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

项目摘要 暴露于环境化学混合物可能会增加心脏代谢疾病的风险。特别 令人担忧的是产前接触全氟烷基物质（PFAS），这是一类用于加工的化学品。 用于防油/防水纺织品、含氟聚合物制造、食品包装、清洁产品和 消防泡沫PFAS暴露无处不在，来源于受污染的食物和饮用水。超过6 在美国，有100万人的饮用水受到PFAS污染，还有更多的人受到低水平的污染。 动物和人类研究表明，产前PFAS暴露可能会增加肥胖的风险，胰岛素 阻力、血脂异常和高血压--心脏代谢综合征的组成部分， 增加成年期心血管疾病的风险。然而，很少有研究调查健康状况。 PFAS混合物的影响，以及这些影响的生物学途径知之甚少。指导 通过我们的初步研究和假设，即血清代谢组中代表的生物学途径 对生命早期的PFAS混合物暴露敏感，并预测生命后期的心脏代谢健康，我们将使用 非靶向高分辨率代谢组学来量化产前PFAS混合物之间的关联， 代谢组学和心脏代谢疾病。基于两个已建立和正在进行的前瞻性队列， 来自加拿大（MIREC研究，n = 500）和辛辛那提，俄亥俄州（HOME研究， n = 250），我们将测量分娩时和3 - 5岁以及7 - 12岁时血清代谢组的> 25，000个特征。 我们将把这些数据与以前收集的或将要测量的产前PFAS生物标志物联系起来， 7 - 12岁时的心脏代谢结局。我们将使用复杂的生物统计技术来减少 这些数据的维度，并发现与产前PFAS MIREC中的混合物和心脏代谢结果，复制我们使用HOME的发现。具体而言，我们将： 1)描述生命最初12年中血清代谢组的轨迹; 2）识别血清代谢组的特征 预测青少年心脏代谢疾病的前12年代谢组轨迹; 3） 确定代谢组学特征是否介导产前暴露于PFAS混合物与 青少年心脏代谢疾病;和4）确定代谢组学特征的化学特性 在目标3中发现。这个跨学科的建议，包括流行病学家，临床医生，生物统计学家， 化学家们将有效地利用两项正在进行的队列研究来实现这些及时的目标。最终 拟议的研究将通过提高我们对PFAS健康影响的认识， 确定与PFAS混合物和青少年健康相关的新的代谢改变， 我们对影响心脏代谢疾病的生物学途径的理解。这些结果对于 正在进行的PFAS毒性评估，可能有助于确定暴露人群的心脏代谢风险 疾病，并可能改善PFAS暴露的影响。

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.