Uteroplacental Vasculature and Fetal Growth after Plastic Particle Exposure

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有关 发病率、死亡率和对成年期疾病的易感性。在怀孕的动物中，吸入颗粒物会改变 子宫胎盘血管系统的功能，导致胎盘和胎儿发育受损。颗粒物 物质(PM)可通过多种途径靶向子宫胎盘血管系统。粒子可以破坏的一种方式 子宫胎盘血管系统是通过损害血管扩张来实现的。怀孕期间，子宫血管必须是敏感的 血管扩张剂，以满足胎盘和胎儿的动态需求。这种血管反应性的中心是 将信号从血液传递到血管平滑肌细胞的内皮细胞，从而导致血管 扩张或收缩。此外，胎盘是氧气扩散和运输的关键器官。 营养物质给发育中的胎儿。PM会损害胎盘血管系统的发育，从而允许 母胎交换，降低胎盘与胎儿组织的比例，称为胎盘效率。我们的 实验室最近表明，塑料颗粒可以通过胎盘转移到胎儿肺后 暴露，表明颗粒直接与子宫胎盘血管系统相互作用。环境问题 塑料的负担正在呈指数级增长。微纳米塑料(MNP)代表着一种无处不在的暴露 关注普通民众和弱势群体，如孕妇，重要的是 说明吸入MNP对胎儿发育有何影响。这些粒子产生并悬浮在 通过燃烧散装塑料或通过较慢的过程，如机械降解，散装塑料产生的空气 塑料碎片分成微小颗粒(&gt；100 nm)和纳米颗粒(&lt；100 nm)大小范围。我们的 初步数据显示，在处女大鼠体内吸入MNP会破坏子宫血管的反应性。 此外，使用在整个妊娠期间吸入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，提示胎盘是MNPs的靶器官。 因此，这一建议的中心假设是，母亲在整个怀孕期间吸入MNP 通过损害子宫血管扩张和扰乱胎盘发育来降低胎盘效率 大鼠的血管系统。这项提案的目的是调查重复的母体MNP的机制 吸入使子宫血管和胎盘发育失调，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血管内皮细胞功能是如何改变的 母体MNP暴露。目标2将确定母亲吸入MNP如何改变儿童的发育 胎盘血管形成的组织病理学分析和免疫组织化学方法。这项研究将确定 MNP诱导FGR的机制及可能的治疗靶点。通过填写 建议的研究、课程和培训首席调查员将接受独立培训，开展国家- 最先进的实验技术，并开展心血管和生殖毒理学研究。

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.