The Comparative Toxicogenomics Database CTD Predicting mechanisms of

The Comparative Toxicogenomics Database (CTD): Predicting mechanisms of toxicity Carolyn J. Mattingly The Mount Desert Island Biological Laboratory Salisbury Cove, Maine

Chemicals in commerce • > 80, 000 • ~2, 000 added/year • ~8, 000 are carcinogens • No toxicity data for ~40% of the 3, 300 “high production volume” chemicals • Full toxicity data for only 25% of chemicals in consumer products

Time, 1947

What’s the relationship between chemicals and disease? Genes/Proteins Chemical Distribution/ Metabolism DNA Repair Cell Cycle Control Disease Cell Death/ Differentiation DISEASE

Exploring environment-gene-disease connections • What diseases are associated with Bisphenol A (BPA)? • Which BPA-induced genes function during development? • What biological functions are affected by BPA? • Which molecular pathways are affected by exposure to BPA? • Which other chemicals have interaction profiles similar to BPA? • What are target genes that are common to BPA and arsenic?

Curated Data Me. SH® (modified) CTD interactions Entrez-Genes Chemicals chemical-gene interactions chemical-disease relationships gene-disease relationships Diseases Me. SH/OMIM

Prioritizing Curation • • EPA Superfund EPA Tox. Cast NTP Users/Collaborators

Curated Data Chemicals 199, 453 Genes chemical-gene interactions chemical-disease relationships gene-disease relationships 9, 524 6, 143 Diseases

Integrated Data Chemicals chemical-gene interactions Genes chemical-disease relationships gene-disease relationships Diseases

Creating inferences Chemicals chemical-gene interactions Genes chemical-disease relationships gene-disease relationships Diseases

Inferred chemical-disease relationships BPA AGR 2… Prostatic Neoplasms

BPA-Prostate cancer genes Cancer and urologic diseases Generated using Ingenuity Pathway Analysis

Chemical-disease inferences • ~190, 000 transitive inferences between chemicals and diseases • Transitive Inference – If ‘A’ interacts with ‘B’ and ‘C’ interacts with ‘B’, then infer that ‘A’ interacts with ‘C’ A B C • How to assess which inferences are “good” or not?

Bisphenol A and Lung Neoplasms Geometric Cvw = |N(v) N(w)|2 |N(v)|. |N(w)| BPA 457 other genes or diseases g 1 g 2 22 Genes g 3 … g 22 Lung Neoplasms

Geometric Cvw for “Real” C-D Inferences Geometric Cvw for shuffled C-D Inferences

Inferred chemical-pathway relationships BPA IKBKB… AML

Tools

Tools: Venn. Viewer Interacting Genes/Proteins Arsenicals Folic acid 127 118 1357 Pathways Arsenicals Folic acid 4 21 76

Tools

MDIBL: Effects of arsenic on immune function Array data 64 0 10 100 20 CTD data 1689

MDIBL: Effects of arsenic on immune function Array data 64 0 10 100 Mattingly, C. J. , T. Hampton, K. Brothers, N. E. Griffin and A. J. Planchart (2009). Perturbation of defense pathways by low-dose arsenic exposure in zebrafish embryos. Environ Health Perspect doi: 10. 1289/ehp. 0900555. 20 CTD data 1689

NIEHS: Identifying chemical-gene-disease networks Gohlke, J. , R. Thomas, Y. Zhang, M. D. Rosenstein, A. P. Davis, C. Murphy, C. J. Mattingly, K. G. Becker and C. J. Portier (2009). The Genetic And Environmental Pathways to Complex Diseases. BMC Syst Biol. May 5 3: 46.

EPA: Exploring the environmental etiology of autistic disorders • Characterizing these chemicals – Structure – Regulatory features (e. g. , High production, Carcinogen) 2096 Chemicals 213 Genes – Function (e. g. , Associated pathways) – Other associated diseases (e. g. , Neurological) Mark Coralles, EPA 213 Genes Autism

In Progress • Tag Clouds • Text mining • Statistical analysis of data inferences • Gene Ontology enrichment analysis

Coming Up • Analysis tools and visualization capabilities • Integration of additional data sets (SNPs, Chemical codes) • Exposure data curation

Curating exposure data • Develop exposure ontology Exposure data Chemicals • Define scope of data to be curated chemical-gene interactions chemical-disease relationships • Test curation protocol • Curate and integrate data in CTD Genes gene-disease relationships Diseases

Acknowledgements Scientific Curators Allan Peter Davis, Ph. D Cindy Murphy, Ph. D Cynthia Saraceni-Richards, Ph. D Susan Mockus, Ph. D Scientific Software Engineers Michael C Rosenstein, JD Thomas Wiegers http: //ctd. mdibl. org/ System Administrator Roy Mc. Morran Zebrafish work James L. Boyer, MD (Yale) Antonio Planchart, Ph. D Thomas Hampton (Dartmouth) Funding Contact Us! cmattin@mdibl. org ctd@mdibl. org NIEHS AND NLM (ES 014065) NCRR (RR 016463)