Validating a fetal membrane on a chip model for characterizing reproductive toxicant exposure risks

EPA Grant Number: R835736C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R835736
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Vanderbilt–Pittsburgh Resource for Organotypic Models for Predictive Toxicology (VPROMPT)
Center Director: Hutson, Michael Shane
Title: Validating a fetal membrane on a chip model for characterizing reproductive toxicant exposure risks
Investigators: Osteen, Kevin G. , Aronoff, David , Bruner-Tran, Kaylon L.
Institution: University of Pittsburgh - Main Campus , Vanderbilt University
Current Institution: Vanderbilt University , University of Pittsburgh - Main Campus
EPA Project Officer: Klieforth, Barbara I
Project Period: December 1, 2014 through November 30, 2018
Project Amount: Refer to main center abstract for funding details.
RFA: Organotypic Culture Models for Predictive Toxicology Center (2013) RFA Text |  Recipients Lists
Research Category: Safer Chemicals , Health , Human Health

Objective:

Leveraging the unique expertise available to us from the larger VPROMPT Center, the objective of Project 3 is to develop a micro-scaled, instrumented fetal membrane on a chip (IFMOC) system, which will enable higher throughput screening of multiple toxicants that may negatively impact pregnancy. We will validate this new technology using primary cultures of human fetal membranes. We have previously found that a prior toxicant exposure of human endometrial tissue exacerbates the immune response to infection. Thus, validation studies will include the examination of the IFMOC model in response to an inflammatory challenge after a toxicant exposure. We hypothesize that environmental toxicants prime the gravid uterus for exaggerated inflammatory responses to microbial invasion. 

Approach:

We will initially use established human fetal membrane models (punch biopsies and within a transwell) exposed to TCDD (a toxicant known to disrupt pregnancy) to determine the optimum biomarkers indicating appropriate versus exaggerated inflammatory responses. Next, we will establish the IFMOC using commercially available human cell lines representing the heterogeneity of native human fetal membrane. The IFMOC will be exposed to >20 compounds (tested individually) and biomarkers identified above will be examined. Following these screening studies, a small subset of compounds will be analyzed again using the whole tissue fetal membrane transwell to compare to and validate the IFMOC results. Additional studies on these >20 compounds will be conducted using a liver organoid culture model placed directly upstream of the IFMOC to include the potential for hepatic detoxification and/or metabolic activation. 

Expected Results:

Thousands of chemicals with unknown toxicity are present in our environment. It is not feasible to conduct human or animal studies on each of these compounds; thus higher-throughput models are needed. We expect that our IFMOC model will enable the rapid screening of a large number of toxicants which may negatively impact the maintenance of pregnancy. Prematurity is a leading cause of perinatal morbidity and mortality; thus, there is a need to understand the potential role of toxicant exposure on maternal response to infection. 

Publications and Presentations:

Publications have been submitted on this subproject: View all 6 publications for this subprojectView all 64 publications for this center

Journal Articles:

Journal Articles have been submitted on this subproject: View all 4 journal articles for this subprojectView all 15 journal articles for this center

Supplemental Keywords:

toxicants, risk assessment, human health effects, reproductive effects, sensitive populations, pathophysiology

Progress and Final Reports:

2015 Progress Report
2016 Progress Report


Main Center Abstract and Reports:

R835736    Vanderbilt–Pittsburgh Resource for Organotypic Models for Predictive Toxicology (VPROMPT)

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R835736C001 Mammosphere Bioreactor For Life-Stage Specific Toxicology
R835736C002 Organotypic Culture Model to Analyze Developmental Limb Malformations Resulting from Toxicant/Teratogen Exposure
R835736C003 Validating a fetal membrane on a chip model for characterizing reproductive toxicant exposure risks
R835736C004 Organotypic Liver Model for Predictive Human Toxicology and Metabolism
R835736C005 Systems Engineering & Analysis for Organotypic Culture Models