The project will comprehensively map pathways of endocrine disruption (ED), representing a first step towards mapping the human toxome. The area of ED is especially suited to pioneer this approach for several reasons: First, several large-scale testing programs, whose results can be leveraged for this project, are already under way. Second, these testing programs have led to the prioritization of cellular assays and reference compounds (by EPA, NIEHS and the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM)) on the national level and OECD (Organisation for Economic Co-operation and Development) on the international level that will be used in the project. Finally, the physiological pathways of the endocrine system are relatively well understood, making Pathways of Toxicity (PoT) identification simpler for ED than for other potential target organs. The central goal of this project is to define, experimentally verify and systematically annotate ED PoT, as a proof of concept of mapping PoT by systems toxicology. Beyond that, this project will develop a common, community-accessible framework and databases that will enable the toxicology community at large to comprehensively and cooperatively map the human toxome using integrated testing strategies that combine “omics” data with computational models. To that end, we will achieve the following specific aims: 

  • Use complementary “omics” approaches (transcriptomics, metabolomics), to map and annotate PoT for a defined set of endocrine disruptors.
  • Complete the development of software and visualization tools to enable the integration, analysis and visualization of data across multiple omics hardware platforms.
  • Identify PoT and develop a consensus-driven process for pathway annotation, validation, sharing; establishment of the public database on PoT.
  • Validate PoT and extend the PoT concept to additional toxicants.

Principal investigator:
Thomas Hartung, MD PhD
Professor of Toxicology (Chair for Evidence-based Toxicology), Pharmacology, Molecular Microbiology and Immunology at Johns Hopkins Bloomberg School of Public Health, Baltimore, and University of Konstanz, Germany
Centers for Alternatives to Animal Testing (CAAT) at Johns Hopkins and University of Konstanz, Germany
Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD

Co- investigators:
James Yager PhD, Professor of Toxicology, Bloomberg School of Public Health, Johns Hopkins University
David Dix PhD, Acting Director of the National Center for Computational Toxicology, US EPA
Michael Rosenberg PhD, Director of Genomics Software Life Science Group, Agilent Technologies
Melvin Andersen PhD, Associate Director of the Hamner Institute for Chemical Safety Sciences
Kim Boekelheide MD, Professor of Medical Science, Brown University
Albert J. Fornace, Jr. MD, Molecular Cancer Research Chair at Lombardi Comprehensive Cancer Center, Georgetown University Medical Center

NIEHS grant (R01ES020750; Mapping the Human Toxome by Systems Toxicology)