Uteroplacental Vasculature and Fetal Growth after Plastic Particle Exposure

塑料颗粒暴露后的子宫胎盘脉管系统和胎儿生长

• 批准号: 10677264
• 负责人: Chelsea Cary
• 金额: $ 4.29万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677264
• 关键词: Adult; Adverse effects; Affect; Air; Air Pollution; Animals; Area; Arteries; Biological; Biology; Blood; Blood Vessels; Blood flow; Cardiometabolic Disease; Cardiovascular system; Cell physiology; Data; Development; Diffusion; Disease; Distal; Endothelial Cells; Endothelium; Exposure to; Fellowship; Female; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetal Tissues; Fetal Weight; Fetus; General Population; Grant; Growth; Health; Hour; Human; Immunohistochemistry; Impairment; Inhalation; International; Intervention; Invaded; Knowledge; Laboratories; Labyrinth; Lung; Maternal-Fetal Exchange; Measures; Mechanics; Mediator; Modeling; Molecular Target; Morphogenesis; Mothers; Myography; NOS3 gene; Nitric Oxide; Nutrient; Nylons; Occupational Exposure; Organ; Oxygen; Particulate Matter; Pathway interactions; Perinatal mortality demographics; Physiology; Placenta; Placentation; Plastics; Predisposition; Pregnancy; Pregnant Women; Principal Investigator; Process; Rattus; Research; Risk Assessment; Signal Transduction; Site; Smooth Muscle Myocytes; Spiral Artery of the Endometrium; Structure; Structure of parenchyma of lung; Surface; Techniques; Testing; Therapeutic Intervention; Tissues; Toxicology; Training; Translating; Uterus; Vascular Smooth Muscle; Vasodilation; Vulnerable Populations; Weight; air filter; angiogenesis; arteriole; biomass fuel; cardiometabolic risk; constriction; endothelial dysfunction; hemodynamics; indoor particulate matter; infant morbidity; infant morbidity/mortality; intravital microscopy; migration; nanoparticle; particle; particle exposure; pharmacologic; pregnant; pressure; protein expression; radial artery; reproductive; targeted treatment; therapeutic target; tool; Adult; Adverse effects; Affect; Air; Air Pollution; Animals; Area; Arteries; Biological; Biology; Blood; Blood Vessels; Blood flow; Cardiometabolic Disease; Cardiovascular system; Cell physiology; Data; Development; Diffusion; Disease; Distal; Endothelial Cells; Endothelium; Exposure to; Fellowship; Female; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetal Tissues; Fetal Weight; Fetus; General Population; Grant; Growth; Health; Hour; Human; Immunohistochemistry; Impairment; Inhalation; International; Intervention; Invaded; Knowledge; Laboratories; Labyrinth; Lung; Maternal-Fetal Exchange; Measures; Mechanics; Mediator; Modeling; Molecular Target; Morphogenesis; Mothers; Myography; NOS3 gene; Nitric Oxide; Nutrient; Nylons; Occupational Exposure; Organ; Oxygen; Particulate Matter; Pathway interactions; Perinatal mortality demographics; Physiology; Placenta; Placentation; Plastics; Predisposition; Pregnancy; Pregnant Women; Principal Investigator; Process; Rattus; Research; Risk Assessment; Signal Transduction; Site; Smooth Muscle Myocytes; Spiral Artery of the Endometrium; Structure; Structure of parenchyma of lung; Surface; Techniques; Testing; Therapeutic Intervention; Tissues; Toxicology; Training; Translating; Uterus; Vascular Smooth Muscle; Vasodilation; Vulnerable Populations; Weight; air filter; angiogenesis; arteriole; biomass fuel; cardiometabolic risk; constriction; endothelial dysfunction; hemodynamics; indoor particulate matter; infant morbidity; infant morbidity/mortality; intravital microscopy; migration; nanoparticle; particle; particle exposure; pharmacologic; pregnant; pressure; protein expression; radial artery; reproductive; targeted treatment; therapeutic target; tool

