A Study of Telomeres in an Arsenic-Exposed Bangladesh Cohort

描述（由申请人提供）：在美国和世界范围内，饮用水中的慢性砷暴露是一个严重的公共卫生问题，因为全世界有近2亿人长期暴露于这种一级人类致癌物中。砷增加了一系列人类疾病的风险，包括皮肤癌、膀胱癌和肾癌；然而，砷中毒的机制尚不清楚。我们假设端粒可能在癌症相关的砷毒性中起关键作用。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（主要的端粒维持酶）具有有害影响。在这项研究中，我们建议以一种高度可行和有效的方式描述砷暴露、各种端粒相关特征和砷相关结果之间的关系，使用来自孟加拉国砷暴露纵向队列研究的现有数据（n=27,000），随访数据约6-8年。本研究采用病例-队列设计，从队列研究中抽取个体样本，创建三个病例组（1000例皮肤病变病例，200例非黑色素瘤皮肤癌（MNSC）和400例死亡病例）和一个单一对照组（1000名队列成员的随机样本）。使用前瞻性血液样本，我们将测量端粒长度，端粒功能障碍的血清标志物和端粒酶表达（对于可用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中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。在这项工作的第二个组成部分，我们将测量端粒长度和端粒酶表达在MNSC组织和邻近的正常组织中，这些组织是从该队列中MNSC病例的皮肤活检中获得的。将比较正常皮肤和癌变皮肤以及不同癌症亚型之间的端粒相关特征，并评估砷暴露与皮肤端粒相关特征之间的关系。最后，我们将利用现有的全基因组生殖系遗传变异数据来确定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果的影响，(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关系。该项目是了解人体砷毒性机制的关键一步。在这项正在进行的队列研究中，随着后续数据的积累，所有端粒相关测量的效用将会增加，从而进一步研究癌症、心血管疾病和其他砷相关的慢性疾病

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