NTP Workshop: Role of Environmental Chemicals in the Development of Diabetes and Obesity January 11-13, 2011

Transcription

1 NTP Workshop: Role of Environmental Chemicals in the Development of Diabetes and Obesity January 11-13, 2011 Kristina Thayer National Institute of Environmental Health Sciences (NIEHS)/National Toxicology Program (NTP)

2 Goals Critical review of the existing literature Main chemicals: arsenic, cadmium, chlorinated POPs, other halogenated POPs, BPA, organotin, phthalate, nicotine, pesticides Evaluate strength/weaknesses, consistency, and biological plausibility of findings Identify the most useful and relevant endpoints in experimental animals and in vitro models Conduct original analysis related to Tox21 high throughput screening initiative How useful is this information as an initial screen? Identify data gaps and areas for future evaluation/research

3 Workshop Format ~50 invited participants Epidemiology to bioinformatics to domestic livestock Includes experts in diabetes and obesity who do not work with environmental chemicals Draft literature review document prepared prior to meeting Meeting is mix of breakout sessions and plenary reports/discussion All sessions open to the public (space for ~100) Final report will be published as an NTP Monograph

4 Tox21 High Throughput Screening (HTS) Data

5 Tox21 Collaborative program between the EPA, NIEHS/NTP, NIH/NCGC, and FDA ( EPA s ToxCast and up at the NCGC Includes a variety of platforms/technologies Assays do not necessarily identify directionality of effect (agonist/antagonist) ToxCast most useful for workshop 497 assays in Phase 1 (better coverage than NCGC, ~70 assays) 309 data rich chemicals tested in Phase 1, mostly pesticide actives Screening patterns from chemicals tested in ToxCast and NCGC cannot be directly compared Different assay target coverage

6 Use of HTS Data Look at HTS data for chemicals already on our radar Vacor, nicotine in NCGC; amitraz, PFOS/PFOA, organophosphates, others in ToxCast Identify HTS patterns that suggest further studies appropriate

7 Goal: Present Patterns of HTS Data that Promote Focused Follow-up Research Focus on biological processes related to diabetes and obesity e.g., Adipocyte differentiation, glucose uptake, islet cell function, feeding behavior/neural pathways C. elegans as model for feeding behavior and energy regulation Use EPA s ToxPi schematic to visualize (next slide) Consider heat maps too Expect the proposed strategy to be refined and expanded before and during meeting

8 Template: EPA s ToxPi for Endocrine Profiling Visual of toxicity by weighted combinations of data (10 slices) from in vitro assays, AR/ER/TR interactions, chemical properties, pathways and XME/ADME The slices can be anything, i.e., genes, diseases, biological processes

9 Longer pie slices = lower (more potent) AC 50 values

10 Approach to Develop ToxPi Schemes for Adipocyte Differentiation, Islet Function, Glucose Uptake, Feeding Behavior/Neuro Pathways Identify genes associated with these processes in CoPub and Gene Ontology databases Focus on causal pathways when possible Cross-reference with gene-based HTS assays in ToxCast This approach should also let us identify key targets not included in Tox21/ToxCast Use brain power of experts to review and identify ToxPi slices Key genes on individual slices Relevant but more peripheral genes in an other slice

11 Example: Adipocyte Differentiation PPARα PPARΔ RXRα Expert input to determine slice content -length of slice reflect AC50 value -alter slice size to reflect importance? PPARγ RARα for PPARγ, ~20 for GR, 3 for insulin receptor PFOS active for GR, insulin receptor, PPARγ Insulin receptor CCAAT/enhancer binding protein (C/EBP) Glucocorticoid receptor Vitamin D receptor Others : LXR, FXR, THRA, CCL2, AKT2, E2F4, etc

12 Others Glucose Uptake >10 for adrenergic receptors Islet Cell Function for muscarinic cholinergic receptors Feeding Behavior & Neurological Pathways 9 for NPY