Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Environ Health Perspect. 2010 Nov;118(11):1557-63. doi: 10.1289/ehp.1001928.
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.
We examined the role of mouse and human PPARalpha in TRI-induced hepatic steatosis and toxicity.
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.
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.
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.
三氯乙酸是三氯乙烯（TRI）的氧化代谢物，是过氧化物酶体增殖物激活受体α（PPARα）的配体，该受体参与脂质稳态和抗炎反应。
我们研究了小鼠和人 PPARα 在 TRI 诱导的肝脂肪变性和毒性中的作用。
雄性野生型（mPPARα）、Pparalpha 基因敲除和人源化 PPARα（hPPARα）小鼠在 Sv/129 背景下通过吸入暴露于 0、1000 和 2000ppm TRI 中，每天 8 小时，连续 7 天。我们通过生化和组织病理学测量评估 TRI 诱导的脂肪变性或肝损伤。
暴露于 1000 和 2000ppm TRI 后，所有小鼠品系的血浆丙氨酸氨基转移酶和天冬氨酸氨基转移酶活性均升高。暴露诱导所有小鼠品系的肝细胞坏死和炎症细胞，但仅在 Pparalpha 基因敲除和 hPPARα 小鼠中观察到肝脂肪堆积。除了 mPPARα 和 hPPARα 小鼠之间存在差异的少数基因外，未观察到 TRI 介导的肝 PPARα 靶基因的诱导存在差异。然而，TRI 显著增加了 Pparalpha 基因敲除和 hPPARα 小鼠中甘油三酯（TG）合成酶、二酰基甘油酰基转移酶和 PPARγ的表达，这可能是其肝脏 TG 增加的原因。TRI 暴露增加了所有小鼠的核因子-κB（NFκB）p52mRNA 和蛋白，无论 PPARα 基因型如何。
NFκB-p52 是 TRI 引起的炎症的候选分子标志物，PPARα 可能参与 TRI 诱导的肝脂肪变性。然而，与小鼠 PPARα 相比，人源化 PPARα 可能仅提供对 TRI 介导的作用的微弱保护。
