A Multi-scale Dose-response Model of AHR Toxicity Pathway Activation in the Human Liver

EPA Grant Number: R835000
Title: A Multi-scale Dose-response Model of AHR Toxicity Pathway Activation in the Human Liver
Investigators: Bhattacharya, Sudin , Andersen, Melvin E. , Clewell, Harvey
Current Investigators: Bhattacharya, Sudin
Institution: The Hamner Institutes
EPA Project Officer: Peterson, Todd
Project Period: June 1, 2011 through May 30, 2015 (Extended to April 30, 2016)
Project Amount: $750,000
RFA: Computational Toxicology: Biologically-Based Multi-Scale Modeling (2010) RFA Text |  Recipients Lists
Research Category: Computational Toxicology , Health , Safer Chemicals

Description:

Computational models help toxicologists understand and quantify the effects of exposure to chemicals on various tissues of the human body. For simplicity these models have traditionally treated tissues as homogeneous masses of cells. However our knowledge of biological processes and available computational tools have progressed to a point where we can begin to build tissue models that incorporate more realistic biological structure. Such “virtual tissue” models can also help limit the use of animals in high-dose toxicity studies while providing scientifically accurate predictions of the toxic effects of chemicals on human beings.

Objective:

In this project, we will develop a spatial, multicellular model of a human liver lobule to study the effects of exposure to the common environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Acting through the intracellular aryl hydrocarbon receptor (AhR) pathway, this chemical can produce a range of harmful effects on the body – from immune suppression to birth defects to cancer. Our “virtual tissue” model of the human liver will help understand the sequence of events leading from early gene expression in response to AhR toxicity pathway activation by TCDD, to cell proliferation and progression to cancer.

Approach:

The PIs propose developing an agent-based model of hepatotoxicity. In this project, the PIs will develop a spatial, multicellular model of a human liver lobule to study the effects of exposure to the common environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The agent-based approach to modeling presumes that behavior of a complex system being simulated can be reduced to computational algorithms that codify the rules according to which the system components interact, thus approximating system behavior. In this case, the PI proposes building a model to explain how the cellular components of the liver interact and how they respond to a toxic event.

Expected Results:

This model will help understand the sequence of events leading from early gene expression in response to AhR toxicity pathway activation by TCDD, to cell proliferation and progression to cancer. By integrating the biological information across multiple scales to explain liver toxicity, the project moves society closer to being able to understand how different pathways mediated by different cell types in the liver might interact to produce a toxic event.

Publications and Presentations:

Publications have been submitted on this project: View all 11 publications for this project

Journal Articles:

Journal Articles have been submitted on this project: View all 2 journal articles for this project

Progress and Final Reports:

2011 Progress Report
2012 Progress Report
2013 Progress Report
2014 Progress Report
Final Report