Journal
TOXICOLOGY IN VITRO
Volume 22, Issue 6, Pages 1534-1538Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tiv.2008.05.010
Keywords
phthalate ester; DEHP; MEHP; oxidized metabolite; PPAR; peroxisome proliferator; coactivator
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Funding
- Research Institute of Meijo University
- Scientific Frontier Research Project
- Ministry of Education, Culture, Sports, Science and Technology of Japan
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Phthalate esters (PEs), a group of environmental chemicals, affect biological systems via endocrine and lipid metabolism modulations. These effects are believed to be mediated in part by peroxisome proliferator-activated receptors (PPARs). Evaluations of PE activities as ligands toward PPARs have been investigated in many studies on their primary metabolites, monoesters. However, the activities of various other metabolites, including oxidized derivatives, remain to be determined. Here, we have evaluated the PPAR ligand activities of these PE derivatives by in vitro coactivator recruiting assay. Mono(2-ethyl-5-hydroxyhexyl)phthalate, the most abundant metabolite of di-(2-ethylhexyl)phthalate (DEHP), was less active than mono(2-ethylhexyl)phthalate (MEHP) as a PPAR ligand. Other derivatives oxidized at the alkyl group and benzene ring of DEHP, MEHP dibutyl phthalate and its monoester were also investigated and some affected PPAR activities. Unexpectedly, MEHP as well as its further oxidized metabolite did not show clear activity for PPAR alpha, although MEHP is believed to interact with PPAR alpha. This might imply indirect PPAR-mediated mechanisms that lead to observed biological effects such as peroxisome proliferation. (C) 2008 Elsevier Ltd. All rights reserved.
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