Project Research Results
Grantee Research Project Results
The Texas-Indiana Virtual STAR Center; Data-Generating in vitro and in silico Models of Developmental Toxicity in Embryonic Stem Cells and ZebrafishEPA Grant Number: R834289
Center: Texas - Indiana Virtual STAR Center
Center Director: Gustafsson , Jan-Ake
Title: The Texas-Indiana Virtual STAR Center; Data-Generating in vitro and in silico Models of Developmental Toxicity in Embryonic Stem Cells and Zebrafish
Investigators: Gustafsson , Jan-Ake , Finnell, Richard H. , Glazier, James A
Institution: University of Houston - University Park , Indiana University - Bloomington , Texas A & M University
EPA Project Officer: Pascual, Pasky
Project Period: November 1, 2009 through October 31, 2012
Project Amount: $3,190,993
RFA: Computational Toxicology Research Centers: in vitro and in silico Models Of Developmental Toxicity Pathways (2009)
Research Category: Computational Toxicology
As chemical production increases worldwide, there is increasing evidence as to their hazardous effects on human health at today’s exposure levels, which further implies that current chemical regulation is insufficient. Thus, a restructuring of the risk assessment procedure will be required to protect future generations. Given the very large number of man-made chemicals and the likely complexity of their various and synergistic modes of action, emerging technologies will be required for the restructuring. The main objective of the proposed multidisciplinary Texas Indiana Virtual STAR (TIVS) Center is to contribute to a more reliable chemical risk assessment through the development of high throughput in vitro and in silico screening models of developmental toxicity. Specifically, the TIVS Center aims to generate in vitro models of murine embryonic stem cells and zebrafish for developmental toxicity. The data produced from these models will be further exploited to produce predictive in silico models for developmental toxicity on processes that are relevant also for human embryonic development.Approach:
The project is divided into three Investigational Areas; zebrafish models, murine embryonic stem cells models and in silico simulations. The approaches are to:
- Generate developmental models suitable for high throughput screening. Zebrafish developmental models (transgenic GFP/EGFP/RFP models of crucial steps in development) and embryonic stem cell (ESC) differentiation models (transgenic beta-geo models of crucial steps in differentiation) will be generated. Important morphology features and signaling pathways during development will be documented. The impact of environmental pollutants on development and differentiation will be assessed in the models. Finally, the models will be refined for high throughput screening and automation.
- Generate a computational model that faithfully recreates the major morphological features of normal wild-type zebrafish development (ie- segmentation into somites, proper patterning of vascular and neural systems) and the differentiation to three primitive layers (endoderm, mesoderm and ectoderm) in mouse embryonic stem cells. The data for simulations are produced from developed high information content zebrafish and ESC models. Once a working model of normal development has been generated, we will carry out a directed series of parameter sweeps to try to create developmental defects in silico. We will compare the results of computationally created defects with experimentally-generated defects in zebrafish and embryonic stem cells. Best matches between the two datasets will suggest hypotheses about possible mechanisms by which defects occur.
- Perform proof-of-concept experiments of the in vitro and in silico test platforms with a blind test of chemicals.
Techniques will be molecular biology techniques on zebrafish and ESC models, such as cloning, imaging, in vitro differentiation and in vitro exposure studies, and in silico mathematical simulations.Expected Results:
In collaboration with other initiatives taken in the field of chemical safety, our generated results and models will contribute to large screening effort to prioritize chemicals for further risk assessment. We will specifically contribute with:
- 9 transgenic fish lines validated for toxicity screening
- 16 embryonic stem cell models validated for toxicity screening
- High information content models on development and differentiation to produce data for in silico simulations, within the project and elsewhere
- Computational models for developmental toxicology of normal development and of mechanisms by which chemical perturbations cause experimentally-observed developmental defects
- Information on developmental toxicity on 39 compounds
All the data produced in this project will be released to public databases. The developed models will be automated for high throughput screening.
Journal Articles: 2 Displayed | Download in RIS Format
|Other center views:||All 12 publications||2 publications in selected types||All 2 journal articles|
|| Bondesson M, Gustafsson J-A. Does consuming isoflavones reduce or increase breast cancer risk? Genome Medicine 2010;2(12):90.
|| Hester SD, Belmonte JM, Gens JS, Clendenon SG, Glazier JA. A multi-cell, multi-scale model of vertebrate segmentation and somite formation. PLoS Computational Biology 2011;7(10):e1002155.
Risk assessment, effects, dose-response, teratogen, organism, cellular, infants, chemicals, toxics, aquatic ecosystem protection, pollution prevention, green chemistry, public policy, environmental chemistry, biology, physics, genetics, mathematics, modeling, measurement methods,
Progress and Final Reports:
2010 Progress Report