Journal
JOURNAL OF OCCUPATIONAL HEALTH
Volume 50, Issue 2, Pages 169-180Publisher
WILEY
DOI: 10.1539/joh.L7105
Keywords
di (2-ethylhexyl) phthalate; peroxisome proliferator-activated receptor alpha; tumorigenesis; apoptotic peptidase activating factor 1; DNA-damage-inducible 45 alpha
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Funding
- Intramural NIH HHS [Z01 BC005708, Z01 BC005561, Z01 BC005562] Funding Source: Medline
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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.
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