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

 描述（由申请方提供）：越来越多的证据表明，环境污染物，如多氯联苯（PCB）、双酚A、邻苯二甲酸酯和砷，可能在2型糖尿病（T2 DM）、肥胖和代谢综合征（MetS）的病理生理学中发挥重要作用。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，但在人群中建立因果关系仍然存在几个重要挑战：1）很少有前瞻性纵向队列研究，引起了与因果关系推断和反向因果关系问题有关的担忧; 2）缺乏关于在我们环境中广泛存在的新污染物的数据，如溴化阻燃剂、抗菌剂和防腐剂; 3）缺乏关于人类潜在机制的数据; 4）由于统计挑战，缺乏关于多种污染物对代谢疾病的综合影响的数据。虽然妇女在绝经过渡期由于激素的变化而变得更容易患上心脏代谢紊乱，但在这一敏感性的关键窗口期间，对环境污染物在代谢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流行病学研究旨在解决这些研究空白，并提高我们对暴露于多种污染物如何影响发展T2 DM，肥胖和MetS风险的理解。我们建议：1）确定与2型糖尿病、肥胖和代谢综合征相关的潜在环境污染物; 2）评估环境污染物与中间代谢性状（包括血压、身体组成（例如，脂肪量和体脂百分比）、脂质分布、胰岛素抵抗和C-反应蛋白，以及与脂肪因子的横截面关联（例如，瘦素和脂联素）;（3）同时评价多种污染物对T2 DM、肥胖和代谢综合征的综合影响，并构建环境风险评分。我们还将探讨潜在的污染物与污染物之间的相互作用与代谢结果的关系。我们将进行一项病例队列研究（n=950; 1999年至2010年期间发生了382例T2 DM、肥胖和/或MetS新发病例，在全国妇女健康研究（SWAN）中随机分组了753名妇女（185例与新发病例重叠），这是一项多中心、多种族的中年妇女队列，代谢风险增加，10年以上每年或每两年进行一次评估。我们将评估120多种环境污染物，如多氯联苯，有机氯农药，阻燃剂，有机磷农药和代谢物，重金属，邻苯二甲酸酯，双酚A，以及在血清或尿液样本中评估的其他酚类化合物。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了解综合环境暴露引起的疾病发病机制。我们将使用创新的分析方法来解决这些问题，这些方法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.