Differential interaction of the methoxychlor metabolite 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichlor with estrogen receptors α and β
Differential interaction of the methoxychlor metabolite 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichlor with estrogen receptors α and β
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DOI：
10.1210/en.140.12.5746
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发表时间：
1999-12-01
期刊：
影响因子：
4.8
通讯作者：
Safe, S
中科院分区：
文献类型：
--
作者：
Gaido, KW;Leonard, LS;Safe, S
我们环境中的一些化学品可能会通过干扰正常的内分泌功能而影响人类健康，这一担忧促使人们研究环境污染物与类固醇激素受体的相互作用。我们比较了有机氯农药甲氧滴滴涕的雌激素代谢产物2，2-双-（对羟基苯基）-1，1，1-三氯乙烷（HPTE）对雌激素受体α（ER α）和雌激素受体β（ER β）的活性。用人或大鼠ER α或ER β加上雌激素应答性补体3-荧光素酶构建体瞬时转染人肝癌细胞（CHepG 2），该构建体含有与荧光素酶报告基因连接的补体3基因启动子序列。转染后，在17 β-雌二醇存在（用于检测拮抗作用）或不存在（用于检测激动作用）的情况下，用各种浓度的HPTE处理细胞。HPTE是HepG 2细胞中的一种有效ER α激动剂，对人和大鼠ER α的EC 50值分别约为5 × 10 - 8和10 - 8 M。相反，HPTE对人或大鼠ERP具有最小的激动剂活性，并且几乎完全消除了17 β-雌二醇诱导的ERP介导的活性。此外，HPTE在HepG 2和HeLa细胞中表现为ER α激动剂和ER β拮抗剂以及其他雌激素应答启动子（ERE-MMTV和vtERE）。这项研究表明，在确定内分泌活性化学品的作用机制，可能作为激动剂或拮抗剂，通过一个或多个激素受体的复杂性。
Concern that some chemicals in our environment may affect human health by disrupting normal endocrine function has prompted research on interactions of environmental contaminants with steroid hormone receptors. We compared the activity of 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), an estrogenic metabolite of the organochlorine pesticide methoxychlor, at estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta). Human hepatoma cells (CHepG2) were transiently transfected with either human or rat ER alpha or ER beta plus an estrogen-responsive, complement 3-luciferase construct containing a complement 3 gene promoter sequence Linked to a luciferase reporter gene. After transfection, cells were treated with various concentrations of HPTE in the presence (for detecting antagonism) or absence (for detecting agonism) of 17 beta-estradiol. HPTE was a potent ER alpha agonist in HepG2 cells, with EC50 values of approximately 5 x 10(-8) and 10(-8) M for human and rat ER alpha, respectively. In contrast, HPTE had minimal agonist activity with either human or rat ERP and almost completely abolished 17 beta-estradiol-induced ERP-mediated activity. Moreover, HPTE behaved as an ER alpha agonist and an ER beta antagonist with other estrogen-responsive promoters (ERE-MMTV and vtERE) in HepG2 and HeLa cells. This study demonstrates the complexity involved in determining the mechanism of action of endocrine-active chemicals that may act as agonists or antagonists through one or more hormone receptors.