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

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，胎儿生长受限（FGR）和胎盘发育受损与婴儿出生缺陷有关。 发病率和死亡率以及对成年期疾病的易感性。在怀孕的动物中，吸入颗粒会改变 子宫胎盘血管系统的功能，导致胎盘和胎儿生长受损。颗粒 物质（PM）可以多种方式靶向子宫胎盘脉管系统。一种粒子可以破坏 子宫胎盘脉管系统是通过损害血管舒张。在怀孕期间，子宫血管必须敏感 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 内皮细胞将信号从血液传递到血管平滑肌细胞，导致血管 扩张或收缩。此外，胎盘是氧气扩散和运输的关键器官。 对发育中的胎儿的营养。PM可损害胎盘血管系统的发育， 母体-胎儿交换并降低胎盘与胎儿组织的比率，称为胎盘效率。我们 实验室最近表明，塑料颗粒可以通过胎盘转移到胎儿后，肺 暴露，表明颗粒直接与子宫胎盘血管系统相互作用。环境 塑料的负担呈指数级增长。微纳米塑料（MNP）代表了无处不在的暴露 为了关注广大民众和孕妇等弱势群体， 阐明MNP吸入如何影响胎儿发育。这些颗粒产生并悬浮在 空气通过散装塑料的燃烧或通过较慢的过程，如机械降解， 塑料碎片在微粒（>100 nm）和纳米颗粒（<100 nm）尺寸范围内变成小碎片。我们 初步数据表明，在未交配的雌性大鼠中吸入MNP破坏了子宫血管反应性。 此外，使用整个妊娠期间吸入MNP的妊娠模型，我们观察到FGR增加， 胎盘重量和胎盘效率降低，表明胎盘是大鼠中MNP的靶器官。 因此，这一建议的中心假设是，母亲在整个妊娠期间吸入MNP 通过损害子宫血管舒张和破坏胎盘发育而降低胎盘效率 大鼠的血管。本研究的目的是探讨重复母体MNP的机制， 吸入会使子宫脉管系统和胎盘发育失调，从而导致FGR。目标1将 确定子宫血管反应性受损的机制，以及内皮细胞功能如何改变， 母体MNP暴露。目标2将确定母体MNP吸入如何改变发育 胎盘血管的组织病理学分析和免疫组织化学。这项研究将确定 MNP诱导FGR的机制，并提出了潜在的治疗干预的目标。通过完成 拟议的研究、课程和培训主要研究者将接受独立培训， 最先进的实验技术，并开展心血管和生殖毒理学研究。