Mapping the human toxome by systems toxicology

Abstract

Toxicity testing typically involves studying adverse health outcomes in animals subjected to high doses of toxicants with subsequent extrapolation to expected human responses at lower doses. The low-throughput of current toxicity testing approaches (which are largely the same for industrial chemicals, pesticides and drugs) has led to a backlog of more than 80,000 chemicals to which human beings are potentially exposed whose potential toxicity remains largely unknown. Employing new testing strategies that employ the use of predictive, high-throughput cell-based assays (of human origin) to evaluate perturbations in key pathways, referred as pathways of toxicity, and to conduct targeted testing against those pathways, we can begin to greatly accelerate our ability to test the vast 'storehouses' of chemical compounds using a rational, risk-based approach to chemical prioritization and provide test results that are more predictive of human toxicity than current methods. The NIH Transformative Research Grant project Mapping the Human Toxome by Systems Toxicology aims at developing the tools for pathway mapping, annotation and validation as well as the respective knowledge base to share this information.

Figure 1

Components and timeline of the “Human Toxome” project.

Figure 2

Summary of standardized 72/48 protocol for MCF-7 cell culture experiments (72 and 48 referring to the times in hours the cells are maintained in complete medium (Day -5 to Day -2) and then stripped serum (Day -2 to Day 0) containing phenol red free medium, respectively).

Figure 3

Untargeted metabolomics workflow. Metabolites are extracted from the sample and analysed using MS. Features of interest are selected from raw data using statistical approaches. Features are then identified using database searches. Identified features can then be used for PoT analysis, and metabolic network reconstruction.