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In vitro screening of 200 pesticides for agonistic activity via mouse peroxisome proliferator-activated receptor (PPAR)alpha and PPAR gamma and quantitative analysis of in vivo induction pathway RID A-3835-2012

Author:
Takeuchi, Shinji  Matsuda, Tadashi  Kobayashi, Satoshi  Takahashi, Tetsuo  Kojima, Hiroyuki  


Journal:
TOXICOLOGY AND APPLIED PHARMACOLOGY


Issue Date:
2006


Abstract(summary):

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors and key regulators of lipid metabolism and cell differentiation. However, there have been few studies reporting on a variety of environmental chemicals, which may interact with these receptors. In the present study, we characterized mouse PPAR alpha and PPAR gamma agonistic activities of 200 pesticides (29 organochlorines, I I diphenyl ethers, 56 organophosphorus pesticides, 12 pyrethroids, 22 carbamates, I I acid amides, 7 triazines, 8 ureas and 44 others) by in vitro reporter gene assays using CV-1 monkey kidney cells. Three of the 200 pesticides, diclofop-methyl, pyrethrins and imazalil, which have different chemical structures, showed PPAR alpha-mediated transcriptional activities in a dose-dependent manner. On the other hand, none of the 200 pesticides showed PPAR gamma agonistic activity at concentrations <= 10(-5) M. To investigate the in vivo effects of diclofop-methyl, pyrethrins and imazalil, we examined the gene expression of PPAR alpha-inducible cytochrome P450 4As (CYP4As) in the liver of female mice intraperitoneally injected with these compounds (<= 300 mg/kq). RT-PCR revealed significantly high induction levels of CYP4A10 and CYP4A14 mRNAs in diclofop-methyl- and pyrethrins-treated mice. whereas imazalil induced almost no gene expressions of CYP4As. In particular, diclofop-methyl induced as high levels of CYP4A mRNAs as WY-14643, a potent PPAR alpha agonist. Thus, most of the 200 pesticides tested do not activate PPAR alpha or PPAR gamma in in vitro assays, but only diclofop-methyl and pyrethrins induce PPAR alpha agonistic activity in vivo as well as in vitro. (c) 2006 Elsevier Inc. All rights reserved.


Page:
235---244


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