Project 3

项目3摘要 接触环境有害物质，包括自然和人为造成的物质 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，由于缺乏可靠的证据，在暴露与怀孕风险之间建立明确的联系具有挑战性。 毒物激活母胎组织中引起 PTB 的途径的机制知识。 不幸的是，当前的体外和体内毒性测试模型不足以评估危害 受试物质对妊娠结局的影响，并不代表人体在子宫内的结构和功能 准确，或者成本太高且吞吐量低。此外，评估暴露造成的危害 对于可能含有多种危险化学品的复杂环境样本，通常在之后观察到 灾害频发，更具挑战性。在这里，我们建议开发胎儿-母体（F-M）界面组织芯片—— 基于测试策略评估环境物质对PTB对人类健康的危害。我们的中央 假设是模仿复杂多细胞 F-M 界面生理学的组织芯片模型将 能够评估受复杂环境暴露影响的机械病理生理途径 可能增加 PTB 风险的有害物质。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，并将用于评估机制病理生理途径 在复杂的混合环境有害物质施加的 F-M 界面中。这将实现 通过以下三个目标。在目标 1 中，我们将开发一个 PTB 机制模型来响应 使用胎膜组织芯片模型研究环境毒物。在目标 2 中，我们将开发一种机制 使用胎盘组织芯片模型建立 PTB 响应环境毒物的模型。在目标 3 中， 重点关注我们的灾难研究响应（DR2）新颖模型的应用，我们将展示快速 评估环境暴露对破坏 F-M 稳态的潜在人类健康危害 通过使用更高通量的 F-M 组织芯片模型可以导致 PTB。这项拟议研究的成功 将使用组织芯片为有毒物质对 PTB 影响的危害评估提供关键而及时的信息 模型，特别是与现有超级基金站点和紧急灾难相关的有毒物质有关的模型 污染物。从主题上讲，该项目很好地融入了德克萨斯农工大学超级基金研究 该中心致力于解决在期间和期间接触有害物质的人类健康风险 紧急情况发生后，特别是对特别弱势群体（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).