Takeuchi Shinji, Matsuda Tadashi, Kobayashi Satoshi, Takahashi Tetsuo, Kojima Hiroyuki
Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo 060-0819, Japan.
Toxicol Appl Pharmacol. 2006 Dec 15;217(3):235-44. doi: 10.1016/j.taap.2006.08.011. Epub 2006 Sep 6.
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 PPARalpha and PPARgamma agonistic activities of 200 pesticides (29 organochlorines, 11 diphenyl ethers, 56 organophosphorus pesticides, 12 pyrethroids, 22 carbamates, 11 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 PPARalpha-mediated transcriptional activities in a dose-dependent manner. On the other hand, none of the 200 pesticides showed PPARgamma agonistic activity at concentrations <or =10(-5) M. To investigate the in vivo effects of diclofop-methyl, pyrethrins and imazalil, we examined the gene expression of PPARalpha-inducible cytochrome P450 4As (CYP4As) in the liver of female mice intraperitoneally injected with these compounds (< or =300 mg/kg). 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 PPARalpha agonist. Thus, most of the 200 pesticides tested do not activate PPARalpha or PPARgamma in in vitro assays, but only diclofop-methyl and pyrethrins induce PPARalpha agonistic activity in vivo as well as in vitro.
过氧化物酶体增殖物激活受体（PPARs）是配体依赖性转录因子，也是脂质代谢和细胞分化的关键调节因子。然而，关于可能与这些受体相互作用的多种环境化学物质的研究却很少。在本研究中，我们通过使用CV-1猴肾细胞的体外报告基因测定法，对200种农药（29种有机氯农药、11种二苯醚、56种有机磷农药、12种拟除虫菊酯、22种氨基甲酸酯、11种酰胺、7种三嗪、8种脲和44种其他农药）的小鼠PPARα和PPARγ激动活性进行了表征。200种农药中的三种，即具有不同化学结构的精稳杀得、除虫菊素和抑霉唑，以剂量依赖性方式显示出PPARα介导的转录活性。另一方面，在浓度≤10^(-5) M时，200种农药中没有一种表现出PPARγ激动活性。为了研究精稳杀得、除虫菊素和抑霉唑的体内效应，我们检查了腹腔注射这些化合物（≤300 mg/kg）的雌性小鼠肝脏中PPARα诱导的细胞色素P450 4A（CYP4A）的基因表达。逆转录-聚合酶链反应（RT-PCR）显示，在精稳杀得和除虫菊素处理的小鼠中，CYP4A10和CYP4A14 mRNA的诱导水平显著升高，而抑霉唑几乎未诱导CYP4A的基因表达。特别是，精稳杀得诱导的CYP4A mRNA水平与强效PPARα激动剂WY-14643一样高。因此，在体外试验中，所测试的200种农药中的大多数不会激活PPARα或PPARγ，但只有精稳杀得和除虫菊素在体内和体外均诱导PPARα激动活性。
