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

Yuki Ito,Nozomi Yamagishi,Hisao Naito,Doni Hikmat Ramdhan,Frank J Gonzalez,Michihiro Kamijima,Tamie Nakajima,Yukie Yanagiba,Toshiki Nakamura

doi:10.1155/2012/201284

Abstract

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) α, 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 PPARα by these plasticizers using wild-type (mPPARα) and humanized PPARα (hPPARα) 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 PPARα of mPPARα mice was more strongly activated than that of hPPARα mice when several target genes involving β-oxidation of fatty acids were evaluated. Interestingly, all plasticizers also activated hepatic constitutive androstane receptor (CAR) more in hPPARα mice than in mPPARα mice. Taken together, these plasticizers activated mouse and human hepatic PPARα as well as CAR. The activation of PPARα was stronger in mPPARα mice than in hPPARα mice, while the opposite was true of CAR.

Highlights

Dibutylphthalate (DBP), di(2-ethylhexyl)phthalate (DEHP), and di(2-ethylhexyl)adipate (DEHA) are used as representative industrial plasticizers, though the use of the first two considerably decreased recently
The present study clearly shows that three plasticizers (DEHP, DEHA, and DBP) significantly activated mouse hepatic PPARα in mPPARα mice, but the activation of human hepatic PPARα in humanized PPARα (hPPARα) mice was weaker than that of the former mouse line even at the high-dose exposure, especially in peroxisomal β- or ω-oxidation
DEHP is the strongest from the standpoint of PPARα-mediated gene responses. These results are consistent with in vitro studies [3, 4] which demonstrated that mono (2-ethylhexyl) phthalate (MEHP) activated mouse PPARα at lower concentrations and exhibited a stronger response than those of human PPARα [4], and MEHP activated mouse and human PPARα at a lower concentration than the respective monoesters of DBP and DEHA [3, 4]. These species differences in PPARα activation were most prominent in microsomal PPARα-target gene, Cyp4a14, followed by mitochondrial (MCAD, very long-chain acyl-CoA dehydrogenase (VLCAD)) or peroxisomal enzymes (PH, PT)

Summary

Introduction

Dibutylphthalate (DBP), di(2-ethylhexyl)phthalate (DEHP), and di(2-ethylhexyl)adipate (DEHA) are used as representative industrial plasticizers, though the use of the first two considerably decreased recently. These chemicals are involved in peroxisome proliferations, similar to endogenous fatty acids, exogenous fibrates, and thiazolidinediones [1,2,3,4]. Once most plasticizers are taken into the body, they are metabolized by lipase in several organs such as liver and small intestine, and their metabolites, especially monocarboxylic acids, activate peroxisome proliferator-activated receptor alpha (PPARα), and influence the receptor-related lipid metabolism, anti-inflammation, glucose metabolism, and ketogenesis [5].

Methods

Results

Conclusion