title: Different mechanisms of DEHP-induced hepatocellular adenoma tumorigenesis in wild-type and Ppar alpha-null mice.
abstract: Di (2-ethylhexyl) phthalate (DEHP) exposure is thought to lead to hepatocellular hypertrophy and hyperplasia in rodents mediated via peroxisome proliferator-activated receptor alpha (PPAR alpha). A recent study revealed that long-term exposure to relatively low-dose DEHP (0.05%) caused liver tumors including hepatocellular carcinomas, hepatocellular adenomas, and chologiocellular carcinomas at a higher incidence in Ppar alpha-null mice (25.8%) than in wild-type mice (10.0%). Using tissues with hepatocellular adenoma, microarray (Affymetrix MOE430A) as well as, in part, real-time quantitative PCR analysis was conducted to elucidate the mechanisms of the adenoma formation resulting from DEHP exposure in both genotyped mice. The microarray profiles showed that the up- or down-regulated genes were quite different between hepatocellular adenoma tissues of wild-type and Ppar alpha-null mice exposed to DEHP. The gene expressions of apoptotic peptidase activating factor 1 (Apaf1) and DNA-damage-inducible 45 alpha (Gadd45a) were increased in the hepatocellular adenoma tissues of wild-type mice exposed to DEHP, whereas they were unchanged in corresponding tissues of Ppar alpha-null mice. On the other hand, the expressions of cyclin B2 and myeloid cell leukemia sequence 1 were increased only in the hepatocellular adenoma tissues of Ppar alpha-null mice. Taken together, DEHP may induce hepatocellular adenomas, in part, via suppression of G2/M arrest regulated by Gadd45a and caspase 3-dependent apoptosis in Ppar alpha-null mice, but these genes may not be involved in tumorigenesis in the wild-type mice. In contrast, the expression level of Met was notably increased in the liver adenoma tissue of wild-type mice, which may suggest the involvement of Met in DEHP-induced tumorigenesis in wild-type mice.
authors.affiliation: Department of Preventive Medicine, Shinshu University Graduate School of Medicine, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Takashima
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ito
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Tamie
authors.initials: T
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053477:Apoptotic Protease-Activating Factor 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053148:Caspase 3 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002455:Cell Division / Q000235:genetics; D004051:Diethylhexyl Phthalate / Q000008:administration & dosage / Q000633:toxicity*; D016195:G2 Phase / Q000235:genetics; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000187:drug effects; D006965:Hyperplasia; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D047493:PPAR alpha / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010968:Plasticizers / Q000633:toxicity; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000097642:GADD45 Proteins
chemical_list: D053477:Apoptotic Protease-Activating Factor 1; D053148:Caspase 3; D018797:Cell Cycle Proteins; D004051:Diethylhexyl Phthalate; D009687:Nuclear Proteins; D047493:PPAR alpha; D010968:Plasticizers; D012333:RNA, Messenger; C506593:Apaf1 protein, mouse; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins