Project 3 - Fetal Membranes Chip
Professor Kevin Osteen is the Co-PI of Project 3 " Validating a fetal membrane on a chip model for characterizing reproductivetoxicant exposure risks ". He is Professor of Obstetrics and Gynecology, Professor of Pathology, Microbiology and Immunology at Vanderbilt University School of Medicine and his lab is especially focused on environmental endocrine disruptors in the pathophysiology of infertility related to endometriosis and the potential of early life exposure to environmental toxicants for adult onset diseases affecting reproductive success.
This project will develop an instrumented fetal membrane on-a-chip (IFMOC) using primary cultures of human fetal membranes as a medium-throughput system in which to specifically identify toxicants that amplify the response to microbial infection at the maternal-fetal interface and subsequently jeopardize the existing pregnancy (Fig. 3A). This strategy is based on the investigator’s published evidence that the aryl hydrocarbon receptor agonist dioxin compromises progesterone action in humans and mice.
Background: More than 80,000 chemicals have been released into our environment while only a limited number of these potential toxicants have undergone controlled experimental examination. The current gold standard for the evaluation of the toxicity of a compound relies on animal models of exposure, which screen only a limited number of chemicals at a time.
Chorioamnionitis (CAM), or intrauterine infection during pregnancy, is a leading cause of preterm birth (PTB), triggering fetal membrane inflammation that drives labor processes. However, subsets of women with microbial contamination of the amniotic cavity carry their pregnancy to term, suggesting host factors likely influence the risk for CAM-associated PTB. Using a mouse model, we identified a doubling in the occurrence of spontaneous PTB when an infective agent represented a “second hit” following a previous exposure to an environmental toxicant (2,3,7,8- tetrachlorodibenzo-p-dioxin, TCDD). This 2-hit hypothesis is supported by our in vitro models using isolated human endometrial cells, which following TCDD exposure, exhibit an enhanced response to an inflammatory challenge related to infection (e.g., IL-1, TNF-a).
This data suggest the novel hypothesis that environmental toxicants prime the gravid uterus for exaggerated inflammatory responses to microbial invasion (Figure 3A).
|Aim 1:||Define the temporal and concentration-dependent effects of TCDD on native fetal membrane immune responses to infection.|
|Aim 2:||Implement an in vitro, microscaled, living, instrumented fetal membrane-on-a-chip (IFMOC) that recapitulates the physiological properties of the human tissue.|
|Aim 3:||Validate the IFMOC as a model of environmental toxicant immunomodulation compared with primary human fetal membranes.|
Here is a link to our publicly accessible, annual report of Research Project Results.