Exposure to Multipollutants and Obesity, Type-2 Diabetes and Metabolic Syndrome

 描述(申请人提供)：越来越多的证据表明，环境污染物，如多氯联苯(PCBS)、双酚A、邻苯二甲酸盐和砷，可能在2型糖尿病(T2 DM)、肥胖和代谢综合征(METS)的病理生理中发挥重要作用。虽然证据支持环境污染物作为代谢性疾病的潜在风险因素的作用，但在确定人类种群之间的因果关系方面仍面临若干重要挑战：1)几乎没有前瞻性的纵向队列研究，提出了与因果推论和反向因果关系问题有关的关切；2)缺乏关于广泛存在于我们的环境中的新污染物的数据，如溴化阻燃剂、抗菌剂和防腐剂；3)缺乏关于人类种群潜在机制的数据；4)由于统计挑战，缺乏多种污染物与代谢性疾病的联合影响的数据。虽然由于荷尔蒙的变化，女性在绝经过渡期间更容易受到心脏代谢紊乱的影响，但在这一关键的易感窗口，环境污染物在代谢性疾病中的作用知之甚少。这项在多种族女性队列中进行的新的流行病学研究试图填补这些研究空白，并提高我们对暴露于多种污染物如何影响患T2 DM、肥胖症和METS风险的理解。我们建议1)确定与T2 DM、肥胖和METS事件相关的潜在环境污染物；2)评估环境污染物与中间代谢特征的纵向变化的关系，包括血压、身体成分(例如脂肪质量和体脂百分比)、血脂谱、胰岛素抵抗和C反应蛋白，以及与脂肪因子(例如瘦素和脂联素)的横断面关联；3)研究多种污染物对T2 DM、肥胖症和METS的联合影响，并同时评估环境风险评分。我们还将探索潜在的污染物-污染物相互作用与代谢结果的关系。我们将在全国妇女健康研究(SWAN)中进行一项病例队列研究(n=950；1999年至2010年期间发生382例新的T2 DM、肥胖症和/或METS病例，以及753名女性的随机子队列(185例与新病例重叠))。SWAN是一个多地点、多种族的中年妇女队列，她们的代谢风险增加，每年或每两年评估一次，评估时间超过10年。我们将评估超过120种环境污染物，如多氯联苯、有机氯农药、阻燃剂、有机磷农药及其代谢物、重金属、邻苯二甲酸盐、双酚A和其他酚类化合物，在血清或尿样中进行评估。该项目涉及国家环境健康科学研究所(NIEHS)的战略优先事项，包括确定共同的生物途径和通过综合环境暴露了解疾病的发病机制。我们将使用创新的分析方法来解决这些问题，这可能会对多种污染物和人类健康的研究产生新的见解。

 DESCRIPTION (provided by applicant): A growing body of evidence suggests that environmental pollutants, such as polychlorinated biphenyls (PCBs), bisphenol-A, phthalates and arsenic, may play an important role in the pathophysiology of type-2 diabetes mellitus (T2DM), obesity, and metabolic syndrome (MetS). While the evidence supports the role of environmental pollutants as potential risk factors for metabolic diseases, several important challenges remain to establish causality in human populations: 1) there have been few prospective longitudinal cohort studies, raising concerns related to causal inferences and problems of reverse causality; 2) data on emerging pollutants widespread in our environment such as brominated flame retardants and antibacterial agents and preservatives is lacking; 3) data on underlying mechanisms in human populations is lacking; and 4) data on combined effects of multiple pollutants in relation to metabolic diseases is lacking due to statistical challenges. Although women become more susceptible to cardio-metabolic disorders during the menopausal transition due to the hormonal changes, little is known about the role of environmental pollutants in metabolic diseases during this critical window of susceptibility. This new epidemiologic study in a multi-ethnic cohort of women seeks to address these research gaps and improve our understanding of how exposure to multiple pollutants affects the risks of developing T2DM, obesity and MetS. We propose 1) to identify potential environmental pollutants associated with incident T2DM, obesity and MetS; 2) to assess the associations of environmental pollutants with longitudinal changes in intermediate metabolic traits including blood pressure, body composition (e.g., fat mass and percent body fat), lipid profiles, insulin resistance and C-reactive protein, and with cross-sectional associations with adipokines (e.g., leptin and adiponectin); and 3) to examine the combined effects of multiple pollutants on T2DM, obesity and MetS evaluated simultaneously and construct an Environmental Risk Score. We will also explore potential pollutant-pollutant interactions in relation to metabolic outcomes. We will conduct a case-cohort study (n=950; 382 new cases of T2DM, obesity and/or MetS occurred between 1999 and 2010 and a random subcohort of 753 women (185 overlap with new cases)) in the Study of Women's Health Across the Nation (SWAN), a multi-site, multi-ethnic cohort of midlife women who are at increased metabolic risk, evaluated annually or bi-annually for more than 10 years. We will evaluate more than 120 environmental pollutants such as PCBs, organochlorine pesticides, flame retardants, organophosphate pesticides and metabolites, heavy metals, phthalates, bisphenol-A, and other phenolic compounds assessed in either serum or urine samples. This project addresses strategic priorities of the National Institute of Environmental Health Sciences (NIEHS), including identifying common biological pathways and understanding disease pathogenesis by combined environmental exposures. We will address these issues using innovative analytic approaches likely to yield new insights on the study of multiple pollutants and human health.