Species differences in response to diethylhexylphthalate: suppression of apoptosis, induction of DNA synthesis and peroxisome proliferator activated receptor alpha-mediated gene expression

Diethylhexylphthalate (DEHP) is a phthalate plasticizer that belongs to the peroxisome proliferator (PP) class of rodent nongenotoxic hepatocarcinogen s. Previously, we have shown that MEHP (a principal metabolite of DEHP and the proximal PP) induced DNA synthesis and suppressed apoptosis in rat but not in human hepatocytes in vitro. Here, we present further studies of spec ies differences in response to DEHP. In rats, 4 days of exposure to DEHP (9 50 mg/kg per day by gavage) induced peroxisomal beta-oxidation, DNA synthes is and suppressed apoptosis. In contrast, there was no response of guinea p ig liver to DEHP. In rat hepatocytes in vitro, MEHP (250, 500 and 750 mu M) induced peroxisomal beta-oxidation, DNA synthesis and suppressed apoptosis . In contrast to the pleiotropic response noted in rat hepatocytes, there w as no response of human hepatocytes to 250, 500 or 750 mu M MEHP. PPs activ ate the peroxisome proliferator activated receptor alpha (PPAR alpha) that binds to DNA at peroxisome proliferator response elements (PPREs) within th e promoters of PP-responsive genes such as rat acyl CoA oxidase (ACO). Howe ver, the human ACO gene promoter differs at three bases within the PPRE fro m the rat ACO promoter and appears refractory to PPs. To address species di fferences in response to DEHP at the molecular level, we used promoter-repo rter gene assays to compare the ability of MEHP to induce gene expression f rom the rat or the human ACO promoter. MEHP gave a concentration-dependent increase in reporter gene expression from the rat ACO gene promoter with ei ther mouse or human PPAR alpha. In contrast, the human ACO promoter was una ble to drive MEHP- induced gene transcription irrespective of the species o rigin of PPAR alpha. These data provide further weight of evidence at the c ellular and molecular levels for a lack of risk to human health from the ph thalate DEHP.