Microvascular mechanisms of growth restriction after environmental toxicant exposure

环境毒物暴露后生长受限的微血管机制

• 批准号: 10514620
• 负责人: Phoebe Stapleton
• 金额: $ 59.92万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10514620
• 关键词: Acute; Aerosols; Air Pollution; Airborne Particulate Matter; Animals; Arachidonic Acids; Attenuated; Biological Availability; Blood Vessels; Blood flow; Cardiovascular Diseases; Child; Chronic; Circulation; Clinical; Data; Development; Dietary Intervention; Diffusion; Dose; Eicosanoids; Elderly; Endothelial Cells; Endothelium; Environment; Environmental Exposure; Epoprostenol; Equilibrium; Evaluation; Exposure to; Fetal Death; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetal Malnutrition; Fetal Weight; Fetal health; Fetus; Gases; Generations; Goals; Growth; Impairment; In Vitro; Inhalation; Intervention; Laboratories; Left; Low Birth Weight Infant; Maternal Exposure; Maternal-fetal medicine; Metabolic Diseases; Metabolism; Methodology; Microvascular Dysfunction; Modeling; Molecular; Mothers; Myography; Neonatal Mortality; Nitric Oxide; Nutrient; Oxygen; Particulate; Particulate Matter; Pathogenesis; Patients; Perfusion; Pharmacological Treatment; Physiology; Placenta; Placental Circulation; Predisposition; Pregnancy; Pregnant Women; Premature Birth; Preparation; Production; Prostaglandins I; Qualifying; Rattus; Regulation; Research; Resources; Risk; Risk Factors; Rodent Model; Role; Severities; Signal Transduction; Spontaneous abortion; Testing; Therapeutic; Therapeutic Intervention; Thromboxane A2; Toxic Environmental Substances; Toxic effect; Toxicant exposure; Treatment Efficacy; Uteroplacental Circulation; Uterus; Vascular Endothelium; Vasodilation; Vasodilator Agents; Work; absorption; arteriole; constriction; cost; design; dietary; epidemiology study; exhaust; fetal; fetal blood; fetal loss; fetus hypoxia; fine particles; folic acid metabolism; folic acid supplementation; healthy pregnancy; hemodynamics; improved; innovation; insight; intravital microscopy; mechanical signal; nano; nanomaterials; nanosized; neonatal morbidity; novel; novel strategies; particle; patient population; pharmacologic; pregnant; pressure; prevent; response; skills; targeted treatment; titanium dioxide; ultrafine particle; vasoconstriction

ABSTRACT The uterine circulation and placenta are specifically designed to regulate the flow of blood and transport of es- sential 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 op- tions 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. An understanding of the mechanisms underlying dysregulation in uterine and placental blood flow is critical for developing treatments and reducing IUGR. Based on previous findings, we hypothesize that maternal inhalation of nano-TiO2 aerosols during pregnancy promotes the development of IUGR by disrupting endothelium-dependent NO and AA signaling cascades, resulting in reduced uterine vasodilation and blood flow. Moreover, folic acid (FA) supplementation will rescue this utero-placental hemodynamic imbalance and prevent IUGR through its action in NO signaling. Using novel approaches and methodolo- gies, 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 mi- crocirculation 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 intervention- al 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.

抽象的 子宫循环和胎盘是专门为调节血液流动和ES的运输而设计的。 怀孕期间母体血流动力学调节的破坏会对胎儿产生不利影响。 影响胎儿健康，导致流产和宫内生长受限（IUGR）。 针对 IUGR 患者的治疗方案极其有限，主要集中于早期分娩，因此，将母亲和 流行病学研究表明，怀孕的孩子有发生早产并发症的风险。 暴露于细颗粒物 (PM) 的女性存在胎儿流产和 IUGR 发展的呼吸道风险。 我们在实验室啮齿动物模型中重现了这种现象，其中动物暴露于纳米尺寸的环境中 二氧化钛（纳米 TiO2）气溶胶会导致 IUGR 并遭受更多“流产”（胎儿 我们已经证明，急性和慢性暴露会显着损害子宫血管。 内皮依赖性扩张，严重限制母体至胎儿的血流量并影响胎儿生长。 了解子宫和胎盘血流失调的机制对于 开发治疗方法并减少 IUGR 根据之前的研究结果，我们与该母亲进行了接触。 怀孕期间吸入纳米二氧化钛气溶胶可通过扰乱促进 IUGR 的发展 内皮依赖性 NO 和 AA 信号级联反应，导致子宫血管舒张减少 此外，补充叶酸（FA）将改善子宫胎盘血流动力学。 使用新的方法和方法通过其在 NO 信号传导中的作用来平衡失衡并预防 IUGR。 这些研究将：（1）评估子宫一氧化氮驱动的血管舒张，（2）确定子宫内膜是否发生改变 花生四烯酸代谢损害子宫血管反应性并影响胎盘灌注，以及（3）评估 膳食叶酸治疗性补充剂改善子宫胎盘血流和减弱的益处 这些研究是概念性的。 创新，因为我们将利用我们独特的资源来确定子宫胎盘 MI 内的机械目标 这项工作在技术上具有创新性，我们将对此进行研究。 使用为评估母胎医学环境毒性而开发的新方法。 总体而言，这些研究的成功完成将：（1）创建概念框架来识别 (2) 揭示新的机制见解 纳米材料暴露引起的血管发病机制；（3）提供分子基础来确定如何发生 纳米材料暴露表现为血管破坏；(4) 确定治疗的机制目标； 改善微血管功能障碍和改善子宫胎盘血流的策略 - 所有策略不仅限于 PM，而且广泛适用于理解一系列的角色 环境毒物在IUGR病理生理发展中的作用。