Environmental Disruption of Uterine Function

描述（由申请人提供）：多环芳烃（PAH），来源于化石燃料和烟草烟雾的不完全燃烧，主要通过激活芳烃受体（AHR）对组织产生毒性作用。AHR是Per/ARNT/Sim转录因子家族的一员，该家族在生理或病理（例如环境毒物）提示下调节“靶”基因表达。事实上，在怀孕期间，这种蛋白质在子宫中的表达或功能一无所知。AHR在母胎界面的表达，加上AHR缺陷的雌性小鼠产仔数减少的事实，表明这种转录因子在怀孕期间具有生物学功能。ahr激活配体，如多环芳烃，在流行病学和动物研究中都被认为对生殖功能有有害影响。根据我们自己的体内给药方案，我们知道在妊娠早期给药时，多环芳烃对妊娠有深远的影响。利用妊娠早期子宫蜕膜组织进行的基因谱分析实验表明，体内对多环芳烃治疗的反应是几种细胞周期基因的大规模抑制。观察到间质细胞有丝分裂相应减少。基于计算机的序列分析在许多这些细胞周期基因的启动子中发现了一致的AHR反应元件，表明AHR可能参与基因抑制机制的一部分。有趣的是，在妊娠早期，AHR蛋白的表达反映了两种I型组蛋白去乙酰化酶（HDAC）的表达，免疫沉淀显示AHR在体内与HDAC2形成物理相互作用。据推测，多环芳烃选择性抑制子宫中几个细胞周期调节基因是通过表观遗传措施发生的，涉及AHR和组蛋白去乙酰化酶之间的相互作用。如果发现是这样的话，这将表明在我们的环境中几乎无处不在的有害化学物质可以通过组蛋白修饰在全球范围内改变基因的表观遗传表达。此外，我们认为当细胞暴露于环境毒物如多环芳烃时，AHR作为环境哨兵信号细胞周期停止。

DESCRIPTION (provided by applicant): Polycyclic aromatic hydrocarbons (PAH), derived from the incomplete combustion of fossil fuels and tobacco smoke, elicit their toxic actions on tissues primarily through activation of the aryl hydrocarbon receptor (AHR). The AHR is a member of the Per/ARNT/Sim family of transcription factors that regulates 'target' gene expression in response to physiological or pathological (e.g., environmental toxicants) cues. Virtually nothing is known about the expression or function of this protein in the uterus during pregnancy. Expression of AHR at the maternal-fetal interface, coupled with the fact that AHR-deficient female mice have reduced litter sizes, suggests that this transcription factors serves a biological function during pregnancy. AHR-activating ligands, such as PAH, have been implicated from both epidemiological and animal studies to have deleterious effects on reproductive function. From our own in vivo dosing scheme, we know that PAH profoundly effect pregnancy when administered early in gestation. Gene profiling experiments using uterine decidual tissue of early pregnancy demonstrate that wholesale repression of several cell cycle genes occurs in response to PAH treatment in vivo. A corresponding decrease in decidual stromal cell mitosis was observed. Computer-based sequence analysis identified consensus AHR response elements in the promoters of many of these cell cycle genes, suggesting possible involvement of AHR as part of the gene repression mechanism. Interestingly, AHR protein expression through early gestation mirrors that of two type I histone deacetylases (HDAC) and AHR was shown by immunoprecipitation to form a physical interact with the HDAC2 in vivo. It is hypothesized that selective repression of several cell cycle regulatory genes in the uterus by PAH occurs through epigenetic measures involving an interaction between the AHR and histone deacetylases. If found to be the case, this would suggest that hazardous chemicals found essentially everywhere in our environment can epigenetically alter the expression of genes on a global scale through histone modifications. Furthermore, we believe that AHR functions as an environmental sentinel to signal cell cycle arrest when cells are exposed to environmental toxicants such as PAH.