Teratogenic phthalate esters and metabolites activate the nuclear receptors PPARs and induce differentiation of F9 cells
Teratogenic phthalate esters and metabolites activate the nuclear receptors PPARs and induce differentiation of F9 cells
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DOI：
10.1016/s0041-008x(03)00014-0
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发表时间：
2003-04-01
影响因子：
3.8
通讯作者：
Nau, H
中科院分区：
文献类型：
--
作者：
Lampen, A;Zimnik, S;Nau, H
邻苯二甲酸酯等工业增塑剂可诱导过氧化物酶体增殖。一些邻苯二甲酸酯，例如邻苯二甲酸二（2-乙基己基）酯（DEHP）及其代谢物邻苯二甲酸单（2-乙基己基）酯和2-乙基己酸也是已知的致畸剂。最近，我们介绍了两个在体外测试系统组成的F9畸胎瘤细胞分化和激活过氧化物酶体增殖物激活受体（PPAR）配体结合域在中国banister卵巢报告细胞检测致畸化合物的抗癫痫药物丙戊酸。我们现在通过在体外检测2种邻苯二甲酸二酯和19种邻苯二甲酸单酯，将这些方法应用于邻苯二甲酸酯及其代谢物。在F9细胞测定中，仅发现五种化合物，邻苯二甲酸单-2-乙基己酯、邻苯二甲酸单-1-甲基庚酯、邻苯二甲酸单苄酯、邻苯二甲酸苄丁酯和2-乙基己酸诱导F9细胞分化。其他测试化合物不能诱导F9细胞的分化。发现三种化合物（邻苯二甲酸单甲酯、邻苯二甲酸单乙酯、邻苯二甲酸单-2，2-二甲基-1-苯基丙基酯和邻苯二甲酸二甲酯）不与任何PPARs相互作用。所有其他邻苯二甲酸酯均激活了PPARs。大多数化合物激活PPARalpha和PPARgamma。有趣的是，在大多数情况下，PPARgamma比PPARalpha激活更强。只有五种测试化合物，单-2-乙基-己基-邻苯二甲酸酯、单-1-甲基-庚基-邻苯二甲酸酯、单苄基-邻苯二甲酸酯、苄基-丁基-邻苯二甲酸酯和2-乙基-己酸激活了PPARdelta并与特定的PPARdelta-响应元件相互作用。这些是诱导F9细胞分化的相同化合物，其中三种是已知的致畸化合物。邻苯二甲酸酯类化合物通过激活PPARs发挥激素的作用。F9细胞分化试验和PPARdelta活化试验的组合检测了可能的致畸邻苯二甲酸酯及其衍生物。因此，该测试系统可用于新增塑剂早期开发的筛选测试系统。(C)2003 Elsevier Science（美国）。All rights reserved.
Industrial plasticizers such as phthalates can induce peroxisome proliferation. Some phthalates such as di-2-ethyl-hexyl-phthalate (DEHP) and its metabolites mono-2-ethyl-hexyl-phthalate and 2-ethyl-hexanoic acid are also known teratogens. Recently, we introduced two in vitro test systems consisting of F9 teratocarcinoma cell differentiation and activation of peroxisome proliferator-activated receptor (PPAR)-ligand-binding domain in Chinese banister ovary-reporter cells for the detection of teratogenic compounds related to the antiepileptic drug valproic acid. We now applied these methods to the class of phthalate esters and their metabolites by testing 2 diphthalate esters and 19 monophthalate esters in vitro. In the F9 cell assay only five compounds, mono-2-ethyl-hexyl-phthalate, mono-1-methylheptyl-phthalate, mono-benzyl-phthalate, benzyl-butyl-phthalate, and 2-ethyl-hexanoic acid were found to induce F9 cell differentiation. The other test Compounds were not able to induce differentitation of F9 cells. Three compounds (mono-methyl-phthalate, mono-ethylphthalate, and mono-2,2-dimethyl-1-phenyl-propyl-phthalate, and phthalic acid di-methyl-ester were found not to interact with any PPARs. All other phthalate esters activated PPARs. Most compounds activated PPARalpha and PPARgamma. Interestingly PPARgamma in most cases was activated stronger than PPARalpha. Only the five test compounds, mono-2-ethyl-hexyl-phthatate, mono-1-methyl-heptyl-phthalate, monobenzyl-phthalate, benzyl-butyl-phthalate, and 2-ethyl-hexanoic acid activated PPARdelta and interacted with a specific PPARdelta-response element. These are the same compounds that induced F9 cell differentiation and three of them are known teratogenic compounds. It is Concluded that phthalate esters are acting like hormones by activating PPARs. The combination of F9 cell differentiation assay and PPARdelta activation assay detected possible teratogenic phthalate-ester and derivatives. Therefore the test systems seeni useful for a screening test system in the early development of new plasticizers. (C) 2003 Elsevier Science (USA). All rights reserved.