα mice, which may account for the increased TG in their livers. TRI exposure elevated nuclear factor-kappa B (NFκB) p52 mRNA and protein in all mice regardless of PPARα genotype. Conclusions: NFκB-p52 is a candidate molecular marker for inflammation caused by TRI, and PPARα may be involved in TRI-induced hepatosteatosis. However, human PPARα may afford only weak protection against TRI-mediated effects compared with mouse PPARα.

元の言語English
ページ(範囲)1557-1563
ページ数7
ジャーナルEnvironmental Health Perspectives
118
発行部数11
DOI
出版物ステータスPublished - 01-11-2010

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All Science Journal Classification (ASJC) codes

  • Public Health, Environmental and Occupational Health
  • Health, Toxicology and Mutagenesis

これを引用

Ramdhan, D. H., Kamijima, M., Wang, D., Ito, Y., Naito, H., Yanagiba, Y., Hayashi, Y., Tanaka, N., Aoyama, T., Gonzalez, F. J., & Nakajima, T. (2010). Differential response to trichloroethylene-induced hepatosteatosis in wild-type and pparα-humanized mice. Environmental Health Perspectives, 118(11), 1557-1563. https://doi.org/10.1289/ehp.1001928