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.

项目摘要 在过去的40年中，儿童肥胖的发生率增加了两倍以上，其中18.5％的儿童和 被归类为肥胖的青少年。内分泌干​​扰化学物质，尤其是环境无处不在的化学物质 诸如per和多氟烷基物质（PFA）之类的度者被认为有助于快速增加 实际上，已经证明产前PFAS暴露有助于特定性别的肥胖症 儿童的发展。有趣的是，怀孕期间发生的PFA暴露会越过plapeta 导致宫颈组织中直接暴露于子宫内，并且在安置组织中检测到PFA。除了支持 胎儿生长，plapeta可能与后代长期持续作用有关。然而， 产前PFA之间的相互关系，对plapeta的影响以及产后生长和代谢健康 被理解。此外，生活方式干预包括饮食培训，体育锻炼和行为 已证明修饰可减弱较高的PFA与更高体重之间的关联。 但是，在产前暴露和儿童健康的背景下尚未进行类似的研究 结果。那就是我们对影响和预防机会的关键差距 产前PFAS暴露：暴露时间和/或组织特异性浓度是否重要； PFA是否会破坏斑点的分子活性；以及是否在 怀孕可能会减轻这些影响。对于此提案，我们组装了新成立的合作 具有独特专业知识在儿童成长和代谢健康方面具有独特专业知识的研究人员（MPI Andres，AIM 1）， 环境健康和占地功能基因组学（MPI Everson，AIM 2）和体育锻炼干预措施 （MPI Pearson，目标3）解决这些知识差距。使用现有的纵向队列，我们​​旨在量化 每个三个月以及脐带血清和斑点时机中的PFA 它们与出生体重，胎盘功能基因组学以及小儿肥胖的关联。此外， 由于PFA是普遍的，因此避免暴露可能很困难，我们还将探索 作为正在进行的一部分 在怀孕期间进行随机对照试验。我们假设1）产前PFAS Burnen将 显着影响出生体重，儿童成长和肥胖积聚； 2）产前PFAS暴露将 影响斑点表观基因组学调节，对转录和代谢特征产生影响； 3）运动 在怀孕期间，孕产妇和脐带血清中的PFA燃烧会降低。拟议的研究将提供 创新的新见解，以了解PFAS化合物作为肥胖症在人类中的作用 开发，它们对占地功能的影响，这可能导致干预或预防的新目标， 并确定运动是否减轻PFAS暴露风险。