摘要：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 (m PPAR α), Ppar α-null, and humanized PPARα (h PPAR α) 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 α-null and h PPAR α mice. No differences were observed in TRI-mediated induction of hepatic PPARα target genes except for a few genes that differed between m PPAR α and h PPAR α mice. However, TRI significantly increased expression of triglyceride (TG)-synthesizing enzymes, diacylglicerol acyltransferases, and PPARγ in Ppar α-null and h PPAR α 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 PPAR α 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.
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