Plasticizers may activate human hepatic peroxisome proliferator-activated receptor α 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) , 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 by these plasticizers using wild-type (mPPAR) and humanized PPAR (hPPAR) 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 5.0mmol/kg DBP (696, 1392mg/kg), DEHP (977, 1953mg/kg), and DEHA (926, 1853mg/kg), respectively. Generally, hepatic PPAR of mPPAR mice was more strongly activated than that of hPPAR mice when several target genes involving -oxidation of fatty acids were evaluated. Interestingly, all plasticizers also activated hepatic constitutive androstane receptor (CAR) more in hPPAR mice than in mPPAR mice. Taken together, these plasticizers activated mouse and human hepatic PPAR as well as CAR. The activation of PPAR was stronger in mPPAR mice than in hPPAR mice, while the opposite was true of CAR.