Diversity Supplement to Microvascular mechanisms of growth restriction after environmental toxicant exposure (R01ES031285)

父级赠款摘要 子宫循环和胎盘是专门设计来调节血液流动和运输的 胎儿必需的营养物质。妊娠期母体血流动力学调节的紊乱可能会对 影响胎儿健康，导致流产和胎儿宫内生长受限。当前的治疗方案 对IUGR患者的治疗极其有限，主要集中在早产；因此，将母婴 面临早产相关并发症的风险。流行病学研究表明，孕妇 暴露于细颗粒物(PM)会增加胎儿丢失和发生IUGR的风险。我们有 在实验室的啮齿动物模型中重现了这种现象，在这些动物中，接触纳米钛的动物 二氧化钛(纳米二氧化钛)气雾剂会导致胎儿宫内发育迟缓，并遭受更多的“流产”(胎儿再吸收)。 我们已经证明，急性和慢性暴露显著损害子宫血管内皮细胞。 依赖性扩张，严重限制母体与胎儿之间的血流，影响胎儿生长。不幸的是， 目前的研究策略还没有阐明与血管发生相关的机制。 母亲接触颗粒物后的宫内发育迟缓。根据之前的发现，我们假设母体吸入 怀孕期间纳米二氧化钛气雾剂通过破坏内皮促进IUGR的发展- 依赖的信号级联，导致子宫血管扩张和血流量的净减少。我们 进一步的假设是，营养后血管信号和功能的改善将缓解IUGR 补充叶酸。利用新的途径和方法，这些研究将：(1)评估 子宫一氧化氮驱动的血管扩张，(2)确定花生四烯酸代谢的改变是否损害 子宫血管反应性和对胎盘血流的影响，以及(3)评估饮食叶酸的治疗益处 补酸改善子宫胎盘血流及延缓宫内发育迟缓 母亲暴露在纳米二氧化钛气雾剂中。这些研究在概念上是创新的，因为我们将利用我们独特的 确定子宫-胎盘微循环中的机械性靶点和测试定向营养的资源 对宫内发育迟缓的干预。这项工作在技术上具有创新性，因为我们将使用为 母婴药物的环境毒性评价。总体而言，这些项目的圆满完成 研究将：(1)建立概念性框架，以确定环境暴露为 IUGR的发展；(2)揭示了血管发病机制的新见解 纳米材料暴露；(3)提供分子基础，以确定纳米材料暴露如何表现为 血管破裂；以及(4)确定用于改善微血管的治疗策略的机制靶点 功能障碍，改善子宫-胎盘血流。这些干预策略不仅限于PM， 但广泛适用于理解一系列环境毒物在环境污染中的作用 胎儿宫内发育迟缓的病理生理发展。

PARENT GRANT ABSTRACT The uterine circulation and placenta are specifically designed to regulate the flow of blood and transport of essential nutrients to the fetus. Disruption of maternal hemodynamic regulation during pregnancy can adversely impact fetal health, resulting in miscarriage and intrauterine growth restriction (IUGR). Current treatment options for IUGR patients are extremely limited, focusing primarily on early delivery; thus, putting the mother and child at risk for complications associated with preterm birth. Epidemiological studies indicate that pregnant women exposed to fine particulate matter (PM) have a heightened risk of fetal loss and development of IUGR. We have reproduced this phenomenon in laboratory rodent models, wherein animals exposed to nanosized titanium dioxide (nano-TiO2) aerosols develop IUGR and suffer a greater number of ‘miscarriages’ (fetal reabsorptions). We have demonstrated that acute and chronic exposures significantly impair uterine vascular endothelium dependent dilation, severely limiting maternal-to-fetal blood flow and impacting fetal growth. Unfortunately, current research strategies have yet to elucidate the vascular mechanisms associated with the development of IUGR after maternal particulate exposure. Based on previous findings, we hypothesize that maternal inhalation of nano-TiO2 aerosols during pregnancy promotes the development of IUGR by disrupting endothelium- dependent signaling cascades, resulting in a net reduction in uterine vasodilation and blood flow. We further postulate that IUGR will be mitigated by improved vascular signaling and function after nutritional supplementation with folic acid. Using novel approaches and methodologies, these studies will: (1) evaluate uterine nitric oxide-driven vasodilation, (2) determine whether alterations in arachidonic acid metabolism impair uterine vascular reactivity and impact placental perfusion, and (3) assess the therapeutic benefit of dietary folic acid supplementation to improve utero-placental blood flow and attenuate the development of IUGR after maternal exposure to nano-TiO2 aerosols. These studies are conceptually innovative as we will utilize our unique resources to identify mechanistic targets within the utero-placental microcirculation and test directed nutritional interventions for IUGR. This work is technically innovative as we will use novel methodologies developed for the evaluation of environmental toxicity in maternal-fetal medicine. Overall, the successful completion of these studies will: (1) create the conceptual framework to identify environmental exposure as a risk factor for the development of IUGR; (2) reveal new mechanistic insight into the vascular pathogenesis resulting from nanomaterial exposure; (3) provide a molecular basis to identify how nanomaterial exposure manifests as vascular disruptions; and (4) identify mechanistic targets for therapeutic strategies to ameliorate microvascular dysfunction and improve utero-placental blood flow. These interventional strategies are not only limited to PM, but are widely applicable to understanding the role of a spectrum of environmental toxicants in the pathophysiological development of IUGR.