Gestational PFAS Mixture Exposures, Longitudinal Metabolomic Profiles, and Adolescent Cardiometabolic Health

项目摘要 暴露在环境化学混合物中可能会增加患心脏代谢性疾病的风险。特别的 令人担忧的是产前暴露于全氟烷基物质(PFAS)，这是一类用于加工的化学品 防油/防水纺织品、含氟聚合物制造、食品包装、清洁产品和 灭火泡沫。接触全氟辛烷磺酸无处不在，源于受污染的食物和饮用水。超过6个 美国有数百万人的饮用水受到了全氟辛烷磺酸的污染，还有更多的人暴露在低水平的饮用水中。 动物和人类研究表明，产前接触PFAS可能会增加肥胖的风险，胰岛素 抵抗力、血脂异常和高血压-心脏代谢综合征的显著组成部分 增加成年后患心血管疾病的风险。然而，很少有研究对健康进行调查 全氟辛烷磺酸混合物的影响以及这些影响背后的生物途径还知之甚少。引导式 根据我们的初步研究和假设，血清代谢组中代表的生物途径 对早年的PFAS混合物暴露敏感，并预测晚年的心脏代谢健康，我们将使用 非靶向高分辨率代谢组学为了量化产前PFAS混合物之间的关联， 代谢组和心脏代谢性疾病。建立在两个既定的和正在进行的预期队列的基础上 来自加拿大(MIREC研究，n=500)和俄亥俄州辛辛那提(家庭研究， N=250)，我们将在分娩时和3-5岁和7-12岁时测量&gt；25,000个血清代谢组特征。 我们将把这些数据与以前收集的或将要测量的产前PFAS生物标志物和 7-12岁时的心脏代谢结果。我们将使用先进的生物统计学技术来减少 这些数据的维度，并发现与产前PFAS相关的代谢特征 在MIREC中，混合物和心脏代谢结果，重复了我们使用HOME的发现。具体来说，我们会： 1)描述生命最初12年中血清代谢物的轨迹；2)确定血清的特征 预测青少年心脏代谢性疾病的前12年代谢组轨迹；3) 确定代谢组特征是否中介产前暴露于PFAS混合物与 青少年心脏代谢性疾病；以及4)确定代谢组特征的化学特性 在AIM 3中发现。这项包括流行病学家、临床医生、生物统计学家、 化学家将有效地利用正在进行的两项队列研究来解决这些及时的目标。归根结底， 拟议的研究将通过提高我们对全氟辛烷磺酸对健康影响的了解而产生重大影响， 确定与全氟辛烷磺酸混合物和青少年健康相关的新的代谢变化，并改善 我们对影响心脏代谢性疾病的生物途径的理解。这些结果对于 正在对全氟辛烷磺酸的毒性进行评估，并可能有助于识别暴露于心脏代谢风险的人群 并有可能改善暴露于全氟辛烷磺酸的影响。

Project Abstract Exposure to environmental chemical mixtures may increase the risk of cardiometabolic disease. Of particular concern are prenatal exposure to perfluoroalkyl substances (PFAS), a class of chemicals used as processing aids for oil/water repellant textiles, fluoropolymer manufacturing, food packaging, cleaning products, and firefighting foams. PFAS exposure is ubiquitous, deriving from contaminated food and drinking water. Over 6 million people in the US have PFAS contaminated drinking water, and many more have low-level exposure. Animal and human studies show that prenatal PFAS exposure may increase the risk of obesity, insulin resistance, dyslipidemia, and hypertension – components of the cardiometabolic syndrome that markedly increase the risk of adulthood cardiovascular diseases. However, few studies have investigated the health effects of PFAS mixtures, and the biological pathways underlying these effects are poorly understood. Guided by our preliminary studies and the hypothesis that biological pathways represented in the serum metabolome are sensitive to early life PFAS mixture exposure and predictive of later life cardiometabolic health, we will use non-targeted high-resolution metabolomics to quantify the associations between prenatal PFAS mixtures, the metabolome, and cardiometabolic disease. Building upon two established and ongoing prospective cohorts of pregnant women and their children from Canada (MIREC Study, n=500) and Cincinnati, Ohio (HOME Study, n=250), we will measure >25,000 features of the serum metabolome at delivery and ages 3-5, and 7-12 years. We will link these data to previously collected or to be measured prenatal PFAS biomarkers and cardiometabolic outcomes at age 7-12 years. We will use sophisticated biostatistical techniques to reduce the dimensionality of these data and discover metabolomic signatures associated with both prenatal PFAS mixtures and cardiometabolic outcomes in MIREC, replicating our findings using HOME. Specifically, we will: 1) characterize trajectories of the serum metabolome in the first 12 years of life; 2) identify features of serum metabolome trajectories in the first 12 years of life that predict adolescent cardiometabolic disease; 3) determine if metabolome features mediate the association of prenatal exposure to PFAS mixtures with adolescent cardiometabolic disease; and 4) determine the chemical identity of metabolome features discovered in Aim 3. This interdisciplinary proposal that includes epidemiologists, clinicians, biostatisticians, and chemists will efficiently leverage two ongoing cohort studies to address these timely aims. Ultimately, the proposed studies will have substantial impact by improving our knowledge of the health effects of PFAS, identifying novel metabolic alterations associated with PFAS mixtures and adolescent health, and improving our understanding of biological pathways affecting cardiometabolic disease. These results are critical to ongoing evaluations of PFAS toxicity and may help identify exposed populations at risk of cardiometabolic disease and potentially ameliorate the effects of PFAS exposure.