Project 3

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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).