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Can shift-work shift epigenetic changes?

轮班工作可以改变表观遗传变化吗？

基本信息

批准号：
8098987
负责人：
YONG ZHU
金额：
$ 18.95万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8098987
关键词：
Address Alcohol consumption Alu Elements Animals Archives Biological Biological Assay Blood specimen Breast Cancer Prevention Circadian Rhythms Communities DNA DNA Methylation Data Denmark Developed Countries Development Dietary intake Employment Environmental Exposure Environmental Risk Factor Epidemiologic Studies Epidemiology Epigenetic Process Etiology Event Exposure to Female Future Gene Expression Regulation Genes Goals High Prevalence Human Individual International Agency for Research on Cancer Investigation Laboratory Study Lead Light Link Malignant Neoplasms Measures Methylation Molecular Epidemiology National Institute of Environmental Health Sciences Nature Occupational Occupations Participant Pattern Phenotype Physical activity Population Primary Prevention Process Promoter Regions Public Health Recording of previous events Reproductive History Research Resources Risk Role Societies Susceptibility Gene T-Lymphocyte Telephone Interviews Testing Time Traction Woman Work anticancer research base cancer prevention cancer risk carcinogenesis carcinogenicity cohort design genetic association genetic variant genome-wide human study malignant breast neoplasm member novel oncology promoter prospective public health relevance shift work tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): It has been hypothesized that light-at-night (LAN) in modern societies might be partially responsible for the elevated risk of breast cancer observed in industrialized nations, and shift work is regarded as the most extreme form of LAN exposure. In October 2007, the International Agency for Research on Cancer (IARC) assembled an expert panel to assess the role of shift work in human cancer development by reviewing the evidence from laboratory and epidemiological studies. This expert panel concluded that "shift work that involves circadian disruption is probably carcinogenic to humans" (Lancet Oncology, 2007). Our group has completed pioneering work on the molecular epidemiology of circadian genes, and we have demonstrated that both genetic variants and methylation changes in circadian genes predispose individuals to breast cancer. However, whether shift work may contribute to epigenetic changes is still an unanswered question. Considering that millions of women worldwide are being exposed to ill-timed light, particularly through occupations involving shift work, there exists an urgent need to systematically study the biological impact of shift work, including the epigenetic consequences of this exposure. Here, we propose a human study to examine both global and locus-specific methylation changes that may result from shift work. In the proposed study, a total of 600 female subjects will be selected from an established Danish prospective cohort (300 subjects with no history of shift work and 300 long-term (10+ years) shift workers). These participants have archived blood samples available, which will be used for DNA extraction and subsequent epigenetic analysis, in order to determine the impact of shift work on global DNA methylation, as well as methylation in the promoter regions of the core circadian genes. In light of the recent IARC conclusion, along with an increasing body of epidemiological and biological evidence, this exploratory study will extend our previous discoveries and break new ground toward a more comprehensive understanding of the clock-cancer connection. More importantly, because of the preventable nature of some epigenetic events, the results obtained from this study will have considerable public health implications and could lead to new strategies for breast cancer prevention. PUBLIC HEALTH RELEVANCE: This proposed study, based on data and biosamples available from a prospective cohort, will be the first to examine the epigenetic impact of long-term exposure to light at night (night shift work). In light of the recent IARC conclusion that "shift work that involves circadian disruption is probably carcinogenic to humans", along with an increasing body of both epidemiological and biological evidence, the findings from this study may provide possible biological mechanisms for the role of shift work in breast cancer development, and will be valuable in directing future resources to appropriate strategies for primary prevention. Due to the high prevalence of exposure to occupational shift work worldwide, the proposed study has the potential for broad public health implications.

描述（由申请人提供）：据推测，现代社会的夜间照明（LAN）可能是工业化国家观察到的乳腺癌风险升高的部分原因，而轮班工作被认为是最极端的LAN暴露形式。2007年10月，国际癌症研究机构（IARC）召集了一个专家小组，通过审查来自实验室和流行病学研究的证据，评估轮班工作在人类癌症发展中的作用。该专家小组得出结论，“涉及昼夜节律中断的轮班工作可能对人类致癌”（《柳叶刀肿瘤学》，2007年）。我们的团队在昼夜节律基因的分子流行病学方面已经完成了开创性的工作，我们已经证明昼夜节律基因的遗传变异和甲基化变化都使个体易患乳腺癌。然而，轮班工作是否会导致表观遗传变化仍然是一个悬而未决的问题。考虑到全世界数以百万计的妇女正暴露在不合时宜的光线下，特别是通过涉及轮班工作的职业，迫切需要系统地研究轮班工作的生物学影响，包括这种暴露的表观遗传后果。在这里，我们提出了一项人类研究，以检查轮班工作可能导致的全球和位点特异性甲基化变化。在拟议的研究中，将从已建立的丹麦前瞻性队列中选择总共600名女性受试者（300名无轮班工作史的受试者和300名长期（10年以上）轮班工人）。这些参与者已经存档了血样，这些血样将用于DNA提取和随后的表观遗传分析，以确定轮班工作对全球DNA甲基化的影响，以及核心昼夜节律基因启动子区域的甲基化。鉴于国际癌症研究机构最近的结论，以及越来越多的流行病学和生物学证据，这项探索性研究将扩展我们以前的发现，并为更全面地了解时钟与癌症之间的联系开辟新的领域。更重要的是，由于一些表观遗传事件的可预防性，从这项研究中获得的结果将具有相当大的公共卫生影响，并可能导致乳腺癌预防的新策略。