Energy Balance, Organochlorine Exposure, and Possible Toxicologic Effects

描述（由申请人提供）：多氯联苯（PCB）被认为是潜在的致癌物质，特别是在非霍奇金淋巴瘤的研究中。尽管已停止生产，但多氯联苯仍然是一个公共卫生问题，因为它在食物链中具有生物累积性，而且几乎存在于每个人的脂肪组织中。多氯联苯和其他有机氯在脂肪中找到稳定的储存库;然而，在负能量平衡期间（例如体重减轻），它们会随着脂质动员而排泄到血液中。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，从而为增强毒理效应创造了一个窗口。本研究的目的是调查绝经后妇女运动引起的体重减轻、PCB浓度和免疫功能之间的关系。这项拟议的研究建立在现有的运动随机对照试验的基础上，对免疫功能生物标志物进行了广泛的评估。受试者是绝经后妇女（西雅图，美国），她们参加了一项为期一年的随机试验，以研究运动的生物学效应。在拟议的研究中，我们将测量100名受试者（50名干预组，50名对照组）在干预前和12个月随访访视时的血浆样本中的PCB浓度。关于PCB浓度的数据和现有的试验数据将用于：1）评估能量平衡特征与血浆PCB之间的关系，无论是在干预之前还是在整个试验期间; 2）调查PCB暴露的免疫效应，无论是在干预之前还是在运动干预导致PCB浓度发生任何变化之后。我们将探讨循环PCB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，身体成分，包括腹部肥胖，以及干预期间体重和身体成分的变化。此外，研究设计将允许调查试验期间体重减轻导致的PCB“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。我们假设运动干预与血浆PCB浓度的增加有关，并且PCB的增加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相关。拟议中的研究代表了一个独特的机会，通过研究这些关系，在一个以人群为基础的健康女性样本，在现有的框架内，一个随机试验与丰富的数据资源，以扩大有关能量平衡，有机氯暴露和可能的毒理学影响的知识状态。拟议项目将描述体重和/或身体成分变化与接触有机氯之间的联系，并将调查体重减轻前后接触多氯联苯对免疫的影响。这项研究与公共卫生有着重要的相关性，因为美国的肥胖和体重循环问题日益严重，而且PCB污染无处不在。了解体重减轻后有机氯暴露可能产生的毒理学影响，可能会为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.