Yoo Hong Sik, Cichocki Joseph A, Kim Sungkyoon, Venkatratnam Abhishek, Iwata Yasuhiro, Kosyk Oksana, Bodnar Wanda, Sweet Stephen, Knap Anthony, Wade Terry, Campbell Jerry, Clewell Harvey J, Melnyk Stepan B, Chiu Weihsueh A, Rusyn Ivan
*Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina;
Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA;
Toxicol Sci. 2015 Oct;147(2):339-49. doi: 10.1093/toxsci/kfv134. Epub 2015 Jul 1.
Exposure to the ubiquitous environmental contaminant trichloroethylene (TCE) is associated with cancer and non-cancer toxicity in both humans and rodents. Peroxisome proliferator-activated receptor-alpha (PPARα) is thought to be playing a role in liver toxicity in rodents through activation of the receptor by the TCE metabolite trichloroacetic acid (TCA). However, most studies using genetically altered mice have not assessed the potential for PPARα to alter TCE toxicokinetics, which may lead to differences in TCA internal doses and hence confound inferences as to the role of PPARα in TCE toxicity. To address this gap, male and female wild type (129S1/SvImJ), Pparα-null, and humanized PPARα (hPPARα) mice were exposed intragastrically to 400 mg/kg TCE in single-dose (2, 5 and 12 h) and repeat-dose (5 days/week, 4 weeks) studies. Interestingly, following either a single- or repeat-dose exposure to TCE, levels of TCA in liver and kidney were lower in Pparα-null and hPPARα mice as compared with those in wild type mice. Levels of trichloroethanol (TCOH) were similar in all strains. TCE-exposed male mice consistently had higher levels of TCA and TCOH in all tissues compared with females. Additionally, in both single- and repeat-dose studies, a similar degree of induction of PPARα-responsive genes was observed in liver and kidney of hPPARα and wild type mice, despite the difference in hepatic and renal TCA levels. Additional sex- and strain-dependent effects were observed in the liver, including hepatocyte proliferation and oxidative stress, which were not dependent on TCA or TCOH levels. These data demonstrate that PPARα status affects the levels of the putative PPARα agonist TCA following TCE exposure. Therefore, interpretations of studies using Pparα-null and hPPARα mice need to consider the potential contribution of genotype-dependent toxicokinetics to observed differences in toxicity, rather than attributing such differences only to receptor-mediated toxicodynamic effects.
接触普遍存在的环境污染物三氯乙烯（TCE）与人类和啮齿动物的癌症及非癌症毒性相关。过氧化物酶体增殖物激活受体α（PPARα）被认为通过TCE代谢物三氯乙酸（TCA）激活该受体，从而在啮齿动物肝脏毒性中发挥作用。然而，大多数使用基因改造小鼠的研究并未评估PPARα改变TCE毒代动力学的可能性，这可能导致TCA体内剂量的差异，进而混淆关于PPARα在TCE毒性中作用的推断。为填补这一空白，在单剂量（2、5和12小时）和重复剂量（每周5天，共4周）研究中，对雄性和雌性野生型（129S1/SvImJ）、Pparα基因敲除型和人源化PPARα（hPPARα）小鼠进行灌胃给予400 mg/kg TCE。有趣的是，在单次或重复剂量接触TCE后，与野生型小鼠相比，Pparα基因敲除型和hPPARα小鼠肝脏和肾脏中的TCA水平较低。所有品系中三氯乙醇（TCOH）水平相似。与雌性相比，接触TCE的雄性小鼠在所有组织中的TCA和TCOH水平始终较高。此外，在单剂量和重复剂量研究中，尽管肝脏和肾脏中TCA水平存在差异，但在hPPARα和野生型小鼠的肝脏和肾脏中观察到相似程度的PPARα反应性基因诱导。在肝脏中还观察到其他性别和品系依赖性效应，包括肝细胞增殖和氧化应激，这些效应不依赖于TCA或TCOH水平。这些数据表明，PPARα状态会影响TCE暴露后假定的PPARα激动剂TCA的水平。因此，对使用Pparα基因敲除型和hPPARα小鼠的研究进行解释时，需要考虑基因型依赖性毒代动力学对观察到的毒性差异的潜在贡献，而不是仅将这些差异归因于受体介导的毒效动力学效应。
