DDT and its metabolites alter gene expression in human uterine cell lines through estrogen receptor-independent mechanisms.
DDT and its metabolites alter gene expression in human uterine cell lines through estrogen receptor-independent mechanisms.
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DOI：
10.1289/ehp.021101239
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发表时间：
2002-12
影响因子：
10.4
通讯作者：
McLachlan, John A
中科院分区：
文献类型：
--
作者：
Frigo, Daniel E;Burow, Matthew E;Mitchell, Kamron A;Chiang, Tung-Chin;McLachlan, John A
干扰内分泌的有机氯，如杀虫剂二氯二苯基三氯乙烷（DDT），结合并激活雌激素受体（ER），从而引发雌激素样作用。虽然ER主要通过雌激素应答元件激活转录发挥作用，但ER α和β均可与各种转录因子如激活蛋白-1（AP-1）相互作用。此外，雌激素可以调节早期信号事件，表明环境雌激素的生物学效应可能不是通过经典的ER（α和β）活性单独介导的。我们假设，已知的环境雌激素，如滴滴涕及其代谢产物，激活AP-1介导的基因转录通过ER依赖和ER非依赖的手段。使用两种石川人子宫内膜腺癌细胞系变体，我们证实是雌激素反应性[石川（+）]和雌激素无反应性[石川（-）]，我们产生稳定转染AP-1荧光素酶细胞系，以确定在AP-1介导的基因表达的各种刺激的雌激素反应机制的作用。我们的研究结果表明，DDT和二氯二苯基二氯乙烷（DDD）是AP-1活性的最有效的激活剂，2，2-二（对氯苯基）乙酸未能激活。尽管DDT及其同类物在石川（+）和石川（-）细胞中都能刺激AP-1，但AP-1的激活在雌激素无反应的石川（-）细胞中更为明显。此外，DDT，DDD，和二氯二苯基二氯乙烯（DDE）也可以刺激AP-1活性在雌激素无反应的人胚肾293细胞使用不同的启动子上下文。因此，我们的数据表明，DDT及其代谢产物激活AP-1转录因子的ER（α或β）状态无关。
Endocrine-disrupting organochlorines, such as the pesticide dichlorodiphenyltrichloroethane (DDT), bind to and activate estrogen receptors (ERs), thereby eliciting estrogen-like effects. Although ERs function predominantly through activation of transcription via estrogen-responsive elements, both ERs, alpha and ss, can interact with various transcription factors such as activator protein-1 (AP-1). Additionally, estrogens may regulate early signaling events, suggesting that the biological effects of environmental estrogens may not be mediated through classic ER (alpha and ss) activity alone. We hypothesized that known environmental estrogens, such as DDT and its metabolites, activate AP-1-mediated gene transactivation through both ER-dependent and ER-independent means. Using two Ishikawa human endometrial adenocarcinoma cell line variants that we confirmed to be estrogen responsive [Ishikawa(+)] and estrogen unresponsive [Ishikawa(-)], we generated stably transfected AP-1 luciferase cell lines to identify the role of an estrogen-responsive mechanism in AP-1-mediated gene expression by various stimuli. Our results demonstrate that DDT and dichlorodiphenyldichloroethane (DDD) were the most potent activators of AP-1 activity; 2,2-bis(p-chlorophenyl) acetic acid failed to activate. Although stimulated in both Ishikawa(+) and Ishikawa(-) cells by DDT and its congeners, AP-1 activation was more pronounced in the estrogen-unresponsive Ishikawa(-) cells. In addition, DDT, DDD, and dichlorodiphenyldichloroethylene (DDE) could also stimulate AP-1 activity in the estrogen-unresponsive human embryonic kidney 293 cells using a different promoter context. Thus, our data demonstrate that DDT and its metabolites activate the AP-1 transcription factor independent of ER (alpha or ss) status.