title: Investigation of the mechanism of triclosan induced mouse liver tumors.
abstract: Chronic dietary exposure to Triclosan (TCS) produced increased incidence of liver tumors in mice. The mechanism for liver tumor induction has been attributed to activation of either peroxisome proliferator activated receptor α (PPARα) or constitutive androstane receptor (CAR). To further define the mechanism of TCS induced liver tumors, male CD-1 and C57BL/6 mice were treated with TCS at 0, 10, 100 and 200 mg/kg diet/day for 14 or 28 days. In addition, a recovery group and positive control groups for CAR or PPARα activation with either phenobarbital or diethylhexyl-phthalate were included in the 14-day study. TCS induced a dose-dependent increase in relative liver weight and centrilobular hypertrophy in both strains of mice. Hepatocyte DNA synthesis (BrdU labeling) was also increased in a dose-related pattern. In comparison with previous studies, TCS induced a significant increase in CAR/PXR (Cyp2b10, Cyp3a11) and PPARα (Cyp4a10) responsive genes in both CD-1 and C57BL/6 mice. The corresponding enzyme activity for CAR (7-pentoxyresorufin-O-dealkylase) and PPARα (peroxisomal Acyl-CoA oxidase) were also significantly increased in a similar fashion. Oxidative stress related genes Gpx1 and Aox1 were increased in the C57BL/6 but not in CD-1 mice. The increases in gene expression and enzyme activities returned to control levels after 14-day recovery. The present results demonstrate that both CAR and PPARα activation are involved in the TCS induced mouse liver tumor.
authors.affiliation: Laboratory of Investigative Toxicology and Pathology, Department of Environmental Health, Indiana University, Bloomington, IN 47408, United States. Electronic address: zemwang@indiana.edu.
authors.forename: Zemin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Laboratory of Investigative Toxicology and Pathology, Department of Environmental Health, Indiana University, Bloomington, IN 47408, United States. Electronic address: lixil@indiana.edu.
authors.forename: Xilin
authors.initials: X
authors.lastname: Li
authors.affiliation: Laboratory of Investigative Toxicology and Pathology, Department of Environmental Health, Indiana University, Bloomington, IN 47408, United States. Electronic address: jklauni@indiana.edu.
authors.forename: James E
authors.initials: JE
authors.lastname: Klaunig
mesh_terms: D042962:Acyl-CoA Oxidase; D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D000090702:Constitutive Androstane Receptor; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010088:Oxidoreductases / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D014260:Triclosan / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D002273:Carcinogens; D000090702:Constitutive Androstane Receptor; D047493:PPAR alpha; D018160:Receptors, Cytoplasmic and Nuclear; D014260:Triclosan; D010088:Oxidoreductases; C107176:peroxisomal acyl-CoA oxidase; D042962:Acyl-CoA Oxidase
keywords: Constitutive androstane receptor; Mechanism of action; Non-genotoxic carcinogens; Peroxisome proliferator-activated receptor alpha; Rodent liver; Triclosan