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




Plasticizers May Activate Human Hepatic Peroxisome Proliferator-Activated Receptor Less Than That of a Mouse but May Activate Constitutive Androstane Receptor in Liver - Download this document for free, or read online. Document in PDF available to download.

PPAR ResearchVolume 2012 2012, Article ID 201284, 11 pages

Research Article

Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan

Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan

Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

Received 31 January 2012; Revised 19 March 2012; Accepted 21 March 2012

Academic Editor: Yuji Kamijo

Copyright © 2012 Yuki Ito et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Dibutylphthalate DBP, di2-ethylhexylphthalate DEHP, and di2-ethylhexyladipate 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.





Author: Yuki Ito, Toshiki Nakamura, Yukie Yanagiba, Doni Hikmat Ramdhan, Nozomi Yamagishi, Hisao Naito, Michihiro Kamijima, Frank J

Source: https://www.hindawi.com/



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