Open AccessDifferent Mechanisms of DEHP‐induced Hepatocellular Adenoma Tumorigenesis in Wild‐type and Ppar α‐null Mice
Author(s) -
Takashima Kayoko,
Ito Yuki,
Gonzalez Frank J,
Nakajima Tamie
Publication year - 2008
Publication title -
journal of occupational health
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.664
H-Index - 59
ISSN - 1348-9585
DOI - 10.1539/joh.l7105
Subject(s) - hepatocellular adenoma , adenoma , null cell , carcinogenesis , endocrinology , hepatocellular carcinoma , cancer research , medicine , biology , peroxisome proliferator activated receptor , apoptosis , carcinogen , pathology , receptor , gene , cancer , biochemistry
Different Mechanisms of DEHP‐induced Hepatocellular Adenoma Tumorigenesis in Wild‐type and Pparα ‐null Mice: Kayoko T akashima , et al . Department of Preventive Medicine, Shinshu University Graduate School of Medicine —Di (2‐ethylhexyl) phthalate (DEHP) exposure is thought to lead to hepatocellular hypertrophy and hyperplasia in rodents mediated via peroxisome proliferator‐activated receptor alpha (PPARα). 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 Pparα ‐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 Pparα 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 Pparα ‐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 Pparα ‐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 Pparα‐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.