PROJECT SUMMARY/ABSTRACT In humans, fetal growth restriction (FGR) and impaired placental development are associated with infant morbidity and mortality and susceptibility to adulthood diseases. In pregnant animals, inhalation of particles alters the functionality of the uteroplacental vasculature, leading to impaired placental and fetal growth. Particulate matter (PM) can target the uteroplacental vasculature in multiple ways. One way by which particles can disrupt the uteroplacental vasculature is by impairing vasodilation. During pregnancy, uterine vessels must be sensitive to vasodilation mediators to meet the dynamic needs of the placenta and fetus. Central to this vasoreactivity is the endothelial cell that translates signals from the blood to the vascular smooth muscle cells, leading to vessel dilation or constriction. Additionally, the placenta is a critical organ for the diffusion of oxygen and transport of nutrients to the developing fetus. PM can impair development of the placental vasculature that allows for maternal-fetal exchange and decrease the ratio of placental-to-fetal tissue, known as placental efficiency. Our laboratory recently showed that plastic particles can translocate through the placenta to the fetus after pulmonary exposure, suggesting that the particles directly interact with the uteroplacental vasculature. The environmental burden of plastics is exponentially increasing. Micro’ nanoplastics (MNPs) represent a ubiquitous exposure concern for the general population and for vulnerable groups, such as pregnant women, it is important to elucidate how MNP inhalation may affect fetal development. These particles are generated and suspended in the air by the combustion of bulk plastic or through slower processes like mechanical degradation where a bulk plastic fragments into small pieces in the microparticle (>100 nm) and nanoparticle (<100 nm) size range. Our preliminary data demonstrates that MNP inhalation in virgin female rats disrupts uterine vascular reactivity. Furthermore, using a pregnancy model of MNP inhalation throughout gestation, we observed FGR, increased placental weight, and decreased placental efficiency suggesting the placenta is a target organ of MNPs in rats. Therefore, the central hypothesis of this proposal is that maternal inhalation of MNP throughout gestation decreases placental efficiency by impairing uterine vasodilation and disrupting development of the placental vasculature in rats. The aims in this proposal will investigate the mechanisms by which repeated maternal MNP inhalation dysregulates the uterine vasculature and placental development, thus contributing to FGR. Aim 1 will identify mechanisms of impaired uterine vascular reactivity and how endothelial cell function is altered after maternal MNP exposure. Aim 2 will determine how maternal MNP inhalation modifies development of the placental vasculature using histopathological analyses and immunohistochemistry. This research will identify mechanisms of MNP induced FGR and present potential targets for therapeutic intervention. By completing the proposed research, courses, and training the Principal Investigator will be trained independently conduct state- of-the-art experimental techniques and carry out cardiovascular and reproductive toxicological research.

项目摘要/摘要 在人类中，胎儿生长限制（FGR）和占地面积的发育与婴儿有关 发病率，死亡率以及对成年疾病的敏感性。在怀孕的动物中，吸入颗粒会改变 子宫腔脉管系统的功能，导致占地和胎儿生长受损。颗粒 物质（PM）可以以多种方式瞄准子宫校验。粒子可以破坏的一种方式 子宫腔脉管系统是通过损害血管舒张的。怀孕期间，子宫vissels必须敏感 血管舒张介质以满足胎盘和胎儿的动态需求。这种血管反应性的核心是 将信号从血液转换为血管平滑肌细胞的内皮细胞，导致血管 扩张或收缩。另外，plapeta是氧气扩散和运输的关键器官 发育中的胎儿营养。 PM可能会损害允许的位置脉管系统的开发 孕产妇交换并降低了斑点与野性组织的比率，称为占地效率。我们的 实验室最近表明塑料颗粒可以在肺后通过斑点转移到胎儿 暴露，表明颗粒直接与子宫腔脉管系统相互作用。环境 塑料负担呈指数增长。微型纳米塑料（MNP）代表无处不在的暴露 关注普通人群和弱势群体，例如孕妇，重要的是 阐明MNP吸入如何影响胎儿发育。这些颗粒是生成并悬浮在 通过散装塑料或通过较慢的过程（例如机械降解）组合空气的空气 塑料碎片分成微粒（> 100 nm）和纳米颗粒（<100 nm）尺寸范围的小块。我们的 初步数据表明，处女雌性大鼠的MNP吸入会破坏子宫血管反应性。 此外，在妊娠期间使用MNP吸入的怀孕模型，我们观察到FGR，增加 胎盘重量和提高的胎盘效率表明胎盘是大鼠MNP的靶器官。 因此，该提案的核心假设是在妊娠期间对MNP的吸入 通过损害子宫血管舒张和破坏斑点的发育，降低了位置效率 大鼠的脉管系统。该提案的目的将研究重复的Mater MNP的机制 吸入失调的子宫脉管系统和斑点发育，从而导致FGR。目标1意志 确定子宫血管反应受损的机制以及如何改变内皮细胞功能 母体MNP暴露。 AIM 2将确定母体MNP吸入修饰符如何发展 使用组织病理学分析和免疫组织化学的胎盘脉管系统。这项研究将确定 MNP的机制诱导了FGR，并提出了治疗干预的潜在靶标。通过完成 拟议的研究，课程和培训主要研究人员将接受独立培训的国家 - 艺术实验技术并进行心血管和再现的毒理学研究。