Effects of the aryl hydrocarbon receptor agonist 3-methylcholanthrene on the 17β-estradiol regulated mRNA transcriptome of the rat uterus
Effects of the aryl hydrocarbon receptor agonist 3-methylcholanthrene on the 17β-estradiol regulated mRNA transcriptome of the rat uterus
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DOI：
10.1016/j.jsbmb.2017.03.004
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发表时间：
2017-07-01
影响因子：
4.1
通讯作者：
Kretzschmar, Georg
中科院分区：
文献类型：
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作者：
Helle, Janina;Keiler, Annekathrin M.;Kretzschmar, Georg
多环芳烃（PAHs）是有机化合物不完全燃烧的产物，大量存在于废气和香烟烟雾中。它们通过与芳香烃受体（AHR）结合而起作用，芳香烃受体（AHR）诱导肝脏中1相和2相酶的表达。多环芳烃诱导的AHR激活也可能通过调节其他途径（例如女性生殖道中的雌激素受体（ER）信号传导）而导致不良反应。我们研究了PAH 3-甲基胆蒽（3-MC）对卵巢切除大鼠子宫中17 β-雌二醇（E2）依赖性信号传导的影响，以在mRNA转录组范围内表征AHR和ER之间的串扰。在年轻的成年刘易斯大鼠中进行标准的三天子宫营养测定。使用组织学、免疫组织化学以及通过微阵列和qPCR进行的基因表达分析来分析治疗诱导的效应。3-MC对子宫绝大多数E2调节基因的mRNA转录表现出广泛的E2拮抗作用，显著改变前列腺素生物合成、补体激活、凝血途径和其他炎症反应途径。子宫中ER表达的调节，而不是肝脏中E2代谢的调节，被确定为介导这种一般抗雌激素作用的潜在重要因素。E2对前列腺素生物合成的调节对于妊娠期间的炎症样事件（包括分娩开始）非常重要。我们的研究结果表明，多环芳烃对前列腺素相关通路的不利影响可能是由于干扰E2信号，特别是通过抑制E2介导的PGF2 α下调。因此，表征的广义拮抗作用3-MC对E2依赖的信号在大鼠子宫，有助于更好地了解多环芳烃在女性生殖器官的毒性的分子机制。(C)2017爱思唯尔有限公司版权所有
Polycyclic aromatic hydrocarbons (PAHs) are products of incomplete combustion of organic compounds, abundant in exhaust fumes and cigarette smoke. They act by binding to the aryl hydrocarbon receptor (AHR) which induces expression of phase 1 and phase 2 enzymes in the liver. PAH induced AHR activation may also lead to adverse effects by modulating other pathways, for example estrogen receptor (ER) signaling in the female reproductive tract. We have investigated the effects of the PAH 3-methylcholanthrene (3-MC) on 17 beta-estradiol (E2) dependent signaling in the uterus of ovariectomized rats to characterize the cross talk between AHR and ER on an mRNA transcriptome wide scale. A standard three day uterotrophic assay was performed in young adult Lewis rats. Treatment induced effects were analyzed using histology, immunohistochemistry and gene expression analysis by microarray and qPCR. 3-MC shows broad E2 antagonistic effects on uterine mRNA transcription of the vast majority of E2 regulated genes, significantly altering prostaglandin biosynthesis, complement activation, coagulation pathways and other inflammatory response pathways. The regulation of ER expression in the uterus, but not the regulation of E2 metabolism in the liver, was identified as a potentially important factor in mediating this general antiestrogenic effect. The regulation of prostaglandin biosynthesis by E2 is important for inflammation-like events during pregnancy including the initiation of birth. Our results suggest that adverse effects of PAHs on prostaglandin related pathways are likely caused by the interference with E2 signaling, specifically by inhibiting the E2 mediated downregulation of PGF2 alpha. Characterization of the generalized antagonistic effect of 3-MC on E2 dependent signaling in the rat uterus thus contributes to a better understanding of molecular mechanisms of the toxicity of PAHs in female reproductive organs. (C) 2017 Elsevier Ltd. All rights reserved.