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（申请人提供）：本研究的具体目的是调查外周血淋巴细胞中t(14;18)易位频率与TCDD、其他二恶英同系物和二恶英总毒性的身体负荷之间的剂量-反应关系职业接触二恶英的工人群体的等效浓度（TEQ）。在之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 期细胞中的早期事件，是滤泡性淋巴瘤致癌途径中必要但不充分的步骤。个体中 t(14;18) 细胞的总体频率表明了面临这种额外 DNA 损伤风险的细胞数量，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。我们在 1976 年意大利塞维索环境暴露于 2,3,7,8-TCDD 的人群中观察到当前血液 TCDD 水平与 t(14;18) 易位频率之间存在显着的剂量反应关系当前的研究将比较 200 名前 TCP 和 2,4,5-T 工人以及 200 名前 2,4-D 工人的 t(14;18) 易位频率。俄罗斯乌法 Khimprom 化工厂的工人，以及俄罗斯别洛列茨克市 200 名未接触过的工人和退休人员作为参考人群。接触二恶英的工人将从目前正在参与 Khimprom 工人生殖结果研究的工人中招募。参考人群将从加入领土保险基金的俄罗斯别洛列茨克（二恶英接触量最低）居民中随机选择。参考对象的频率将与暴露者的年龄、性别、种族、就业状况和吸烟情况进行匹配。我们将进行健康问卷、皮肤科检查并测量血液中的二恶英水平（同类物特异性和 TEQ）以及外周血淋巴细胞中的 t(14;18) 易位。我们将使用职业史以及 TCDD 和其他同系物的最佳药代动力学模型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。我们将研究增加血液 TCDD 对 BCL2 和 KLF4 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。我们还将建立研究参与者的 DNA 和 RNA 存储库，用于未来的分子和基因表达谱研究。