Plasticizers May Activate Human Hepatic Peroxisome Proliferator-Activated Receptor alpha Less Than That of a Mouse but May Activate Constitutive Androstane Receptor in Liver

Dibutylphthalate (DBP), di(2-ethylhexyl) phthalate (DEHP), and di(2-ethylhexyl) adipate (DEHA) are used as plasticizers. Their metabolites activate peroxisome proliferator-activated receptor (PPAR) alpha, which may be related to their toxicities. However, species differences in the receptor functions between rodents and human make it difficult to precisely extrapolate their toxicity from animal studies to human. In this paper, we compared the species differences in the activation of mouse and human hepatic PPAR alpha by these plasticizers using wild-type (mPPAR alpha) and humanized PPAR alpha (hPPAR alpha) mice. At 12 weeks old, each genotyped male mouse was classified into three groups, and fed daily for 2 weeks per os with corn oil (vehicle control), 2.5 or 5.0 mmol/kg DBP (696, 1392 mg/kg), DEHP (977, 1953 mg/kg), and DEHA (926, 1853 mg/kg), respectively. Generally, hepatic PPAR alpha of mPPAR alpha mice was more strongly activated than that of hPPAR alpha mice when several target genes involving beta-oxidation of fatty acids were evaluated. Interestingly, all plasticizers also activated hepatic constitutive androstane receptor (CAR) more in hPPAR alpha mice than in mPPAR alpha mice. Taken together, these plasticizers activated mouse and human hepatic PPAR alpha as well as CAR. The activation of PPAR alpha was stronger in mPPAR alpha mice than in hPPAR alpha mice, while the opposite was true of CAR.