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

描述(申请人提供)：这项研究的具体目的是调查在职业接触二恶英的人群中，外周血淋巴细胞t(14；18)易位频率与TCDD、其他二恶英同系物和二恶英总毒性当量(TEQ)负担之间的剂量-反应关系。在以前的流行病学调查中，接触二恶英与非霍奇金淋巴瘤(NHL)的风险增加有关。T(14；18)易位是人类淋巴系统恶性肿瘤中最常见的染色体易位。它被认为是发生在前B期细胞的早期事件，这是滤泡性淋巴瘤发生途径中的必要步骤，但不是充分步骤。个体中t(14；18)细胞的总频率指示了有多少细胞面临这种额外DNA损伤的风险，t(14；18)易位已被认为是环境致癌物暴露于NHL的生物标志物。我们观察到，在1976年意大利塞维索环境暴露于2，3，7，8-TCDD的人群中，目前的TCDD水平与t(14；18)易位频率之间存在显著的剂量-反应关系。目前的研究将比较来自俄罗斯乌法的Khimimm化工厂的200名前TCP、2，4，5-T和200名前2，4-D工人与来自俄罗斯别洛雷茨克市的200名未接触过t的工人和退休人员的t(14；18)易位频率。接触二恶英的工人将从目前正在参与一项关于Khimimm工人生殖结果的研究的工人中招募。参考人口将从参加领土保险基金的俄罗斯别洛雷茨克居民人口中随机选择(接触二恶英最低限度)。指导者将在年龄、性别、种族、就业状况和吸烟方面与暴露者进行频率匹配。我们将进行健康问卷调查，皮肤科检查，并测量血液中的二恶英水平(同种特异性和TEQ)和外周血淋巴细胞t(14；18)易位。我们将使用TCDD和其他同系物的职业史和最合适的药代动力学模型来外推二恶英的峰值水平。我们将调查t(14；18)易位阳性细胞与当前血液TCDD、反向外推的血液TCDD、其他二恶英同系物和总二恶英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)易位频率增加的关系。我们还将建立一个来自研究参与者的DNA和RNA储存库，用于未来的分子和基因表达谱研究。

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.