Mechanism for Programming of Offspring Adiposity by Maternal PM2.5 Exposure

摘要 大量流行病学研究表明，母亲接触环境细颗粒物 （PM2.5）对儿童肥胖构成重大风险。在动物模型中，我们和其他人证实了 母体PM2.5暴露对子代肥胖的影响， 因此在这种不利的编程中瘦素表达下调。相比之下，很少有已发表的研究测试了 这种不良编程的母体发病机制。为了制定有效的干预战略， 可能有利于母亲和孩子，我们建议解开其母亲的发病机制，使用我们独特的 转基因动物模型和最先进的PM2.5暴露技术。通过综合两者 根据已发表的和初步的数据，我们假设母体PM2.5暴露计划后代瘦素 表达，从而通过母体肺部炎症和随后的卵母细胞表达下调肥胖 Tet2，并建议通过追求三个独立但相互关联的目标来彻底检验这一假设：目标1： 模拟剂量和成分依赖性的不利编程后代肥胖的母亲 PM2.5暴露。目标2.为了确定母亲PM2.5暴露是否通过以下途径导致后代肥胖， 母体卵母细胞Tet2表达下调，随后后代瘦素表达下调。目标3： 确定PM2.5暴露诱导的肺部炎症是否会导致母体卵母细胞紊乱， 后代肥胖的后续程序。通过揭示关键的发病机制，该项目有望 为了解和制定针对不利因素的干预措施提供强有力的科学框架 通过母体PM2.5暴露来规划后代肥胖。

ABSTRACT Considerable epidemiological studies reveal that maternal exposure to ambient fine particulate matter (PM2.5) poses a significant risk for obesity to the child. In animal models, we and others corroborate the adverse programming of offspring adiposity by maternal PM2.5 exposure and implicate the offspring’s hypermethylated and thus down-expressed Leptin in this adverse programming. In contrast, few published studies have tested the maternal pathogenesis for this adverse programming. In order to develop effective intervention strategies that may benefit both the mother and child, we propose to unravel its maternal pathogenesis using our unique genetically-modified animal models and state-of-the-art PM2.5 exposure technique. Through a synthesis of both published and preliminary data, we hypothesize that maternal PM2.5 exposure programs offspring Leptin expression and thus adiposity via maternal pulmonary inflammation and ensuing oocyte down-expression of Tet2, and propose to thoroughly test this hypothesis through pursuing three discrete yet linked aims: Aim 1: To model the dose- and composition-dependencies for the adverse programming of offspring adiposity by maternal PM2.5 exposure. Aim 2. To determine whether maternal PM2.5 exposure programs offspring adiposity through maternal oocyte down-expression of Tet2 and subsequent offspring down-expression of Leptin. Aim 3: To determine whether pulmonary inflammation induced by PM2.5 exposure elicits maternal oocyte disturbance and subsequent programming of offspring adiposity. By revealing the critical pathogenesis, this project is expected to provide a strong scientific framework for understanding of and developing interventions for the adverse programming of offspring adiposity by maternal PM2.5 exposure.