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

描述（由申请人提供）：本研究的具体目的是调查在职业接触二恶英的工人人群中，外周血淋巴细胞中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）的身体负荷之间的剂量-反应关系。在以前的流行病学调查中，二恶英暴露与非霍奇金淋巴瘤（NHL）风险增加有关。t（14;18）易位是人类淋巴细胞恶性肿瘤中最常见的染色体易位。它被认为是发生在b期前细胞的早期事件，是滤泡性淋巴瘤癌变途径中必要的，但不是充分的步骤。个体中t（14;18）细胞的总体频率指示了有额外DNA损伤风险的细胞数量，并且t（14;18）易位已被提出作为NHL环境致癌物暴露的生物标志物。我们观察到，在1976年意大利塞韦索环境暴露于2,3,7,8-TCDD的人群中，当前血液中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Khimprom化工厂的200名前TCP和2,4,5- t工人和200名前2,4- d工人的t（14;18）易位频率，以及来自俄罗斯别洛列茨克市的200名未暴露的工人和退休人员的参考人群。接触二恶英的工人将从目前正在参加一项关于希姆波姆工人生殖结果的研究的工人中招募。参考人口将从俄罗斯别洛列茨克（二恶英接触最少）的居民人口中随机选择，这些居民已加入领土保险基金。参照对象将在年龄、性别、种族、就业状况和吸烟情况上与暴露者进行频率匹配。我们将进行健康问卷调查，皮肤检查和测量血液中的二恶英水平（同源特异性和TEQ）和外周血淋巴细胞中的t（14;18）易位。我们将利用职业历史和TCDD和其他同类药物动力学模型的最佳拟合来推断二恶英峰值水平。我们将研究t（14;18）易位阳性细胞与当前血液TCDD、反推血液TCDD、其他二恶英同系物和总二恶英TEQ之间的剂量-反应关系。我们将研究血液TCDD增加对BCL2和KLF4表达的影响，以及这些影响如何与t易位频率增加相关（14;18）。我们还将建立一个来自研究参与者的DNA和RNA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.