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转录因子家族的成员，其响应于生理或病理（例如，环境毒物）线索。几乎没有人知道这种蛋白质在怀孕期间子宫中的表达或功能。AHR在母胎界面的表达，再加上AHR缺陷的雌性小鼠的窝仔数减少的事实，表明这种转录因子在妊娠期间发挥生物学功能。AHR激活配体，如PAH，已经从流行病学和动物研究中暗示对生殖功能具有有害影响。从我们自己的体内给药方案中，我们知道PAH在妊娠早期给药时会对妊娠产生深远的影响。使用早孕子宫蜕膜组织的基因分析实验表明，在体内PAH治疗后，几种细胞周期基因发生了大规模抑制。观察到蜕膜基质细胞有丝分裂相应减少。基于计算机的序列分析确定了许多这些细胞周期基因的启动子中的共识AHR反应元件，这表明AHR可能参与基因抑制机制的一部分。有趣的是，AHR蛋白在妊娠早期的表达反映了两种I型组蛋白去乙酰化酶（HDAC）的表达，并且通过免疫沉淀显示AHR在体内与HDAC 2形成物理相互作用。据推测，PAH对子宫中几种细胞周期调控基因的选择性抑制是通过涉及AHR和组蛋白脱乙酰酶之间相互作用的表观遗传措施发生的。如果发现是这种情况，这将表明，在我们的环境中基本上无处不在的危险化学品可以通过组蛋白修饰在全球范围内改变基因的表达。此外，我们相信，当细胞暴露于多环芳烃等环境毒物时，AHR作为环境哨兵发出细胞周期停滞信号。

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.