The Contribution of Peroxisome Proliferator-Activated Receptor Alpha to the Relationship Between Toxicokinetics and Toxicodynamics of Trichloroethylene.
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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 (PPAR) 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 PPAR to alter TCE toxicokinetics, which may lead to differences in TCA internal doses and hence confound inferences as to the role of PPAR in TCE toxicity. To address this gap, male and female wild type (129S1/SvImJ), Ppar-null, and humanized PPAR (hPPAR) 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 Ppar-null and hPPAR 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 PPAR-responsive genes was observed in liver and kidney of hPPAR 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 PPAR status affects the levels of the putative PPAR agonist TCA following TCE exposure. Therefore, interpretations of studies using Ppar-null and hPPAR 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.
author list (cited authors)
Yoo, H. S., Cichocki, J. A., Kim, S., Venkatratnam, A., Iwata, Y., Kosyk, O., ... Rusyn, I.
complete list of authors
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