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的剂量-反应之间的关系的频率t（14;18）易位在外周血淋巴细胞和身体负担的TCDD，其他二恶英同系物，二恶英总毒性当量（TEQ）的工人与职业暴露于二恶英的人口。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）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阶段细胞中的早期事件，这是滤泡性淋巴瘤致癌途径中的必要但不充分的步骤。个体中t（14;18）细胞的总体频率给出了处于这种额外DNA损伤风险中的细胞数量的指示，并且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。1976年，在意大利塞维索，我们观察到在环境中暴露于2，3，7，8-TCDD的个体人群中，目前血液中的TCDD水平与t（14;18）易位频率之间存在显著的剂量反应关系。本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工人与来自俄罗斯Beloretsk市的200名未暴露工人和退休人员的t（14;18）易位频率。接触二恶英的工人将从目前参加Khimprom工人生殖结果研究的工人中招募。参考人群将从俄罗斯别洛列茨克的居民（二恶英暴露最低）中随机选择，这些居民参加了地区保险基金。参考人群的频率将与年龄，性别，种族，就业状况和吸烟情况相匹配。我们将进行健康问卷调查，皮肤科检查和测量血液中二恶英水平（同源物特异性和TEQ）和外周血淋巴细胞中的t（14;18）易位。我们将使用职业史和TCDD和其他同类物的最佳拟合药代动力学模型来反推二恶英峰值水平。我们将研究t（14;18）易位阳性细胞与当前血液TCDD、后推血液TCDD、其他二恶英同系物和总二恶英TEQ之间的剂量反应关系。我们将研究增加血液中TCDD对BCL 2和KLF 4表达的影响，以及这些影响如何与t（14;18）易位频率增加相关。我们还将建立一个研究参与者的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.