(Mannaerts et al., 1993). PPARs are members of the steroid hormone receptor superfamily, and three related isotypes, specifically PPARα, PPARβ and PPARγ, have been identified (Desvergne and Wahli, 1999). Based on target gene expression patterns, PPARα appears to have critical roles in the regulation of fatty acid metabolism, including fatty acid β-oxidation, apolipoproteins, and fatty acid transport proteins (Lee et al., 1995;Auwerx et al., 1996;Aoyama et al., 1998;Peters et al., 1997;Ren et al., 1997;Martin et al., 1997). Additionally, chronic exposure to numerous PPARα agonists has been reported to increase the incidence of hepatocellular tumors in rodents ABSTRACT -The 26-week oral toxicity of diheptyl phthalate (DHP), a peroxisome proliferator-activated receptor α (PPARα) agonist, with special emphasis on the potential induction of hepatocellular proliferative lesions was investigated in this study. DHP was administered to male F344 rats via gavage at 0 (control), 1,000 or 2,000 mg/kg/day for 26 weeks. Body weight gain was significantly lower, whereas food and water consumption was significantly higher in DHP-treated rats compared with controls. DHPtreated rats exhibited decreases in blood triglyceride, total cholesterol, phospholipid and glucose levels, which were likely related to biological effects of the PPARα agonist. Absolute and relative organ weights of the livers with pale brown discoloration and dark brown spots significantly increased in DHP-treated rats. Histopathological examinations revealed remarkable diffuse hypertrophy of hepatocytes with groundglass appearance, intracytoplasmic inclusion bodies and/or vacuolation in the DHP-treated groups. These findings were associated with increases in serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and γ-glutamyltranspeptidase. The number and area of glutathione S-transferase placental form positive foci, a marker of hepatocellular preneoplastic lesions in rats, significantly increased in DHP-treated groups. Additionally, proliferating cell nuclear antigen positive liver cell counts in DHPtreated groups were significantly higher than those of the controls. Testicular alterations were not detected histopathologically, whereas absolute and relative prostate weights significantly decreased at both doses. These results indicate that DHP induces liver pre-neoplastic foci, and suggest the possibility that DHP is a possible genotoxic carcinogen in the liver of rats.