Vanderbilt-Pittsburgh Resource for Organotypic Models for Predictive Toxicology (VPROMPT)

EPA Grant Number: R835736
Center: Vanderbilt–Pittsburgh Resource for Organotypic Models for Predictive Toxicology (VPROMPT)
Center Director: Hutson, Michael Shane
Title: Vanderbilt-Pittsburgh Resource for Organotypic Models for Predictive Toxicology (VPROMPT)
Investigators: Hutson, Michael Shane , Aronoff, David , Bruner-Tran, Kaylon L. , Cliffel, David , Davidson, Jeffrey M. , Gough, Albert , Markov, Dmitry , McCawley, Lisa J. , McLean, John , Osteen, Kevin G. , Shotwell, Matt , Taylor, D. Lansing , Tuan, Rocky , Vernetti, Lawrence , Wikswo, John
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: $6,000,000
RFA: Organotypic Culture Models for Predictive Toxicology Center (2013) RFA Text |  Recipients Lists
Research Category: Human Health , Health , Safer Chemicals

Objective:

VPROMPT’s primary objective is advancing alternative methods of chemical toxicity testing using organotypic culture models (OCMs) – 3D cultures of heterotypic cells with appropriate extracellular matrices to better approximate the in vivo cellular microenvironment. We aim to use OCMs as experimentally accessible systems of intermediate complexity to advance predictive toxicology: (1) by elucidating the scale(s) of organismal complexity that most severely confound predictions of in vivo toxicity from in vitro data sets; and (2) by elucidating the details of adverse outcome pathways from molecular initiating events to tissue-level responses. We further aim to engineer and develop OCM platforms for chemical toxicity testing that will be amenable and affordable for medium to high throughput screening.

Approach:

We will address these objectives using a liver-OCM plus three OCMs relevant to developmental and reproductive toxicology: mammary gland, limb/joint development, and fetal membrane. Each OCM will be screened (in blind and dose-response fashion) against 30-50 chemicals from the ToxCast inventory using both direct chemical exposure and liver-OCM- conditioned exposure. Subsets of chemicals inducing toxic responses in each OCM will then be subjected to in depth adverse outcome pathway analysis using dynamic OCM responses collected in parallel during the screens (via electrochemical sensors, fluorescent reporters of cellular behaviors and signaling pathways, functional assays and imaging of 3D morphology), dynamic responses of additionally targeted signaling pathways, and both targeted and untargeted analysis of stored OCM effluent using Ion Mobility Mass Spectrometry (IM-MS).

Expected Results:

For the four OCMs tested here, VPROMPT Center outputs/outcomes will include: (1) determining whether OCM endpoints are predictive of relevant endpoints from previous animal studies or human epidemiology and/or predictable from ToxCast in vitro assays – thus identifying the level(s) of complexity contributing most strongly to confounding in vitro to in vivo predictions; (2) elucidating key steps along adverse outcome pathways using dynamic reporters of cell health, targeted analysis of suspected signaling pathways and unbiased searches over broader biochemical space using IM-MS; and (3) the transformative step of engineering OCM platforms amenable and affordable for medium to high throughput toxicity screening. These outcomes will improve our ability to predict risks and understand the mechanisms of potential chemical hazards – critical steps in protecting both the environment and human health.


