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

摘要 大量的流行病学研究表明，母亲接触环境中的细颗粒物 (PM2.5)对儿童构成严重的肥胖风险。在动物模型中，我们和其他人证实了不利的 母体PM2.5暴露对子代肥胖的规划及其与子代高甲基化的关系 从而在这种逆向编程中下调瘦素的表达。相比之下，很少有已发表的研究对 母体的发病机制为这一不利的编程。为了制定有效的干预战略， 可能对母亲和孩子都有好处，我们建议用我们独特的 转基因动物模型和最先进的PM2.5暴露技术。通过两者的合成 已公布的和初步的数据，我们假设母体PM2.5暴露计划产生瘦素 通过母体肺部炎症和随后的卵母细胞表达下调而导致肥胖 TET2，并提议通过追求三个离散但相互关联的目标来彻底检验这一假设：目标1： 通过母体建立子代肥胖逆规划的剂量和成分依赖模型 PM2.5暴露。目的2.确定母亲接触PM2.5是否通过以下途径导致后代肥胖 母系卵母细胞TET2表达下调，子代瘦素表达下调。目标3：实现 确定PM2.5暴露引起的肺部炎症是否会引起母体卵母细胞紊乱和 后代肥胖的后续规划。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 母体PM2.5暴露对子代肥胖的规划。

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.