Inflammation and metabolic abnormalities in pollutant-exposed children

项目摘要 代谢性疾病，包括肥胖和2型糖尿病，是多因素导致的主要公共卫生问题 病因学，早期接触环境污染物，如全氟烷基物质 (全氟辛烷磺酸)，被怀疑发挥了作用。PFAS已经使用了60多年，但无处不在的人类 暴露是在不到20年前发现的，对这些高度优先的人群进行的一般研究 污染物是最近才开始排放的。我们最近发现，接触全氟辛烷磺酸与 对某些儿童疫苗的抗体反应减弱。因此，我们假设全氟辛烷磺酸诱导 炎症可能参与了PFAS暴露的可疑致肥胖效应，这些效应有助于 肥胖和代谢性疾病的发病机制。目前的证据，包括我们自己的研究，表明 发育中的全氟辛烷磺酸暴露可能会影响儿童时期的代谢过程。目的是为了确定 PFAS暴露、免疫功能障碍和代谢异常之间的可能联系，我们将在 8岁，来自法罗群岛的一个已经建立的出生队列(N=490)，以探索这种联系 与年龄相关的PFAS暴露情况和代谢异常之间的关系(使用肥胖标记物， 血脂异常、血糖和胰岛素抵抗)。我们还将确定新陈代谢和 与肥胖、胰岛素作用(脂肪细胞因子)和免疫功能障碍相关的炎性血清标志物 (疫苗抗体浓度)。全氟辛烷磺酸和其他环境污染物的暴露数据已经 可从18个月和5岁时的孕妇妊娠血清分析和临床检查中获得 好几年了。用于潜在生物标记物分析的前瞻性数据和银行血清也可以从以前的 法罗群岛队列(N=656)在5岁和7.5岁时对新生儿进行检查，从而允许进行复制研究 新发现。数据分析将考虑重要的协变量，如性别、一天中的时间 采血，孕妇孕前体重指数和孕期体重增加。多元回归 分析将得到结构方程模型和其他高级统计方法的补充， 包括基准剂量计算。拟议中的项目将提供对高技术和高技术 环境污染物对代谢和免疫功能障碍的优先影响及其潜在机制 以及早期预防代谢性疾病的潜在新策略。

Project Summary Metabolic diseases, including obesity and type 2 diabetes, are major public health problems of multifactorial etiology, in which early-life exposures to environmental pollutants, such as the perfluoroalkyl substances (PFASs), are suspected to play a role. PFASs have been in use for over 60 years, but omnipresent human exposures were discovered less than 20 years ago, and general population studies of these high-priority pollutants were initiated only recently. We recently discovered that PFAS exposure is associated with depressed antibody response to certain childhood vaccinations. We therefore hypothesize that PFAS-induced inflammation may be involved in the suspected obesogenic effects of PFAS exposure that contribute to the pathogenesis of obesity and metabolic disease. Current evidence, including our own studies, suggests that developmental PFAS exposure may affect metabolic processes in childhood. With the aim to determine the possible link between PFAS exposures, immune dysfunction, and metabolic abnormalities, we will examine at age 8 years an already established birth cohort from the Faroe Islands (N = 490) to explore the associations between age-related PFAS exposure profiles and metabolic abnormalities (using markers of adiposity, dyslipidemia, glycemia and insulin resistance). We will also determine the possible role of metabolic and inflammatory serum markers related to adiposity and insulin action (adipocytokines) and immune dysfunction (vaccine antibody concentrations). Exposure data for PFAS and other environmental pollutants are already available from analyses of maternal pregnancy serum and from clinical examinations at ages 18 months and 5 years. Prospective data and banked serum for potential biomarker analyses are also available from a previous Faroese cohort (N= 656) examined neonatally and at ages 5 and 7.5 years, thus allowing replication studies of new findings. The data analysis will take into account important covariates, such as sex, time of the day for blood sampling, and maternal prepregnancy body mass index and gestational weight gain. Multiple regression analyses will be complemented by structural equation models and other advanced statistical methods, including benchmark dose calculations. The proposed project will provide new insight into the role of high- priority environmental pollutants on metabolic and immune dysfunction, the potential underlying mechanisms and potential new strategies for early prevention of metabolic disease.