A Study of Telomeres in an Arsenic-Exposed Bangladesh Cohort

描述(申请人提供)：饮用水中的慢性砷暴露在美国和世界范围内是一个严重的公共卫生问题，因为全球近2亿人长期接触这种I类人类致癌物质。砷会增加多种人类疾病的风险，包括皮肤癌、膀胱癌和肾癌；然而，砷毒性的机制尚不清楚。我们推测，端粒可能在癌症相关的砷中毒中发挥关键作用。端粒是调节基因组稳定性的核心，在各种实验环境中，砷对端粒和端粒酶(端粒维持的主要酶)有不利影响。在这项研究中，我们建议以一种高度可行和有效的方式来表征砷暴露、各种端粒相关特征和砷相关结果之间的关系，使用来自孟加拉国(n=27,000)砷暴露的纵向队列研究的现有数据和约6-8年的随访数据。拟议的研究采用病例队列设计，我们从队列研究中抽取个人样本，创建三个病例组(1,000例皮肤皮损事件，200例非黑色素瘤皮肤癌(MNSC)事件和400例死亡)和一个对照组(1000名队列成员的随机样本)。使用预期的血液样本，我们将测量端粒长度、端粒功能障碍的血清标记物和端粒酶的表达(对于具有可用RNA的子集)。使用在饮用水、尿液和血液中测量的基线砷暴露数据，我们将评估砷对对照组和每个病例组所测量的端粒相关特征的影响。我们还将评估基线端粒相关特征与我们感兴趣的三个结果之间的关联。在这项工作的第二部分，我们将测量MNSCC组织和邻近正常组织中的端粒长度和端粒酶表达，这些组织是从该队列中MNSCC病例的皮肤活检中获得的。将比较正常皮肤和癌变皮肤之间以及癌症亚型之间的端粒相关特征，并将评估皮肤中砷暴露与端粒相关特征之间的关联。最后，我们将使用现有的关于生殖系遗传变异的全基因组数据来确定我们的端粒相关性状的遗传决定因素。还将讨论几个次要目标。我们将(1)确定端粒相关性状是否介导砷对健康结局的影响，(2)确定砷是否影响端粒磨损率，以及(3)测试端粒相关性状与血液抗氧化剂水平的相关性。该项目是了解砷对人体毒性机制的关键一步。在这项正在进行的队列研究中，随着更多的随访数据的积累，从这项工作中得出的所有端粒相关测量的实用性将会增加，从而能够进一步研究癌症、心血管疾病和其他与砷相关的慢性疾病

DESCRIPTION (provided by applicant): Chronic arsenic exposure from drinking water is a serious public health issue in the U.S. and worldwide, as nearly 200 million people worldwide are chronically exposed to this class I human carcinogen. Arsenic increases risk for a wide array of human diseases, including cancers of the skin, bladder, and kidney; however, the mechanisms of arsenic toxicity are unclear. We hypothesize that telomeres may play a critical role in cancer-related arsenic toxicity. Telomeres are central to the regulation of genome stability, and arsenic has detrimental effects on telomeres and telomerase, the primary telomere maintenance enzyme, in a wide variety of experimental settings. In this study, we propose to characterize the relationships among arsenic exposure, various telomere-related traits, and arsenic-related outcomes in a highly feasible and efficient manner, using existing data from a longitudinal cohort study of As exposure in Bangladesh (n=27,000) with ~6-8 years of follow-up data. The proposed study uses a case-cohort design, in which we sample individuals from the cohort study to create three case groups (1,000 incident skin lesion cases, 200 incident non-melanoma skin cancer (MNSC), and 400 deaths) and a single control group (a random sample of 1000 cohort members). Using prospective blood samples, we will measure telomere length, serum markers of telomere dysfunction, and telomerase expression (for a subset with available RNA). Using baseline arsenic exposure data measured in drinking water, urine, and blood, we will assess the effect of arsenic on the measured telomere-related traits among controls and each case group. We will also assess the association between baseline telomere-related traits and our three outcomes of interest. In a second component of this work, we will measure telomere length and telomerase expression in MNSC tissue and adjacent normal tissue obtained from skin biopsies carried out for MNSC cases in this cohort. Telomere-related traits will be compared between normal and cancerous skin and among cancer subtypes, and the association between arsenic exposure and telomere- related traits in skin will be assessed. Finally, we will use existing genome-wide data on germline genetic variants to identify genetic determinants of our telomere-related traits. Several secondary aims will also be addressed. We will (1) determine if telomere-related traits mediate the effect of arsenic on health outcomes, (2) determine if arsenic effects telomere attrition rate, and (3) test telomere-related traits for association with blood levels of antioxidants. This project is a critical step towards understanding the mechanisms of arsenic toxicity in humans. The utility of all telomere-related measures derived from this work will increase as additional follow-up data accumulates in this ongoing cohort study, allowing further study of cancer, cardiovascular disease, and other arsenic-related chronic diseases