Journal Articles: 15 Displayed | Download in RIS Format

Other center views: All 64 publications 15 publications in selected types All 15 journal articles
Type Citation Sub Project Document Sources
Journal Article Alexander PG, Clark KL, Tuan RS. Prenatal exposure to environmental factors and congenital limb defects. Birth Defects Research, Part C: Embryo Today: Reviews 2016;108(3):243-273. R835736 (2015)
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  • Journal Article Bruner-Tran KL, Duleba AJ, Taylor HS, Osteen KG. Developmental toxicant exposure is associated with transgenerational adenomyosis in a murine model. Biology of Reproduction 2016;95(4):73 (10 pp.). R835736 (2015)
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  • Journal Article Bruner-Tran KL, Gnecco JS, Ding T, Glore DR, Pensabene V, Osteen KG. Exposure to the environmental endocrine disruptor TCDD and human reproductive dysfunction: translating lessons from murine models. Reproductive Toxicology 2017;68:59-71. R835736 (2015)
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  • Journal Article Gnecco JS, Pensabene V, Li DJ, Ding T, Hui EE, Bruner-Tran KL, Osteen KG. Compartmentalized culture of perivascular stroma and endothelial cells in a microfluidic model of the human endometrium. Annals of Biomedical Engineering January 20, 2017 (12 pp.) [Epub ahead of print]. R835736 (2015)
    R835736C003 (2016)
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  • Journal Article Gough A, Vernetti L, Bergenthal L, Shun TY, Taylor DL. The microphysiology systems database for analyzing and modeling compound interactions with human and animal organ models. Applied In Vitro Toxicology 2016;2(2):103-117. R835736 (2015)
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  • Journal Article Hutson MS, Alexander PG, Allwardt V, Aronoff DM, Bruner-Tran KL, Cliffel DE, Davidson JM, Gough A, Markov DA, McCawley LJ, McKenzie JR, McLean JA, Osteen KG, Pensabene V, Samson PC, Senutovitch NK, Sherrod SD, Shotwell MS, Taylor DL, Tetz LM, Tuan RS, Vernetti LA, Wikswo JP. Organs-on-chips as bridges for predictive toxicology. Applied In Vitro Toxicology 2016;2(2):97-102. R835736 (2015)
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  • Journal Article Hutson MS, Leung MCK, Baker NC, Spencer RM, Knudsen TB. Computational model of secondary palate fusion and disruption. Chemical Research in Toxicology 2017;30(4):965-979. R835736 (2015)
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  • Journal Article Leung MC, Hutson MS, Seifert AW, Spencer RM, Knudsen TB. Computational modeling and simulation of genital tubercle development. Reproductive Toxicology 2016;64:151-161. R835736 (2015)
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  • Journal Article Senutovitch N, Vernetti L, Boltz R, DeBiasio R, Gough A, Taylor DL. Fluorescent protein biosensors applied to microphysiological systems. Experimental Biology and Medicine 2015;240(6):795-808. R835736 (2015)
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  • Journal Article Vernetti LA, Senutovitch N, Boltz R, DeBiasio R, Shun TY, Gough A, Taylor DL. A human liver microphysiology platform for investigating physiology, drug safety, and disease models. Experimental Biology and Medicine 2016;241(1):101-114. R835736 (2015)
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  • Journal Article Vernetti LA, Vogt A, Gough A, Taylor DL. Evolution of experimental models of the liver to predict human drug hepatotoxicity and efficacy. Clinics in Liver Disease 2017;21(1):197-214. R835736 (2015)
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  • Journal Article Vernetti L, Gough A, Baetz N, Blutt S, Broughman JR, Brown JA, Foulke-Abel J, Hasan N, In J, Kelly E, Kovbasnjuk O, Repper J, Senutovitch N, Stabb J, Yeung C, Zachos NC, Donowitz M, Estes M, Himmelfarb J, Truskey G, Wikswo JP, Taylor DL. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Scientific Reports 2017;7:42296 (15 pp.). R835736 (2015)
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  • Journal Article Dodds JN, May JC, McLean JA. Investigation of the complete suite of the leucine and isoleucine isomers:toward prediction of ion mobility separation capabilities. Analytical Chemistry 2017;89(1):952-959. R835736 (2015)
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  • Journal Article Stocks MM, Crispens MA, Ding T, Mokshagundam S, Bruner-Tran KL, Osteen KG. Therapeutically targeting the inflammasome product in a chimeric model of endometriosis-related surgical adhesions. Reproductive Sciences March 21, 2017 [epub ahead of print]. R835736 (2015)
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  • Journal Article Gnecco JS, Anders AP, Cliffel D, Pensabene V, Rogers LM, Osteen K, Aronoff D. Instrumenting a fetal membrane on a chip as emerging technology for preterm birth research. Current Pharmaceutical Design 2017 (in press, ISSN 1381-6128). R835736C003 (2016)
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  • Supplemental Keywords:

    risk assessment, health effects, teratogen, mammalian, cellular, infants, dioxin, pathogens, bacteria, innovative technology, public policy, biology, physics, engineering, genetics, pathology, mathematics, modeling, analytical, measurement methods;

    Progress and Final Reports:

    2015 Progress Report
    2016 Progress Report

    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