title: Modeling toxicodynamic effects of trichloroethylene on liver in mouse model of autoimmune hepatitis.
abstract: Chronic exposure to industrial solvent and water pollutant trichloroethylene (TCE) in female MRL+/+mice generates disease similar to human autoimmune hepatitis. The current study was initiated to investigate why TCE-induced autoimmunity targeted the liver. Compared to other tissues the liver has an unusually robust capacity for repair and regeneration. This investigation examined both time-dependent and dose-dependent effects of TCE on hepatoprotective and pro-inflammatory events in liver and macrophages from female MRL+/+mice. After a 12-week exposure to TCE in drinking water a dose-dependent decrease in macrophage production of IL-6 at both the transcriptional and protein level was observed. A longitudinal study similarly showed that TCE inhibited macrophage IL-6 production. In terms of the liver, TCE had little effect on expression of pro-inflammatory genes (Tnfa, Saa2 or Cscl1) until the end of the 40-week exposure. Instead, TCE suppressed hepatic expression of genes involved in IL-6 signaling (Il6r, gp130, and Egr1). Linear regression analysis confirmed liver histopathology in the TCE-treated mice correlated with decreased expression of Il6r. A toxicodynamic model was developed to estimate the effects of TCE on IL-6 signaling and liver pathology under different levels of exposure and rates of repair. This study underlined the importance of longitudinal studies in mechanistic evaluations of immuntoxicants. It showed that later-occurring liver pathology caused by TCE was associated with early suppression of hepatoprotection rather than an increase in conventional pro-inflammatory events. This information was used to create a novel toxicodynamic model of IL-6-mediated TCE-induced liver inflammation.
authors.affiliation: University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA. Electronic address: gilbertkathleenm@uams.edu.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Gilbert
authors.affiliation: Colorado State University, Fort Collins, CO, USA. Electronic address: brad.reisfeld@colostate.edu.
authors.forename: Brad
authors.initials: B
authors.lastname: Reisfeld
authors.affiliation: Colorado State University, Fort Collins, CO, USA. Electronic address: tjzurlin@rams.colostate.edu.
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Zurlinden
authors.affiliation: University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA. Electronic address: MNKreps@uams.edu.
authors.forename: Meagan N
authors.initials: MN
authors.lastname: Kreps
authors.affiliation: University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA. Electronic address: serickson@uams.edu.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Erickson
authors.affiliation: University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA. Electronic address: blossomsarah@uams.edu.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Blossom
mesh_terms: D000465:Algorithms; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006304:Health Status; D019693:Hepatitis, Autoimmune / Q000235:genetics / Q000473:pathology*; D015850:Interleukin-6 / Q000502:physiology; D008099:Liver / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D008954:Models, Biological; D060888:Real-Time Polymerase Chain Reaction; D014241:Trichloroethylene / Q000633:toxicity*; D014873:Water Pollutants / Q000633:toxicity*
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D014873:Water Pollutants; D014241:Trichloroethylene
keywords: IL-6; Immunotoxicity; Liver; Modeling; Trichloroethylene