Energy Balance, Organochlorine Exposure, and Possible Toxicologic Effects

描述（由申请人提供）：多氯联苯（PCBs）被认为是潜在的致癌物，特别是在非霍奇金淋巴瘤的研究中。尽管多氯联苯已经停止生产，但由于其在食物链中的生物积累以及存在于几乎每个人的脂肪组织中，它仍然是一个令人关注的公共卫生问题。多氯联苯和其他有机氯在脂肪中有一个稳定的储藏库；然而，在负能量平衡时期，如体重减轻，它们随着脂质动员被排泄到血液中。这一有机氯动员过程使细胞和组织暴露于浓度增加的多氯联苯中，从而为增强的毒理学效应创造了一个窗口期。本研究的目的是调查绝经后妇女运动引起的体重减轻、多氯联苯浓度和免疫功能之间的关系。这项拟议的研究基于一项现有的随机对照运动试验的资源，该试验对免疫功能生物标志物进行了广泛的评估。研究对象是绝经后妇女（美国西雅图），她们参加了一项为期一年的随机试验，研究运动的生物学效应。在拟议的研究中，我们将在干预前和12个月的随访中测量100名受试者（50名干预组，50名对照组）血浆样本中的多氯联苯浓度。多氯联苯浓度数据和现有试验数据将用于：1)评估干预前和整个试验期间能量平衡特征与血浆多氯联苯之间的关系；2)调查多氯联苯暴露的免疫效应，包括干预前和运动干预后多氯联苯浓度的变化。我们将探讨循环多氯联苯浓度如何与能量平衡的特定方面相关，如体重和体重循环史、身体组成（包括腹部脂肪）以及干预期间体重和身体组成的变化。此外，研究设计将允许调查试验期间体重减轻导致的多氯联苯“剂量”如何影响免疫功能指标，如淋巴细胞表型、自然杀伤细胞细胞毒性和淋巴细胞增殖。我们假设运动干预将与血浆多氯联苯浓度的增加有关，多氯联苯的增加将在体脂减少最多的女性中最为明显。此外，我们假设试验期间多氯联苯的增加与淋巴细胞增殖和其他免疫功能标志物的减少有关。拟议的研究提供了一个独特的机会，通过在具有丰富数据资源的随机试验的现有框架内，研究以健康妇女为基础的人群样本中的这些关系，来扩大对能量平衡、有机氯暴露和可能的毒理学效应的知识状态。拟议的项目将描述体重和/或身体组成的变化与接触有机氯的关系，并将调查在减肥前后接触多氯联苯（PCB）的免疫影响。由于美国肥胖和体重循环问题日益严重，以及多氯联苯污染无处不在，因此该研究与公共卫生具有重要关系。了解体重减轻后接触有机氯可能产生的毒理学影响，可能为了解能量失衡的某些有害影响提供线索。

DESCRIPTION (provided by applicant): Polychlorinated biphenyls (PCBs) have been implicated as potential carcinogens, particularly in studies of non- Hodgkin's lymphoma. PCBs remain a public health concern despite ceasing production, because of bioaccumulation in the food chain and their presence in adipose tissue of virtually every person. PCBs and other organochlorines find a stable reservoir in fat; however, they are excreted to the bloodstream with lipid mobilization during times of negative energy balance, such as weight loss. This process of organochlorine mobilization exposes cells and tissues to increased concentrations of PCBs, thereby creating a window for enhanced toxicologic effects. Aims of this study are to investigate associations between exercise-induced weight loss, PCB concentrations, and immune function among postmenopausal women. The proposed study builds on resources from an existing randomized controlled trial of exercise with an extensive assessment of immune function biomarkers. Subjects are postmenopausal women (Seattle, USA) who participated in a one- year randomized trial to study biologic effects of exercise. In the proposed study, we will measure PCB concentrations in plasma samples from 100 subjects (50 intervention arm, 50 controls) both prior to the intervention and at a 12-month follow-up visit. Data on PCB concentrations and existing trial data will be used to: 1) Evaluate relationships between energy balance characteristics and plasma PCBs, both prior to the intervention and across the trial period; and 2) Investigate immune effects of PCB exposure, both prior to the intervention and following any changes in PCB concentrations that result from the exercise intervention. We will explore how circulating PCB concentrations are associated with specific aspects of energy balance such as weight and weight cycling history, body composition including abdominal adiposity, and changes in weight and body composition during the intervention. Additionally, the study design will allow investigation of how PCB 'dose' resulting from weight loss during the trial affects immune function measures such as lymphocyte phenotypes, natural killer cell cytotoxicity, and lymphocyte proliferation. We hypothesize that the exercise intervention will be associated with increases in plasma PCB concentrations, and that PCB increases will be most pronounced among women with the greatest body fat loss. Furthermore, we hypothesize that increases in PCBs during the trial will be correlated with decreased lymphocyte proliferation and other markers of immune function. The proposed study represents a unique opportunity to expand the state of knowledge about energy balance, organochlorine exposure, and possible toxicologic effects by studying these relationships in a population-based sample of healthy women, within an existing framework of a randomized trial with rich data resources. The proposed project will describe associations of changes in weight and/or body composition with organochlorine exposure, and will investigate immune effects of polychlorinated biphenyl (PCB) exposure before and after weight loss. The study has significant relevance to public health because of both the growing problems of obesity and weight cycling in the United States and the ubiquitousness of PCB pollution. Understanding possible toxicologic effects of organochlorine exposure following weight loss may provide clues about certain detrimental effects of energy imbalance.