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

项目总结 儿童肥胖率在过去40年里增加了两倍多，18.5%的儿童和 被归类为肥胖的青少年。扰乱内分泌的化学物质，特别是无处不在的环境 肥胖原因，如全氟烷基物质和多氟烷基物质(PFAS)，被认为是导致快速增长的原因 在肥胖方面。事实上，产前接触PFAS已被证明是导致特定性别肥胖的原因之一。 儿童的发展。有趣的是，发生在怀孕期间的PFAS暴露会穿过胎盘。 导致宫内直接暴露，已在胎盘组织中检测到全氟辛烷磺酸。除了支持 在胎儿发育过程中，胎盘可能会对后代产生更长期的持续影响。然而， 产前PFAS、对胎盘的影响以及出生后生长和代谢健康之间的相互关系 都没有得到充分的研究。此外，生活方式干预包括饮食训练、体力活动和行为 修改已经被证明减弱了较高的PFAS与较高的体重之间的关联。 然而，类似的研究还没有在产前暴露和儿童健康的背景下进行 结果。因此，在我们对以下方面的影响和预防机会的理解上存在重大差距 产前全氟辛烷磺酸暴露：暴露时间和/或组织特定浓度是否重要； 胎盘的分子活动是否受到PFAS的干扰；以及在 怀孕可能会减弱这些影响。对于这项提议，我们已经组建了一个新成立的协作组 在儿童成长和代谢健康方面拥有独特专业知识的调查小组(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，目标3)来解决这些知识差距。利用现有的纵向队列，我们的目标是量化 测定各孕期孕妇血清、脐带血清和胎盘组织中的PFAS 它们与出生体重、胎盘功能基因组学以及儿童肥胖症之间的关系。另外， 由于PFAS无处不在，因此很难避免暴露，我们还将探讨 作为正在进行的一项工作的一部分，孕产妇在妊娠期减少孕产妇PFAS负担的练习 孕期运动随机对照试验。我们假设1)产前PFAS负担将 显著影响出生体重以及儿童生长和肥胖的增加；2)产前接触全氟辛烷磺酸将 影响胎盘表观基因组调控，影响转录和代谢特征；3)运动 孕期可降低母血和脐血中PFAS的负担。拟议的研究将提供 理解全氟辛烷磺酸化合物在人类肥胖中的作用的创新见解 发育，它们对胎盘功能的影响，可能导致新的干预或预防目标， 并确定运动是否降低了全氟辛烷磺酸的暴露风险。

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.