Growth and metabolic programming from prenatal PFAS exposure: examining the roles of placental functional genomics and protection by maternal exercise

产前 PFAS 暴露的生长和代谢规划：检查胎盘功能基因组的作用和母亲运动的保护

• 批准号: 10482396
• 负责人: Aline Andres
• 金额: $ 61.04万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-06 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10482396
• 关键词: 2 year old; Address; Adolescent; Adult; Affect; Attenuated; Behavior Therapy; Birth; Birth Weight; Body Composition; Body Weight; Cell physiology; Chemical Exposure; Child; Child Health; Clinical; Cohort Studies; DNA Methylation; Data; Development; Disease; Endocrine Disruptors; Environmental Health; Environmental Pollution; Epigenetic Process; Exercise; Fatty acid glycerol esters; Fetal Growth; Functional disorder; Gender; Gene Expression; Generations; Genetic Transcription; Genomics; Growth; Health; Human Development; Intervention; Intervention Studies; Knowledge; Lead; Longitudinal cohort; Maternal-Fetal Exchange; Measures; Mesenchymal Stem Cells; Metabolic; Metabolism; MicroRNAs; Molecular; Neonatal; Nutrient; Obesity; Obesity Epidemic; Organ; Outcome; Physical activity; Placenta; Poly-fluoroalkyl substances; Pregnancy; Prevention; Preventive; Randomized Controlled Trials; Regulation; Research; Research Personnel; Research Project Grants; Risk; Role; Sampling; Serum; Testing; Time; Tissues; Training; Translating; Umbilical cord structure; Weight Gain; cohort; cost; dietary; epigenetic regulation; epigenome; epigenomics; exercise intervention; functional genomics; high reward; high risk; improved; innovation; insight; intrauterine environment; lifestyle intervention; lipid biosynthesis; maternal serum; metabolomics; novel; obesity development; obesity in children; obesogen; offspring; postnatal; prenatal; prenatal exposure; prenatal influence; protective effect; response; transcriptomics; wasting

PROJECT SUMMARY Rates of childhood obesity have more than tripled over the last 40 years with 18.5% of children and adolescents classified as obese. Endocrine-disrupting chemicals, particularly environmentally ubiquitous obesogens such as per- and polyfluoroalkyl substances (PFAS), are thought to contribute to the rapid increases in obesity. Indeed, prenatal PFAS exposures have been shown to contribute to gender-specific obesity development in children. Interestingly, PFAS exposures that occur during pregnancy can cross the placenta leading to direct in utero exposure, and PFAS have been detected in placental tissues. In addition to supporting fetal growth, the placenta is likely involved in longer term persistent effects in the offspring. However, interrelationships between prenatal PFAS, impacts on the placenta, and postnatal growth and metabolic health are understudied. Additionally, a lifestyle intervention including dietary training, physical activity, and behavioral modifications has been shown to attenuate the association between higher PFAS to higher body weight. However, similar studies have not been performed in the context of prenatal exposure and children’s health outcomes. Thus, there are key gaps in our understanding of the impacts and preventive opportunities regarding prenatal PFAS exposure: whether the timing of exposure and/or tissue-specific concentrations are important; whether molecular activities of the placental are disrupted by PFAS; and whether physical activity during pregnancy may attenuate these effects. For this proposal, we have assembled a newly formed collaborative team of investigators with unique expertise in children’s growth and metabolic health (mPI Andres, Aim 1), environmental health and placental functional genomics (mPI Everson, Aim 2), and physical activity interventions (mPI Pearson, Aim 3) to address these knowledge gaps. Using an existing longitudinal cohort, we aim to quantify PFAS in maternal serum at each trimester as well as in umbilical cord serum and placental tissues to determine their associations with birth weight, placental functional genomics, as well as pediatric obesity. Additionally, because PFAS are pervasive and thus exposure avoidance can be difficult, we will also explore the role of maternal exercise in decreasing maternal PFAS burden during the pregnancy period as part of an ongoing exercise randomized control trial during pregnancy. We hypothesize that 1) prenatal PFAS burden will significantly affect birth weight, as well as child growth, and adiposity accretion; 2) prenatal PFAS exposure will influence placental epigenomic regulation, with impacts on transcription and metabolic features; and 3) exercise during pregnancy will decrease PFAS burden in maternal and umbilical serum. The proposed studies will offer innovative new insights to understanding the role of PFAS compounds as obesogens during human development, their impact on placental function which could lead to novel targets for intervention or prevention, and determine whether exercise mitigates the PFAS exposure risk.

项目概要 过去 40 年来，儿童肥胖率增加了两倍多，其中 18.5% 的儿童肥胖 青少年被归类为肥胖。内分泌干​​扰化学物质，特别是环境中普遍存在的化学物质 全氟烷基物质和多氟烷基物质 (PFAS) 等致肥胖因素被认为是导致肥胖迅速增加的原因 在肥胖中。事实上，产前 PFAS 暴露已被证明会导致特定性别的肥胖 儿童的发展。有趣的是，怀孕期间发生的 PFAS 暴露可以穿过胎盘 导致子宫内直接暴露，并且在胎盘组织中检测到了 PFAS。除了支持 胎儿的生长，胎盘可能参与对后代的长期持续影响。然而， 产前 PFAS、对胎盘的影响以及产后生长和代谢健康之间的相互关系 正在研究中。此外，生活方式干预包括饮食训练、身体活动和行为 研究表明，修改可以减弱更高的 PFAS 与更高的体重之间的关联。 然而，在产前暴露和儿童健康方面尚未进行类似的研究 结果。因此，我们对影响和预防机会的理解存在重大差距 产前 PFAS 暴露：暴露时间和/或组织特异性浓度是否重要； 胎盘的分子活动是否被PFAS破坏；以及期间是否进行体力活动 怀孕可能会减弱这些影响。对于这项提案，我们组建了一个新成立的协作团队 在儿童生长和代谢健康方面拥有独特专业知识的研究团队（mPI Andres，目标 1）， 环境健康和胎盘功能基因组学（mPI Everson，目标 2）以及体育活动干预 （mPI Pearson，目标 3）来解决这些知识差距。使用现有的纵向队列，我们​​的目标是量化 每个妊娠期母体血清以及脐带血清和胎盘组织中的 PFAS 测定 它们与出生体重、胎盘功能基因组以及儿童肥胖的关系。此外， 由于 PFAS 普遍存在，因此避免接触可能很困难，我们还将探讨 作为一项持续的计划的一部分，孕产妇锻炼可减少怀孕期间孕产妇的 PFAS 负担 怀孕期间运动随机对照试验。我们假设 1) 产前 PFAS 负担将 显着影响出生体重、儿童生长和肥胖增加； 2) 产前接触PFAS会 影响胎盘表观基因组调控，从而影响转录和代谢特征； 3）锻炼 怀孕期间服用会减少母体和脐带血清中的 PFAS 负荷。拟议的研究将提供 了解 PFAS 化合物在人类肥胖过程中的作用的创新见解 发育及其对胎盘功能的影响，这可能会导致干预或预防的新目标， 并确定运动是否可以减轻 PFAS 暴露风险。