Epigenetic Remodeling by Environmental Arsenicals

环境砷的表观遗传重塑

• 批准号: 7171953
• 负责人: Bernard W FUTSCHER
• 金额: $ 24.39万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-27 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7171953
• 关键词: arsenic; clinical research; epigenetics; human; model

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.

描述（由申请人提供）：砷及其代谢物的环境暴露对美国和世界人民来说是一个重大的健康问题，在人类病理学（包括癌症）的病因学中发挥着致病作用。拟议研究的长期目标旨在确定环境中砷暴露造成的毒性机制。据推测，砷毒性部分是通过破坏细胞正常表观遗传状态而介导的，该假设基于现有文献的报告以及这些初步研究。这一前提将使用先进的表观遗传学技术来分析砷暴露模型进行测试。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特征明确、具有重要种族意义的人群。通过三个具体目标，将测试砷对从个体基因水平到整个基因组水平的表观遗传调控的影响。目的是：1）研究在砷诱导恶性转化的体外模型中观察到的 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景观的决定性变化，并确定去除该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含量的人群中砷的表观遗传目标。 虽然这项研究应用的重点是砷引起的与人类癌症有关的表观遗传扰动，但如果该假设得到研究的支持，即砷引起的表观遗传变化是一种长期毒性机制，那么所产生的知识可能会扩展到其他金属引起的人类疾病，例如糖尿病和心血管疾病。