Epigenetic Remodeling by Environmental Arsenicals

描述(由申请人提供)：环境中暴露于砷及其代谢物是美国和世界人口的重大健康问题，在包括癌症在内的人类病理的病因中起着致病作用。拟议研究的长期目标是确定因环境暴露于军火库而产生的毒性机制。有人假设，砷的毒性在一定程度上是通过破坏细胞的正常表观遗传状态来调节的，这一假设是基于现有文献中的报道以及这些初步研究。这一前提将使用先进的表观遗传学技术进行测试，以分析砷暴露的模型。这些模型的范围从砷介导的人类尿路上皮细胞恶性转化的体外模型到通过饮用水暴露于已知水平的环境砷的具有良好特征的、具有种族重要性的人群。通过三个具体目标，将测试从单个基因水平到整个基因组水平的砷对表观遗传调控的影响。其目的是：1)研究在砷诱导的体外恶性转化模型中观察到的Wnt5a基因表观遗传激活的机制和表型后果。2)确定砷诱导永生化人膀胱细胞URotsa恶性转化过程中表观基因组图谱的决定性变化，并确定去除这种应激源后这些变化的稳定性。3)确定暴露于饮用水中已知砷水平的人群中砷的表观遗传靶点。虽然这项研究的应用重点是砷对人类癌症的表观遗传扰动，但如果这一假说得到研究的支持，即砷引起的表观遗传变化是长期毒性的一种机制，那么产生的知识可能会延伸到其他金属诱导的人类病理，如糖尿病和心血管疾病。

DESCRIPTION (provided by applicant): Environmental exposure to arsenic and its metabolites is a significant health concern to US and world populations, playing a causative role in the etiology of human pathologies, including cancer. The long-term goal of the proposed study is designed to identify mechanisms of toxicity that are a result of environmental exposures to arsenicals. It is hypothesized that arsenical toxicity, in part, is mediated through its disruption of the normal epigenetic state of cells, and this hypothesis is based on reports in the extant literature as well as these preliminary studies. This premise will be tested using advanced epigenetic technologies to analyze models of arsenical exposure. These models range from in vitro models of arsenical-mediated malignant transformation of human uroepithelial cells to well-characterized, ethnically important human populations exposed to known levels of environmental arsenicals through drinking water. Through three specific aims the effects of arsenicals on epigenetic regulation from the level of the individual gene to the level of the entire genome will be tested. The aims are to: 1) Investigate the mechanisms and phenotypic consequences of epigenetic activation of Wnt5a gene that has been observed in an in vitro model of arsenical-induced malignant transformation. 2) Identify the decisive changes in the epigenomic landscape over the time course of arsenical induced malignant conversion of the immortalized human bladder cell UROtsa, and determine the stability of these changes after removal of this stressor. 3) Identify epigenetic targets of arsenic in human populations exposed to known levels of arsenic in their drinking water. While this research application focuses on the epigenetic perturbations induced by arsenicals with respect to human cancer, it is likely that if the hypothesis is backed by the studies, that of arsenical induced epigenetic changes as a mechanism of long-term toxicity, then the knowledge generated will likely extend to other metal-induced human pathologies, such as diabetes and cardiovascular disease.