Project 3

项目3摘要 暴露于环境有害物质，包括在自然和人为情况下 众所周知，灾害会对怀孕产生负面影响，导致早产(PTB)等不良后果。 然而，在暴露和怀孕风险之间建立明确的联系是具有挑战性的，因为缺乏 毒物激活母胎组织中引起肺结核的途径的机制知识。 不幸的是，目前的体外和体内毒性测试模型都不足以评估危害。 所测试的物质对妊娠结局的影响，并不代表人类在子宫内的结构和功能 准确的，或者是太昂贵和低吞吐量。此外，对暴露所造成的危险的评估 到可能包含多种危险化学物质的复杂环境样本，通常在 灾难，更是具有挑战性。在这里，我们建议开发一种母胎(F-M)界面组织芯片- 基于环境物质对结核病人体健康危害评估的检测策略。我们的中央 假设一个组织芯片模型模拟复杂的多细胞F-M界面的生理学 能够评估暴露在复杂环境中影响的机械性病理生理途径 可能增加肺结核风险的危险物质。这些组织芯片模型模仿胎儿和母体 子宫组织的结构和功能，并将被用来评估机械病理生理途径 在F-M界面上施加复杂的混合环境有害物质。这将会实现的 通过以下三个目标。在目标1中，我们将开发一个结核病的机理模型，以响应 环境毒物采用胎膜组织芯片模型。在目标2中，我们将开发一种机械式 利用胎盘组织芯片模型研究环境毒物对肺结核的反应。在Aim 3中，它将 专注于我们的灾难研究响应(DR2)新模型的应用，我们将展示快速 环境暴露对F-M动态平衡的潜在危害的评估 这可以通过使用更高吞吐量的F-M组织芯片模型来导致肺结核。这项拟议研究的成功 将利用组织芯片为毒物对结核病影响的危害评估提供关键和及时的信息 模型，特别是与现有超级基金站点和与紧急灾难有关的毒物有关的模型 污染物。在主题上，这个项目很好地融入了德克萨斯农工大学超级基金研究 该中心的重点是解决人体健康风险的暴露在危险物质和 在紧急情况之后，特别是对特别脆弱的人群(孕妇和儿童)的影响。

Project 3 Abstract Exposures to environmental hazardous substances, including those in the event of natural and anthropogenic disasters, are known to negatively impact pregnancy, leading to adverse outcomes such as preterm birth (PTB). However, establishing a clear link between exposure and pregnancy risk is challenging, due to lack of a mechanistic knowledge by which toxicants activate pathways causing PTB in maternal-fetal tissues. Unfortunately, current in vitro and in vivo toxicity testing models are either not sufficient in assessing the hazards of tested substances on pregnancy outcomes, do not represent the human in utero structure and functions accurately, or are too costly and low throughput. In addition, assessment of the hazards imposed by exposures to complex environmental samples that may contain multiple hazardous chemicals, often observed after disasters, is even more challenging. Here, we propose to develop a feto-maternal (F-M) interface tissue chip- based testing strategy for assessing the human health hazard of environmental substances on PTB. Our central hypothesis is that a tissue chip model that mimics the physiology of the complex multi-cellular F-M interface will enable evaluation of the mechanistic pathophysiologic pathways affected by exposure to complex environmental hazardous substances that may increase the risk of PTB. These tissue chip models mimic the fetal and maternal uterine tissues structurally and functionally, and will be used to evaluate mechanistic pathophysiologic pathways in the F-M interface imposed by complex mixed environmental hazardous substances. This will be accomplished through the following three aims. In Aim 1, we will develop a mechanistic model of PTB in response to environmental toxicants using a fetal membrane tissue chip model. In Aim 2, we will develop a mechanistic model of PTB in response to environmental toxicants using a placenta tissue chip model. In Aim 3, which will focus on the application of our novel models for Disaster Research Response (DR2), we will demonstrate rapid assessment of the potential human health hazards of environmental exposures on disrupting F-M homeostasis that can lead to PTB by using a higher-throughput F-M tissue chip model. The success of this proposed research will provide critical and timely information for hazard assessment on toxicants’ impact on PTB using tissue chip models, especially related to toxicants from existing Superfund sites and from emergency disaster-related contaminants. Thematically, this project is well integrated into the Texas A&M University Superfund Research Center that is focusing on addressing the human health risks of exposure to hazardous substances during and after emergencies, especially the effects on particularly vulnerable populations (pregnant women and children).