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

项目摘要 在过去的40年里，儿童肥胖率增加了两倍多，18.5%的儿童和 青少年被归类为肥胖。干扰内分泌的化学品，特别是环境中普遍存在的化学品 肥胖原，如全氟烷基和多氟烷基物质（PFAS），被认为是导致快速增加的原因。 肥胖症。事实上，产前PFAS暴露已被证明有助于性别特异性肥胖 儿童的发展。有趣的是，在怀孕期间发生的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PFAS。除了支持 胎儿生长，胎盘可能参与对后代的长期持续影响。然而，在这方面， 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 都是替补此外，生活方式干预，包括饮食训练，体力活动， 已经显示，修饰减弱较高PFAS与较高体重之间的关联。 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，在我们对以下方面的影响和预防机会的理解方面存在重大差距： 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 怀孕可以减轻这些影响。为此，我们组建了一个新的合作组织， 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，Aim 1）， 环境健康和胎盘功能基因组学（mPI Everson，Aim 2），以及体力活动干预 (mPI Pearson，Aim 3）以解决这些知识差距。使用现有的纵向队列，我们的目标是量化 在每个妊娠期母体血清以及脐带血清和胎盘组织中的PFAS，以确定 它们与出生体重、胎盘功能基因组学以及儿童肥胖的关系。此外，本发明还 由于PFAS是普遍存在的，因此避免暴露可能是困难的，我们还将探讨 孕妇运动在减少孕妇PFAS负担方面的作用， 妊娠期运动的随机对照试验。我们假设1）产前PFAS负荷将 显著影响出生体重，以及儿童生长和肥胖增加; 2）产前PFAS暴露将 影响胎盘表观基因组调控，影响转录和代谢特征; 3）运动 在怀孕期间，将降低母体和脐带血中的PFAS负荷。拟议的研究将提供 创新的新见解，以了解PFAS化合物作为肥胖剂在人类 发展，它们对胎盘功能的影响，这可能导致新的干预或预防目标， 并确定运动是否减轻PFAS暴露风险。

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.