title: The Contribution of Peroxisome Proliferator-Activated Receptor Alpha to the Relationship Between Toxicokinetics and Toxicodynamics of Trichloroethylene.
abstract: 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.
authors.affiliation: *Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina;
authors.forename: Hong Sik
authors.initials: HS
authors.lastname: Yoo
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA;
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Cichocki
authors.affiliation: Graduate School of Public Health, Seoul National University, Seoul, Republic of Korea;
authors.forename: Sungkyoon
authors.initials: S
authors.lastname: Kim
authors.affiliation: *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;
authors.forename: Abhishek
authors.initials: A
authors.lastname: Venkatratnam
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA;
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Iwata
authors.affiliation: *Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina;
authors.forename: Oksana
authors.initials: O
authors.lastname: Kosyk
authors.affiliation: *Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina;
authors.forename: Wanda
authors.initials: W
authors.lastname: Bodnar
authors.affiliation: Geochemical and Environmental Research Group, Texas A&M University, College Station, Texas;
authors.forename: Stephen
authors.initials: S
authors.lastname: Sweet
authors.affiliation: Geochemical and Environmental Research Group, Texas A&M University, College Station, Texas;
authors.forename: Anthony
authors.initials: A
authors.lastname: Knap
authors.affiliation: Geochemical and Environmental Research Group, Texas A&M University, College Station, Texas;
authors.forename: Terry
authors.initials: T
authors.lastname: Wade
authors.affiliation: The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina; and.
authors.forename: Jerry
authors.initials: J
authors.lastname: Campbell
authors.affiliation: The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina; and.
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Clewell
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Stepan B
authors.initials: SB
authors.lastname: Melnyk
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA;
authors.forename: Weihsueh A
authors.initials: WA
authors.lastname: Chiu
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA; irusyn@cvm.tamu.edu.
authors.forename: Ivan
authors.initials: I
authors.lastname: Rusyn
mesh_terms: D000818:Animals; D004334:Drug Administration Schedule; D005260:Female; D007668:Kidney / Q000737:chemistry / Q000187:drug effects; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000378:metabolism*; D066007:Toxicokinetics; D014238:Trichloroacetic Acid / Q000032:analysis / Q000378:metabolism; D014241:Trichloroethylene / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D047493:PPAR alpha; D014241:Trichloroethylene; D014238:Trichloroacetic Acid
keywords: PPAR; liver; trichloroethylene