t(14;18) Translocations in Dioxin Exposed Workers from Ufa

t(14;18) 乌法二恶英暴露工人的易位

• 批准号: 7656667
• 负责人: DANIEL Oleh HRYHORCZUK
• 金额: $ 67.93万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7656667
• 关键词: 14; 18; Translocations; Dioxin; Exposed

DESCRIPTION (provided by applicant): The specific aim of this study is to investigate the dose-response relationships between the frequency of t(14;18) translocations in peripheral blood lymphocytes and body burdens of TCDD, other dioxin congeners, and dioxin total toxic equivalent (TEQ) in a population of workers with occupational exposure to dioxin. Dioxin exposure has been associated with an increased risk of non-Hodgkin's lymphoma (NHL) in previous epidemiologic investigations. The t(14;18) translocation is the most frequent chromosomal translocation in human lymphoid malignancies. It is assumed to be an early event occurring in a pre-B stage cell which is a necessary, but not sufficient, step in the carcinogenesis pathway for follicular lymphoma. The overall frequency of t(14;18) cells in an individual gives an indication of the number of cells at risk for this additional DNA damage, and t(14;18) translocation has been proposed as a biomarker of environmental carcinogen exposure for NHL. We observed a significant dose-response relationship between current blood levels of TCDD and frequency of t(14;18) translocations in the population of individuals who had been environmentally exposed to 2,3,7,8-TCDD in Seveso, Italy in 1976. The current study will compare the frequency of t(14;18) translocations in 200 former TCP and 2,4,5-T workers and 200 former 2,4-D workers from the Khimprom chemical plant in Ufa, Russia to a referent population of 200 unexposed workers and retirees from the city of Beloretsk, Russia. The dioxin-exposed workers will be recruited from among workers who are currently participating in a study of reproductive outcomes among Khimprom workers. The referent population will be randomly selected from the population of residents of Beloretsk, Russia (minimal dioxin exposure) who are enrolled in the Territorial Insurance Fund. Referents will be frequency matched to the exposed on age, gender, ethnicity, employment status, and smoking. We will administer a health questionnaire, dermatologic examination and measure dioxin levels (congener- specific and TEQ) in blood and t(14;18) translocations in peripheral blood lymphocytes. We will back extrapolate peak dioxin levels using occupational histories and the best fitting pharmacokinetic models for TCDD and other congeners. We will investigate the dose-response relationship between t(14;18) translocation-positive cells and current blood TCDD, back-extrapolated blood TCDD, other dioxin congeners, and total dioxin TEQ. We will investigate the effect of increasing blood TCDD on BCL2 and KLF4 expression and how these effects are associated with increased frequency of t(14;18) translocations. We will also establish a repository of DNA and RNA from study participants for future molecular and gene expression profiling studies.

描述（由申请人提供）：这项研究的具体目的是研究T（14; 18）t（14; 18）tCDD的易位频率与TCDD的易位，其他二恶英词的易位，二恶英总毒素毒素总毒物（TEQ）（TEQ）在具有占用居住型dioxin的工人中的人群。在先前的流行病学研究中，二恶英暴露与非霍奇金淋巴瘤（NHL）的风险增加有关。 T（14; 18）易位是人淋巴恶性肿瘤中最常见的染色体易位。假定它是在B阶段细胞中发生的早期事件，这是卵泡淋巴瘤的癌变途径中必要但不足的一步。一个个体中t（14; 18）细胞的总频率表明有可能发生这种额外DNA损伤的细胞数量，而T（14; 18）易位已被提议作为NHL环境致癌物暴露的生物标志物。 We observed a significant dose-response relationship between current blood levels of TCDD and frequency of t(14;18) translocations in the population of individuals who had been environmentally exposed to 2,3,7,8-TCDD in Seveso, Italy in 1976. The current study will compare the frequency of t(14;18) translocations in 200 former TCP and 2,4,5-T workers and 200 former 2,4-D workers from the Khimprom chemical来自俄罗斯UFA的工厂，来自俄罗斯贝洛列特斯克市的200名未暴露工人和退休人员的参考人口。暴露于二恶英的工人将是从目前正在研究Khimprom工人中生殖结果研究的工人中招募的。参考人群将从俄罗斯Beloretsk的居民（最小二恶英暴露）中随机选择，这些人被纳入领土保险基金。参考人将与年龄，性别，种族，就业状况和吸烟相匹配。我们将在血液中进行健康问卷，皮肤病学检查和测量二恶英水平（特异性和TEQ），以及T（14; 18）外周血淋巴细胞中的易位。我们将使用职业历史和TCDD和其他同类物的最佳拟合药代动力学模型来反思二恶英水平。我们将研究t（14; 18）易位阳性细胞与当前血液TCDD，背面脱落血液TCDD，其他二恶英同生和总二恶英TEQ之间的剂量反应关系。我们将研究增加血液TCDD对BCL2和KLF4表达的影响，以及这些影响与t（14; 18）易位频率的增加有关。我们还将从研究参与者中建立一个DNA和RNA的存储库，以进行未来的分子和基因表达分析研究。