Different Mechanisms of DEHP‐induced Hepatocellular Adenoma Tumorigenesis in Wild‐type and Pparα‐null Mice

Abstract

Department of Preventive Medicine, ShinshuUniversity 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 downregulated 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 DEHPinduced tumorigenesis in wild-type mice. (J Occup Health 2008; 50: 169-180)

Hepatocarcinogenic Susceptibility of Fenofibrate and Its Possible Mechanism of Carcinogenicity in a Two-Stage Hepatocarcinogenesis Model of rasH2 Mice

“…It has been reported that PPs such as clofibrate, one of the fibrate drugs, and Wy-14,643, a widely used PP-representative compound, increase the number of peroxisomes, up-regulate peroxisomal beta-oxidation, and cause hepatocellular hypertrophy and hyperplasia when administered to rats and mice (Takashima et al 2008). In addition, Takashima et al (2008) added that PPARα-dependent alterations in cell cycle regulatory proteins are likely to contribute to the hepatocarcinogenicity of PPs. In the present study, all of the FF-treated mice exhibited centrilobular hypertrophy and vacuolar degeneration in hepatocytes, and some animals of this group had altered foci.…”

DEHP: Genotoxicity and potential carcinogenic mechanisms—A review

“…Takashima et al [188] reported that that long-term exposure to a relatively low dose of DEHP (0.05%) caused liver tumors including hepatocellular carcinomas, hepatocellular adenomas, and chologiocellular carcinomas at a higher incidence in PPARa-null mice (25.8%) than wild type mice (10.0%). In contrast to Toyosawa et al [190], fewer tissues were examined for gene expression changes by Takashima et al [188].…”

Components of plastic: experimental studies in animals and relevance for human health

“…Data from animal and human studies suggest that EDCs may play a role in the development of cancer (Takashima et al 2008), the reported decline in human sperm count (Mocarelli et al 2008), temporal increases in the frequency of developmental abnormalities of the male reproductive tract (Sharpe & Skakkebaek 2008) and the trend towards precocious puberty in human females (Schoeters et al 2008).…”