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

基本信息

批准号：
10494076
负责人：
Joseph M Braun
金额：
$ 58.84万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
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/10494076
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 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 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 manufacturing facility maternal serum metabolome metabolomics microbiome neonate novel obesity risk prenatal prenatal exposure response small molecule

项目摘要

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。特别关注的是产前暴露于全氟烷基物质（PFAS），这是一类用作加工的化学物质油/水驱剂纺织品的辅助工具，荧光聚合物制造，食品包装，清洁产品和消防泡沫。 PFAS暴露无处不在，源自受污染的食物和饮用水。超过6 美国有百万人的PFA污染了饮用水，还有更多人的暴露量低。动物和人类研究表明，产前PFA的暴露可能会增加肥胖，胰岛素的风险抗药性，血脂异常和高血压 - 心脏代谢综合征的成分显着增加成人心血管疾病的风险。但是，很少有研究研究健康 PFA混合物的影响以及这些作用的生物学途径的理解很少。指导通过我们的初步研究和血清代谢组中代表的生物学途径的假设对PFAS混合物的暴露和预测以后的寿命健康健康状况很敏感，我们将使用非靶向高分辨率代谢组学以量化产前PFAS混合物之间的关联，代谢组和心脏代谢疾病。建立在两个已建立且持续的潜在人群的基础上来自加拿大的孕妇及其子女（Mirec研究，n = 500）和俄亥俄州辛辛那提（家庭学习， n = 250），我们将在分娩时和3-5岁和7至12岁时测量> 25,000个血清代谢组的特征。我们将将这些数据链接到先前收集的或要测量的产前PFA生物标志物和 7-12岁的心脏代谢结果。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两个产前PFA相关的代谢组学特征 MIREC中的混合物和心脏代谢结果，使用家庭复制我们的发现。具体来说，我们将： 1）表征生命的头12年中血清代谢组的轨迹； 2）确定串行的功能代谢轨迹在生命的前12年，预测青少年心脏代谢疾病； 3）确定代谢组特征是否介导了产前暴露于PFA的混合物与青少年心脏代谢疾病； 4）确定代谢组特征的化学身份在AIM 3中发现。该跨学科的建议在内，包括流行病学家，临床医生，生物统计学家，化学家将有效利用两项正在进行的队列研究来解决这些及时的目标。最终，提出的研究将通过提高我们对PFA的健康影响的了解，从而产生重大影响，识别与PFA混合物和青少年健康相关的新型代谢改变，并改善我们对影响心脏代谢疾病的生物学途径的理解。这些结果对对PFA毒性的持续评估，可能有助于确定具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。