Early Exposure to Persistent Organic Pollutants, Breast Milk Extracellular Vesicles and Abnormal Cardiometabolic Programming

项目总结 实验模型和人体研究一再将持久性有机污染物(POP)联系在一起，如 全氟烷基化物质(PFASs)和多氯联苯(PCbs)导致脂肪分布异常， 体重指数，以及生命早期的糖脂代谢异常。它们无处不在。 几乎所有儿童在幼年时期都接触到的化学品：全氟辛烷磺酸用于几种消费者和 工业应用和多氯联苯在食物链中积累。有证据表明，这些异常 儿童早期的心脏代谢轨迹可能预示着胰岛素抵抗、代谢综合征、 肥胖，甚至成年后的心血管事件。然而，没有生物标记物可用于在 出生后即刻有心脏代谢发育异常风险的儿童，从而抑制 提供有效、有针对性的预防的机会。为了解决这一差距，我们的长期目标是确定新的 母乳中反映环境影响和预测异常风险的机械生物标志物 心脏代谢程序与儿童肥胖。 我们将利用关于母乳细胞外小泡(BMEV)在 新陈代谢编程。BMEV是由母乳中的腔上皮细胞释放的小囊泡。 BMEV被认为是从母亲到孩子的分子信号的传送器。特别是， BMEV运输一批microRNAs(MiRNAs)，一旦被儿童摄取，就会融入其中 儿童体内的受体细胞，可以远程影响儿童信使的表达和翻译 RNA。这一过程已被证明是儿童早期新陈代谢编程的关键。到目前为止，没有 已经进行了研究，以确定BMEV作为连接全氟辛烷磺酸的路径的一部分的潜在作用 儿童时期接触多氯联苯对心脏代谢轨迹和肥胖的不利影响。 为了实现这一目标，我们将利用法罗群岛纵向出生队列的独特资源，一个 使用生物库母乳的产前队列(N=300，全部来自哺乳母亲)，广泛的暴露数据，以及 出生后心脏代谢的重复测量超过13年的随访。我们假设BMEV数字， BMEV大小和BMEV包裹的miRNAs被修改以响应产前(妊娠晚期 怀孕)暴露于全氟辛烷磺酸和多氯联苯(目标1)以及BMEV数量、BMEV大小和BMEV- 包裹的miRNA可预测13年随访的心脏代谢结果(目标2)。我们将使用 高级统计建模将BMEV生物标记物整合到连接暴露和异常的路径中 心脏代谢轨迹(探索性目标3)。这项研究是一个高风险/高回报和高成本效益的项目。 这将提供新的无创性工具来识别和减轻心脏代谢异常的负担 童年时期的编程。

PROJECT SUMMARY Experimental models and human studies have repeatedly linked persistent organic pollutants (POPs) such as perfluorinated alkylate substances (PFASs) and polychlorinated biphenyls (PCBs) to abnormal fat distribution, body mass index, and glucose and lipid metabolic abnormalities during early life. These are pervasive chemicals to which nearly all children are exposed during early life: PFASs are used in several consumer and industrial applications and PCBs accumulate in food chains. Evidence suggests that these abnormal cardiometabolic trajectories during early childhood may predict insulin resistance, metabolic syndrome, obesity, and even cardiovascular events in adulthood. However, no biomarkers are available to identify in the immediate postnatal period children who are at risk for abnormal cardiometabolic development, thus curbing opportunities for effective, targeted prevention. To address this gap, our long-term goal is to identify novel mechanistic biomarkers in breast milk that reflect environmental influences and predict the risk of abnormal cardiometabolic programming and childhood obesity. We will leverage groundbreaking evidence on the roles of breast milk extracellular vesicles (BMEVs) in metabolic programming. BMEVs are small vesicles that are released by luminal epithelial cells in breast milk. BMEVs have been proposed as conveyors of molecular signals from the mother to the child. In particular, BMEVs transport a cargo of microRNAs (miRNAs) that, once ingested by the child, integrate themselves in recipient cells in the child's body and can remotely affect the expression and translation of child's messenger RNAs. This process has been shown to be key to the child's metabolic programming in early life. To date, no studies have been conducted to identify the potential roles of BMEVs as part of the paths linking PFASs and PCBs exposure to its adverse effects on cardiometabolic trajectories and obesity during childhood. To achieve this goal, we will leverage the unique resources of the longitudinal Faroe Islands birth cohort, a prenatal cohort with biobanked breast milk (N=300, all from nursing mothers), extensive exposure data, and repeated postnatal cardiometabolic measures over 13 years of follow up. We hypothesize that BMEV number, BMEV size, and BMEV-encapsulated miRNAs are modified in response to prenatal (third-trimester of pregnancy) exposure to PFASs and PCBs (Aim 1) and that BMEV number, BMEV size, and BMEV- encapsulated miRNA predict cardiometabolic outcomes over 13 years of follow up (Aim 2). We will use advanced statistical modeling to integrate BMEV biomarkers in the paths linking exposure and abnormal cardiometabolic trajectories (Exploratory Aim 3). This study is a high-risk/high-reward and cost-effective project that will provide new noninvasive tools to identify and reduce the burden of abnormal cardiometabolic programming during childhood.