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

妊娠期 PFAS 混合物暴露、纵向代谢组学特征和青少年心脏代谢健康

• 批准号: 10673054
• 负责人: Joseph M Braun
• 金额: $ 56.63万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-25 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673054
• 关键词: 12 year old; Acceleration; Address; Adolescent; Adolescent obesity; Adult; Affect; Age; Amino Acids; Analytical Chemistry; Animals; Area; Biological; Biological Markers; Biometry; Biostatistical Methods; Blood; Canada; Cardiometabolic Disease; Cardiovascular Diseases; Carnitine; Chemical Exposure; Chemicals; Child; Childhood; Cohort Studies; Collaborations; Collection; Commerce; Coupled; Data; Databases; Diet; Dimensions; Dissociation; Dyslipidemias; Elderly; Environment; Epidemiologist; Epidemiology; Evaluation; Exposure to; Fatty Acids; Fire - disasters; Food; Food Contamination; Food Packaging; Growth; Health; Home; Human; Hypertension; Individual; Industry; Insulin Resistance; Ions; Knowledge; Life; Link; Measures; Mediating; Metabolic; Metabolism; Modeling; Obesity; Ohio; Oils; Outcome; Pathway interactions; Pediatrics; Persons; Plasma; Poly-fluoroalkyl substances; Populations at Risk; Predisposition; Pregnancy; Pregnant Women; Productivity; Prospective cohort; Publishing; Recording of previous events; Regulation; Research Personnel; Resolution; Risk; Risk Factors; Sampling; Serum; Syndrome; Techniques; Testing; Textiles; Time; Toxic effect; Training; United States; Water; adolescent health; blood pressure elevation; cardiometabolic risk; cardiometabolism; cardiovascular disorder risk; contaminated drinking water; critical period; disorder risk; drinking water; early adolescence; early life exposure; environmental chemical; environmental chemistry; health assessment; improved; innovation; landfill; liquid chromatography mass spectrometry; manufacture; manufacturing facility; maternal serum; metabolome; metabolomics; microbiome; neonate; novel; obesity risk; prenatal; prenatal exposure; response; small molecule

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.

项目摘要 接触环境化学混合物可能会增加患心脏代谢疾病的风险。 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 防油/防水纺织品、含氟聚合物制造、食品包装、清洁产品等的助剂 PFAS 暴露无处不在，源自受污染的食品和饮用水。 美国有 100 万人的饮用水受到 PFAS 污染，还有更多人处于低水平接触状态。 动物和人类研究表明，产前接触 PFAS 可能会增加肥胖、胰岛素风险 抵抗力、血脂异常和高血压——心脏代谢综合征的组成部分，显着 增加成人心血管疾病的风险然而，很少有研究调查其健康状况。 PFAS 混合物的影响以及这些影响背后的生物学途径知之甚少。 根据我们的初步研究和血清代谢组中代表的生物途径的假设 对生命早期 PFAS 混合物暴露敏感并可预测生命后期心脏代谢健康，我们将使用 非靶向高分辨率代谢组学，用于量化产前 PFAS 混合物、 代谢组和心脏代谢疾病建立在两个已建立和正在进行的前瞻性队列的基础上。 来自加拿大（MIREC 研究，n=500）和俄亥俄州辛辛那提（HOME 研究， n=250），我们将测量分娩时、3-5 岁和 7-12 岁血清代谢组的 >25,000 个特征。 我们会将这些数据与之前收集的或待测量的产前 PFAS 生物标志物联系起来， 我们将使用复杂的生物统计技术来减少 7-12 岁的心脏代谢结果。 这些数据的维度并发现与产前 PFAS 相关的代谢组学特征 MIREC 中的混合物和心脏代谢结果，使用 HOME 复制我们的研究结果具体来说，我们将： 1) 描述生命前 12 年血清代谢组的轨迹 2) 识别血清特征； 生命前 12 年的代谢组轨迹可预测青少年心脏代谢疾病 3) 确定代谢组特征是否介导产前接触 PFAS 混合物与 青少年心脏代谢疾病；4) 确定代谢组特征的化学特性 在目标 3 中发现。这项跨学科提案包括流行病学家、民众、生物统计学家、 化学家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。 拟议的研究将通过提高我们对 PFAS 健康影响的了解而产生重大影响， 识别与 PFAS 混合物和青少年健康相关的新代谢变化，并改善 我们对影响心脏代谢疾病的生物学途径的理解对于这些结果至关重要。 持续评估 PFAS 毒性，可能有助于识别有心脏代谢风险的暴露人群 疾病并可能改善 PFAS 暴露的影响。