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526572 
Journal Article 
Different mechanisms of DEHP-induced hepatocellular adenoma tumorigenesis in wild-type and Ppar alpha-null mice 
Takashima, K; Ito, Y; Gonzalez, FJ; Nakajima, T 
2008 
Yes 
Journal of Occupational Health
ISSN: 1341-9145
EISSN: 1348-9585 
J Occup Health. 2008; 50(2):169-80. [Journal of occupational health] 
50 
2 
169-180 
English 
18403868 
WOS:000254884500010 
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(x). 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 DEHR 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 Ppara-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 Ppara-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 Ppara-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. 
di (2-ethylhexyl) phthalate; peroxisome proliferator-activated receptor; alpha; tumorigenesis; apoptotic peptidase activating factor 1; DNA-damage-inducible 45 alpha; activated-receptor-alpha; cell-cycle control; nongenotoxic; hepatocarcinogen; peroxisome proliferators; retinoblastoma protein; clofibric acid; bcl-2 family; mouse-liver; apoptosis; pathway